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Annular lesions on abdomen
The FP concluded that this was a case of nummular eczema, after exploring other elements of the differential diagnosis, which included psoriasis, tinea corporis, and contact dermatitis. The FP looked at the patient's nails and scalp and saw no other signs of psoriasis. He then performed a potassium hydroxide (KOH) preparation and found no evidence of hyphae or fungal elements. (See a video on how to perform a KOH preparation here: http://www.mdedge.com/jfponline/article/100603/dermatology/koh-preparation.) He ruled out contact dermatitis because the history did not support it, and this wouldn’t have been a common location for it.
Nummular eczema is a type of eczema characterized by circular or oval-shaped scaling plaques with well-defined borders. (“Nummus” is Latin for “coin.”) Nummular eczema produces multiple lesions that are most commonly found on the dorsa of the hands, arms, and legs.
In this case, the FP offered to do a biopsy to confirm the clinical diagnosis, but noted that treatment could be started empirically and the biopsy could be reserved for the next visit only if the treatment was not successful. The patient preferred to start with topical treatment and hold off on the biopsy.
The FP prescribed 0.1% triamcinolone ointment to be applied twice daily. The FP knew that this was a mid-potency steroid and a high-potency steroid might work more rapidly and effectively, but the patient's insurance had a large deductible and the patient was going to have to pay for the medication out-of-pocket. Generic 0.1% triamcinolone is far less expensive than any of the high-potency steroids, including generic clobetasol.
Fortunately, at the one-month follow-up, the patient had improved by 95% and the only remaining problem was the hyperpigmentation, which was secondary to the inflammation. The FP suggested that the patient continue using the triamcinolone until there was a full resolution of the erythema, scaling, and itching. He explained that the post-inflammatory hyperpigmentation might take months (to a year) to resolve, and in some cases never resolves. The patient was not worried about this issue and was happy that his symptoms had improved.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Wah Y, Usatine R. Eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
The FP concluded that this was a case of nummular eczema, after exploring other elements of the differential diagnosis, which included psoriasis, tinea corporis, and contact dermatitis. The FP looked at the patient's nails and scalp and saw no other signs of psoriasis. He then performed a potassium hydroxide (KOH) preparation and found no evidence of hyphae or fungal elements. (See a video on how to perform a KOH preparation here: http://www.mdedge.com/jfponline/article/100603/dermatology/koh-preparation.) He ruled out contact dermatitis because the history did not support it, and this wouldn’t have been a common location for it.
Nummular eczema is a type of eczema characterized by circular or oval-shaped scaling plaques with well-defined borders. (“Nummus” is Latin for “coin.”) Nummular eczema produces multiple lesions that are most commonly found on the dorsa of the hands, arms, and legs.
In this case, the FP offered to do a biopsy to confirm the clinical diagnosis, but noted that treatment could be started empirically and the biopsy could be reserved for the next visit only if the treatment was not successful. The patient preferred to start with topical treatment and hold off on the biopsy.
The FP prescribed 0.1% triamcinolone ointment to be applied twice daily. The FP knew that this was a mid-potency steroid and a high-potency steroid might work more rapidly and effectively, but the patient's insurance had a large deductible and the patient was going to have to pay for the medication out-of-pocket. Generic 0.1% triamcinolone is far less expensive than any of the high-potency steroids, including generic clobetasol.
Fortunately, at the one-month follow-up, the patient had improved by 95% and the only remaining problem was the hyperpigmentation, which was secondary to the inflammation. The FP suggested that the patient continue using the triamcinolone until there was a full resolution of the erythema, scaling, and itching. He explained that the post-inflammatory hyperpigmentation might take months (to a year) to resolve, and in some cases never resolves. The patient was not worried about this issue and was happy that his symptoms had improved.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Wah Y, Usatine R. Eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
The FP concluded that this was a case of nummular eczema, after exploring other elements of the differential diagnosis, which included psoriasis, tinea corporis, and contact dermatitis. The FP looked at the patient's nails and scalp and saw no other signs of psoriasis. He then performed a potassium hydroxide (KOH) preparation and found no evidence of hyphae or fungal elements. (See a video on how to perform a KOH preparation here: http://www.mdedge.com/jfponline/article/100603/dermatology/koh-preparation.) He ruled out contact dermatitis because the history did not support it, and this wouldn’t have been a common location for it.
Nummular eczema is a type of eczema characterized by circular or oval-shaped scaling plaques with well-defined borders. (“Nummus” is Latin for “coin.”) Nummular eczema produces multiple lesions that are most commonly found on the dorsa of the hands, arms, and legs.
In this case, the FP offered to do a biopsy to confirm the clinical diagnosis, but noted that treatment could be started empirically and the biopsy could be reserved for the next visit only if the treatment was not successful. The patient preferred to start with topical treatment and hold off on the biopsy.
The FP prescribed 0.1% triamcinolone ointment to be applied twice daily. The FP knew that this was a mid-potency steroid and a high-potency steroid might work more rapidly and effectively, but the patient's insurance had a large deductible and the patient was going to have to pay for the medication out-of-pocket. Generic 0.1% triamcinolone is far less expensive than any of the high-potency steroids, including generic clobetasol.
Fortunately, at the one-month follow-up, the patient had improved by 95% and the only remaining problem was the hyperpigmentation, which was secondary to the inflammation. The FP suggested that the patient continue using the triamcinolone until there was a full resolution of the erythema, scaling, and itching. He explained that the post-inflammatory hyperpigmentation might take months (to a year) to resolve, and in some cases never resolves. The patient was not worried about this issue and was happy that his symptoms had improved.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Wah Y, Usatine R. Eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
Mupirocin plus chlorhexidine halved Mohs surgical-site infections
SYDNEY – All patients undergoing Mohs surgery should be treated with intranasal mupirocin and a chlorhexidine body wash for 5 days before surgery, without any requirement for a nasal swab positive for Staphylococcus aureus, according to Dr. Harvey Smith.
He presented data from a randomized, controlled trial investigating the prevention of surgical-site infection in 1,002 patients undergoing Mohs surgery who had a negative nasal swab result for S. aureus. Patients were randomized to intranasal mupirocin ointment twice daily and chlorhexidine body wash daily for the 5 days before surgery, or no intervention, said Dr. Smith, a dermatologist in group practice in Perth, Australia.
The results add to earlier studies by the same group. The first study – Staph 1 – showed that swab-positive nasal carriage of S. aureus was a greater risk factor for surgical-site infections in Mohs surgery than the Wright criteria, and that decolonization with intranasal mupirocin and chlorhexidine body wash for a few days before surgery reduced the risk of infection in these patients from 12% to 4%.
The second previous study – Staph 2 – showed that using mupirocin and chlorhexidine before surgery was actually superior to the recommended treatment of stat oral cephalexin in reducing the risk of surgical-site infection.
“So, our third paper has been wondering what to do about the silent majority: These are the two-thirds of patients on whom we operate who have a negative swab for S. aureus,” Dr. Harvey said.
A negative nasal swab was not significant, he said, because skin microbiome studies had already demonstrated that humans carry S. aureus in several places, particularly the feet and buttocks.
“What we’re basically saying is we don’t think you need to swab people, because they’ve got it somewhere,” Dr. Harvey said in an interview. “We don’t think risk stratification is useful anymore, because we’ve shown it’s a benefit to everybody.”
The strategy of treating all patients with mupirocin and chlorhexidine, regardless of nasal carriage, rather than using the broad-spectrum cephalexin, fits with the World Health Organization’s global action plan on antimicrobial resistance, Dr. Harvey explained.
While there had been cases of mupirocin resistance in the past, Dr. Harvey said these had been seen in places where the drug had previously been available over the counter, such as New Zealand. However, there was no evidence of resistance developing for such a short course of use as employed in this setting, he said.
An audience member asked about whether there were any side effects from the mupirocin or chlorhexidine. Dr. Harvey said the main potential adverse event from the treatment was the risk of chlorhexidine toxicity to the cornea. However, he said that patients were told not to get the wash near their eyes.
Apart from one or two patients with eczema who could not tolerate the full 5 days of the chlorhexidine, Dr. Harvey said they had now treated more than 4,000 patients with no other side effects observed.
The study was supported by the Australasian College of Dermatologists. No conflicts of interest were declared.
SYDNEY – All patients undergoing Mohs surgery should be treated with intranasal mupirocin and a chlorhexidine body wash for 5 days before surgery, without any requirement for a nasal swab positive for Staphylococcus aureus, according to Dr. Harvey Smith.
He presented data from a randomized, controlled trial investigating the prevention of surgical-site infection in 1,002 patients undergoing Mohs surgery who had a negative nasal swab result for S. aureus. Patients were randomized to intranasal mupirocin ointment twice daily and chlorhexidine body wash daily for the 5 days before surgery, or no intervention, said Dr. Smith, a dermatologist in group practice in Perth, Australia.
The results add to earlier studies by the same group. The first study – Staph 1 – showed that swab-positive nasal carriage of S. aureus was a greater risk factor for surgical-site infections in Mohs surgery than the Wright criteria, and that decolonization with intranasal mupirocin and chlorhexidine body wash for a few days before surgery reduced the risk of infection in these patients from 12% to 4%.
The second previous study – Staph 2 – showed that using mupirocin and chlorhexidine before surgery was actually superior to the recommended treatment of stat oral cephalexin in reducing the risk of surgical-site infection.
“So, our third paper has been wondering what to do about the silent majority: These are the two-thirds of patients on whom we operate who have a negative swab for S. aureus,” Dr. Harvey said.
A negative nasal swab was not significant, he said, because skin microbiome studies had already demonstrated that humans carry S. aureus in several places, particularly the feet and buttocks.
“What we’re basically saying is we don’t think you need to swab people, because they’ve got it somewhere,” Dr. Harvey said in an interview. “We don’t think risk stratification is useful anymore, because we’ve shown it’s a benefit to everybody.”
The strategy of treating all patients with mupirocin and chlorhexidine, regardless of nasal carriage, rather than using the broad-spectrum cephalexin, fits with the World Health Organization’s global action plan on antimicrobial resistance, Dr. Harvey explained.
While there had been cases of mupirocin resistance in the past, Dr. Harvey said these had been seen in places where the drug had previously been available over the counter, such as New Zealand. However, there was no evidence of resistance developing for such a short course of use as employed in this setting, he said.
An audience member asked about whether there were any side effects from the mupirocin or chlorhexidine. Dr. Harvey said the main potential adverse event from the treatment was the risk of chlorhexidine toxicity to the cornea. However, he said that patients were told not to get the wash near their eyes.
Apart from one or two patients with eczema who could not tolerate the full 5 days of the chlorhexidine, Dr. Harvey said they had now treated more than 4,000 patients with no other side effects observed.
The study was supported by the Australasian College of Dermatologists. No conflicts of interest were declared.
SYDNEY – All patients undergoing Mohs surgery should be treated with intranasal mupirocin and a chlorhexidine body wash for 5 days before surgery, without any requirement for a nasal swab positive for Staphylococcus aureus, according to Dr. Harvey Smith.
He presented data from a randomized, controlled trial investigating the prevention of surgical-site infection in 1,002 patients undergoing Mohs surgery who had a negative nasal swab result for S. aureus. Patients were randomized to intranasal mupirocin ointment twice daily and chlorhexidine body wash daily for the 5 days before surgery, or no intervention, said Dr. Smith, a dermatologist in group practice in Perth, Australia.
The results add to earlier studies by the same group. The first study – Staph 1 – showed that swab-positive nasal carriage of S. aureus was a greater risk factor for surgical-site infections in Mohs surgery than the Wright criteria, and that decolonization with intranasal mupirocin and chlorhexidine body wash for a few days before surgery reduced the risk of infection in these patients from 12% to 4%.
The second previous study – Staph 2 – showed that using mupirocin and chlorhexidine before surgery was actually superior to the recommended treatment of stat oral cephalexin in reducing the risk of surgical-site infection.
“So, our third paper has been wondering what to do about the silent majority: These are the two-thirds of patients on whom we operate who have a negative swab for S. aureus,” Dr. Harvey said.
A negative nasal swab was not significant, he said, because skin microbiome studies had already demonstrated that humans carry S. aureus in several places, particularly the feet and buttocks.
“What we’re basically saying is we don’t think you need to swab people, because they’ve got it somewhere,” Dr. Harvey said in an interview. “We don’t think risk stratification is useful anymore, because we’ve shown it’s a benefit to everybody.”
The strategy of treating all patients with mupirocin and chlorhexidine, regardless of nasal carriage, rather than using the broad-spectrum cephalexin, fits with the World Health Organization’s global action plan on antimicrobial resistance, Dr. Harvey explained.
While there had been cases of mupirocin resistance in the past, Dr. Harvey said these had been seen in places where the drug had previously been available over the counter, such as New Zealand. However, there was no evidence of resistance developing for such a short course of use as employed in this setting, he said.
An audience member asked about whether there were any side effects from the mupirocin or chlorhexidine. Dr. Harvey said the main potential adverse event from the treatment was the risk of chlorhexidine toxicity to the cornea. However, he said that patients were told not to get the wash near their eyes.
Apart from one or two patients with eczema who could not tolerate the full 5 days of the chlorhexidine, Dr. Harvey said they had now treated more than 4,000 patients with no other side effects observed.
The study was supported by the Australasian College of Dermatologists. No conflicts of interest were declared.
Key clinical point: Treat all patients undergoing Mohs surgery with intranasal mupirocin and a chlorhexidine body wash for 5 days before surgery, without the need for a nasal swab for Staphylococcus aureus.
Major finding: Treating patients undergoing Mohs surgery with intranasal mupirocin and a chlorhexidine body wash for 5 days before surgery halved the risk of surgical-site infections, even if the patients did not have a positive nasal swab for S. aureus.
Data source: A randomized, controlled trial in 1,002 patients with a negative nasal swab for S. aureus undergoing Mohs surgery.
Disclosures: The study was partly supported by the Australasian College of Dermatologists. No conflicts of interest were declared.
New DES hailed for smallest coronary vessels
Paris – The first multicenter, prospective trial of a drug-eluting stent designed specifically to treat lesions in coronary vessels less than 2.25 mm in diameter showed excellent outcomes, with a 1-year target lesion failure rate of 5% for the Resolute Onyx 2.0 mm diameter zotarolimus-eluting stent.
This result in the pivotal trial easily surpassed the prespecified performance goal of a 19% target lesion failure rate, Matthew J. Price, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
Hemodynamically significant lesions in such small vessels are “not uncommon, particularly in diabetic patients,” Dr. Price said in an interview. Indeed, 47% of patients in the clinical trial had diabetes.
At present, the only ways to treat coronary disease in arteries having a reference vessel diameter less than 2.25 mm are off-label placement of an oversized stent, with its attendant risk of complications; standard balloon angioplasty, which entails a particularly high restenosis rate in this setting; or medical management, the cardiologist noted.
He presented a multicenter, prospective, open-label, single-arm trial of 101 patients with documented ischemia-producing obstructions in coronary arteries having a reference vessel diameter less than 2.25 mm, a lesion length less than 27 mm, and evidence of ischemia attributable to the lesion, typically via fractional flow reserve. The mean diameter by quantitative coronary angiography was 1.91 mm.
The primary endpoint was the rate of target lesion failure at 12 months, a composite comprising cardiac death, target vessel MI, or clinically driven target lesion revascularization. This endpoint occurred in 5% of patients. There was a 3% target vessel MI rate and a 2% target lesion revascularization rate. There were no cardiac deaths.
“Importantly, the stent thrombosis rate in these patients with extremely small vessels was zero,” the cardiologist emphasized.
The mean angiographic in-stent late lumen loss at 13 months was 0.26 mm, which Dr. Price characterized as “quite good.” The in-segment binary angiographic restenosis rate was 20%.
“That’s slightly higher than you would expect to see in vessels with larger reference diameters. I think that’s because of the lack of headroom. You have a very small vessel, and, even with a very small stent, even a small amount of late loss will give you a larger percent diameter restenosis over time,” he explained.
The 19% target lesion failure rate selected as a performance goal in the trial was set somewhat arbitrarily. It wasn’t possible to randomize patients to a comparator arm because there are no approved stents for vessels less than 2.25 mm in diameter. The 19% figure was arrived at in discussion with the Food and Drug Administration on the basis of similarity to the performance goal used in clinical trials to gain approval of 2.25-mm, drug-eluting stents. Because the Onyx 2.0-mm-diameter trial was developed in collaboration with the FDA and the stent aced its primary endpoint and showed excellent clinical outcomes, Dr. Price anticipates the device will readily gain regulatory approval. In April 2017, the FDA approved the Resolute Onyx in sizes of 2.25- to 5.0-mm diameter.
The study met with an enthusiastic reception.
“That was terrific. It’s clearly an incredibly important unmet clinical need,” commented session cochair David R. Holmes Jr., MD, of the Mayo Clinic in Rochester, Minn.
Assuming the stent is approved, how should interventionalists put it into practice? he asked.
Dr. Price replied that, first, it’s important to step back and ask if percutaneous coronary intervention of a particular lesion in a very small coronary artery is clinically indicated. The stent itself is readily manipulatable. It is a thin-strut device constructed of a single strand of a cobalt alloy with enhanced radiopacity.
Investigators in the trial used the standard approach to dual antiplatelet therapy – at least 6 months, with 12 months preferable.
The 20% in-segment binary restenosis rate at 13 months provides a clear message for interventionalists, he continued. “What this tells me is that, while this is a very good stent, we can’t forget to treat the patient aggressively with medical therapy to stop the progression of prediabetes, diabetes, and small vessel disease in addition to treating obstructive lesions with a small stent.”
Asked if the lack of headroom in these extra-small arteries warrants liberal use of intraprocedural imaging to make sure the stent is perfectly apposed, Dr. Price replied that he doesn’t think so. He noted that intravascular ultrasound and optical coherence tomography were seldom used in the trial, yet the results were reassuringly excellent.
The study results were published simultaneously with Dr. Price’s presentation (JACC Cardiovasc Interv. 2017 May 17. doi: 10.1016/j.jcin.2017.05.004). The trial was sponsored by Medtronic. Dr. Price reported serving as a consultant and paid speaker on behalf of that company, as well as AstraZeneca, Boston Scientific, St. Jude Medical, and The Medicines Company.
Paris – The first multicenter, prospective trial of a drug-eluting stent designed specifically to treat lesions in coronary vessels less than 2.25 mm in diameter showed excellent outcomes, with a 1-year target lesion failure rate of 5% for the Resolute Onyx 2.0 mm diameter zotarolimus-eluting stent.
This result in the pivotal trial easily surpassed the prespecified performance goal of a 19% target lesion failure rate, Matthew J. Price, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
Hemodynamically significant lesions in such small vessels are “not uncommon, particularly in diabetic patients,” Dr. Price said in an interview. Indeed, 47% of patients in the clinical trial had diabetes.
At present, the only ways to treat coronary disease in arteries having a reference vessel diameter less than 2.25 mm are off-label placement of an oversized stent, with its attendant risk of complications; standard balloon angioplasty, which entails a particularly high restenosis rate in this setting; or medical management, the cardiologist noted.
He presented a multicenter, prospective, open-label, single-arm trial of 101 patients with documented ischemia-producing obstructions in coronary arteries having a reference vessel diameter less than 2.25 mm, a lesion length less than 27 mm, and evidence of ischemia attributable to the lesion, typically via fractional flow reserve. The mean diameter by quantitative coronary angiography was 1.91 mm.
The primary endpoint was the rate of target lesion failure at 12 months, a composite comprising cardiac death, target vessel MI, or clinically driven target lesion revascularization. This endpoint occurred in 5% of patients. There was a 3% target vessel MI rate and a 2% target lesion revascularization rate. There were no cardiac deaths.
“Importantly, the stent thrombosis rate in these patients with extremely small vessels was zero,” the cardiologist emphasized.
The mean angiographic in-stent late lumen loss at 13 months was 0.26 mm, which Dr. Price characterized as “quite good.” The in-segment binary angiographic restenosis rate was 20%.
“That’s slightly higher than you would expect to see in vessels with larger reference diameters. I think that’s because of the lack of headroom. You have a very small vessel, and, even with a very small stent, even a small amount of late loss will give you a larger percent diameter restenosis over time,” he explained.
The 19% target lesion failure rate selected as a performance goal in the trial was set somewhat arbitrarily. It wasn’t possible to randomize patients to a comparator arm because there are no approved stents for vessels less than 2.25 mm in diameter. The 19% figure was arrived at in discussion with the Food and Drug Administration on the basis of similarity to the performance goal used in clinical trials to gain approval of 2.25-mm, drug-eluting stents. Because the Onyx 2.0-mm-diameter trial was developed in collaboration with the FDA and the stent aced its primary endpoint and showed excellent clinical outcomes, Dr. Price anticipates the device will readily gain regulatory approval. In April 2017, the FDA approved the Resolute Onyx in sizes of 2.25- to 5.0-mm diameter.
The study met with an enthusiastic reception.
“That was terrific. It’s clearly an incredibly important unmet clinical need,” commented session cochair David R. Holmes Jr., MD, of the Mayo Clinic in Rochester, Minn.
Assuming the stent is approved, how should interventionalists put it into practice? he asked.
Dr. Price replied that, first, it’s important to step back and ask if percutaneous coronary intervention of a particular lesion in a very small coronary artery is clinically indicated. The stent itself is readily manipulatable. It is a thin-strut device constructed of a single strand of a cobalt alloy with enhanced radiopacity.
Investigators in the trial used the standard approach to dual antiplatelet therapy – at least 6 months, with 12 months preferable.
The 20% in-segment binary restenosis rate at 13 months provides a clear message for interventionalists, he continued. “What this tells me is that, while this is a very good stent, we can’t forget to treat the patient aggressively with medical therapy to stop the progression of prediabetes, diabetes, and small vessel disease in addition to treating obstructive lesions with a small stent.”
Asked if the lack of headroom in these extra-small arteries warrants liberal use of intraprocedural imaging to make sure the stent is perfectly apposed, Dr. Price replied that he doesn’t think so. He noted that intravascular ultrasound and optical coherence tomography were seldom used in the trial, yet the results were reassuringly excellent.
The study results were published simultaneously with Dr. Price’s presentation (JACC Cardiovasc Interv. 2017 May 17. doi: 10.1016/j.jcin.2017.05.004). The trial was sponsored by Medtronic. Dr. Price reported serving as a consultant and paid speaker on behalf of that company, as well as AstraZeneca, Boston Scientific, St. Jude Medical, and The Medicines Company.
Paris – The first multicenter, prospective trial of a drug-eluting stent designed specifically to treat lesions in coronary vessels less than 2.25 mm in diameter showed excellent outcomes, with a 1-year target lesion failure rate of 5% for the Resolute Onyx 2.0 mm diameter zotarolimus-eluting stent.
This result in the pivotal trial easily surpassed the prespecified performance goal of a 19% target lesion failure rate, Matthew J. Price, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
Hemodynamically significant lesions in such small vessels are “not uncommon, particularly in diabetic patients,” Dr. Price said in an interview. Indeed, 47% of patients in the clinical trial had diabetes.
At present, the only ways to treat coronary disease in arteries having a reference vessel diameter less than 2.25 mm are off-label placement of an oversized stent, with its attendant risk of complications; standard balloon angioplasty, which entails a particularly high restenosis rate in this setting; or medical management, the cardiologist noted.
He presented a multicenter, prospective, open-label, single-arm trial of 101 patients with documented ischemia-producing obstructions in coronary arteries having a reference vessel diameter less than 2.25 mm, a lesion length less than 27 mm, and evidence of ischemia attributable to the lesion, typically via fractional flow reserve. The mean diameter by quantitative coronary angiography was 1.91 mm.
The primary endpoint was the rate of target lesion failure at 12 months, a composite comprising cardiac death, target vessel MI, or clinically driven target lesion revascularization. This endpoint occurred in 5% of patients. There was a 3% target vessel MI rate and a 2% target lesion revascularization rate. There were no cardiac deaths.
“Importantly, the stent thrombosis rate in these patients with extremely small vessels was zero,” the cardiologist emphasized.
The mean angiographic in-stent late lumen loss at 13 months was 0.26 mm, which Dr. Price characterized as “quite good.” The in-segment binary angiographic restenosis rate was 20%.
“That’s slightly higher than you would expect to see in vessels with larger reference diameters. I think that’s because of the lack of headroom. You have a very small vessel, and, even with a very small stent, even a small amount of late loss will give you a larger percent diameter restenosis over time,” he explained.
The 19% target lesion failure rate selected as a performance goal in the trial was set somewhat arbitrarily. It wasn’t possible to randomize patients to a comparator arm because there are no approved stents for vessels less than 2.25 mm in diameter. The 19% figure was arrived at in discussion with the Food and Drug Administration on the basis of similarity to the performance goal used in clinical trials to gain approval of 2.25-mm, drug-eluting stents. Because the Onyx 2.0-mm-diameter trial was developed in collaboration with the FDA and the stent aced its primary endpoint and showed excellent clinical outcomes, Dr. Price anticipates the device will readily gain regulatory approval. In April 2017, the FDA approved the Resolute Onyx in sizes of 2.25- to 5.0-mm diameter.
The study met with an enthusiastic reception.
“That was terrific. It’s clearly an incredibly important unmet clinical need,” commented session cochair David R. Holmes Jr., MD, of the Mayo Clinic in Rochester, Minn.
Assuming the stent is approved, how should interventionalists put it into practice? he asked.
Dr. Price replied that, first, it’s important to step back and ask if percutaneous coronary intervention of a particular lesion in a very small coronary artery is clinically indicated. The stent itself is readily manipulatable. It is a thin-strut device constructed of a single strand of a cobalt alloy with enhanced radiopacity.
Investigators in the trial used the standard approach to dual antiplatelet therapy – at least 6 months, with 12 months preferable.
The 20% in-segment binary restenosis rate at 13 months provides a clear message for interventionalists, he continued. “What this tells me is that, while this is a very good stent, we can’t forget to treat the patient aggressively with medical therapy to stop the progression of prediabetes, diabetes, and small vessel disease in addition to treating obstructive lesions with a small stent.”
Asked if the lack of headroom in these extra-small arteries warrants liberal use of intraprocedural imaging to make sure the stent is perfectly apposed, Dr. Price replied that he doesn’t think so. He noted that intravascular ultrasound and optical coherence tomography were seldom used in the trial, yet the results were reassuringly excellent.
The study results were published simultaneously with Dr. Price’s presentation (JACC Cardiovasc Interv. 2017 May 17. doi: 10.1016/j.jcin.2017.05.004). The trial was sponsored by Medtronic. Dr. Price reported serving as a consultant and paid speaker on behalf of that company, as well as AstraZeneca, Boston Scientific, St. Jude Medical, and The Medicines Company.
AT EUROPCR
Key clinical point:
Major finding: At 12 months’ follow-up, the key outcomes were a 3% rate of target vessel MI, a 2% rate of clinically driven target lesion revascularization, no stent thrombosis, and no cardiac deaths.
Data source: A prospective, multicenter, open-label trial in 101 patients who underwent percutaneous coronary intervention for coronary lesions with a reference vessel diameter of less than 2.25 mm.
Disclosures: The trial was sponsored by Medtronic. Dr. Price reported serving as a consultant to and paid speaker on behalf of that company as well as AstraZeneca, Boston Scientific, St. Jude Medical, and The Medicines Company.
Fighting in a passive manner active against Clostridium difficile
Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.
C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2
Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8
Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.
In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.
Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).
The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.
It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8
This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.
The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8
In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.
Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.
Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.
Contact Dr. Schalk at [email protected].
References
1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202
2. Cornely, OA. Current and emerging management options for Clostridium difficile infection: What is the role of fidaxomicin? Clin Microbiol Infect. 2012;18(Suppl 6):28-35.
3. Bartlett, JG et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-4.
4. Lyras, D et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176-9.
5. Reineke, J et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007;446:415-9.
6. Leav, BA et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-9.
7. Orth, P et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008-21.
8. Wilcox, MH et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-17.
9. Louie, TJ et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;5(Suppl 2):S132-42.
Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.
C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2
Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8
Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.
In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.
Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).
The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.
It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8
This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.
The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8
In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.
Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.
Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.
Contact Dr. Schalk at [email protected].
References
1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202
2. Cornely, OA. Current and emerging management options for Clostridium difficile infection: What is the role of fidaxomicin? Clin Microbiol Infect. 2012;18(Suppl 6):28-35.
3. Bartlett, JG et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-4.
4. Lyras, D et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176-9.
5. Reineke, J et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007;446:415-9.
6. Leav, BA et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-9.
7. Orth, P et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008-21.
8. Wilcox, MH et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-17.
9. Louie, TJ et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;5(Suppl 2):S132-42.
Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.
C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2
Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8
Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.
In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.
Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).
The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.
It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8
This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.
The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8
In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.
Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.
Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.
Contact Dr. Schalk at [email protected].
References
1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202
2. Cornely, OA. Current and emerging management options for Clostridium difficile infection: What is the role of fidaxomicin? Clin Microbiol Infect. 2012;18(Suppl 6):28-35.
3. Bartlett, JG et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-4.
4. Lyras, D et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176-9.
5. Reineke, J et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007;446:415-9.
6. Leav, BA et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-9.
7. Orth, P et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008-21.
8. Wilcox, MH et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-17.
9. Louie, TJ et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;5(Suppl 2):S132-42.
VIDEO: How to recognize, treat central sensitization in endometriosis
VANCOUVER – Sometimes in endometriosis, pain persists despite optimal treatment. Women have multiple lesion excisions, but the pain just doesn’t go away.
Evidence is building that in those cases, central sensitization – an amplified central nervous system pain response common in chronic pain syndromes – is playing a role.
In a video interview at the World Congress on Endometriosis, Katy Vincent, DPhil, MBBS, a senior pain fellow and consultant gynecologist at the University of Oxford, England, explained the latest thinking, as well as how to recognize and treat central sensitization in endometriosis. For some women, focusing on lesions isn’t enough.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
VANCOUVER – Sometimes in endometriosis, pain persists despite optimal treatment. Women have multiple lesion excisions, but the pain just doesn’t go away.
Evidence is building that in those cases, central sensitization – an amplified central nervous system pain response common in chronic pain syndromes – is playing a role.
In a video interview at the World Congress on Endometriosis, Katy Vincent, DPhil, MBBS, a senior pain fellow and consultant gynecologist at the University of Oxford, England, explained the latest thinking, as well as how to recognize and treat central sensitization in endometriosis. For some women, focusing on lesions isn’t enough.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
VANCOUVER – Sometimes in endometriosis, pain persists despite optimal treatment. Women have multiple lesion excisions, but the pain just doesn’t go away.
Evidence is building that in those cases, central sensitization – an amplified central nervous system pain response common in chronic pain syndromes – is playing a role.
In a video interview at the World Congress on Endometriosis, Katy Vincent, DPhil, MBBS, a senior pain fellow and consultant gynecologist at the University of Oxford, England, explained the latest thinking, as well as how to recognize and treat central sensitization in endometriosis. For some women, focusing on lesions isn’t enough.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM THE WORLD CONGRESS ON ENDOMETRIOSIS
VIDEO: When to offer hysterectomy in endometriosis
VANCOUVER – Although hysterectomy will never again be the go-to treatment for endometriosis that it once was, it has become clear in recent years that it still has a role to play.
In a video interview at the World Congress on Endometriosis, Ray Garry, MD, a recently retired professor of obstetrics and gynecology at the University of Western Australia, Perth, explained why – in a limited way – the pendulum is swinging back toward hysterectomy for a select group of women.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
VANCOUVER – Although hysterectomy will never again be the go-to treatment for endometriosis that it once was, it has become clear in recent years that it still has a role to play.
In a video interview at the World Congress on Endometriosis, Ray Garry, MD, a recently retired professor of obstetrics and gynecology at the University of Western Australia, Perth, explained why – in a limited way – the pendulum is swinging back toward hysterectomy for a select group of women.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
VANCOUVER – Although hysterectomy will never again be the go-to treatment for endometriosis that it once was, it has become clear in recent years that it still has a role to play.
In a video interview at the World Congress on Endometriosis, Ray Garry, MD, a recently retired professor of obstetrics and gynecology at the University of Western Australia, Perth, explained why – in a limited way – the pendulum is swinging back toward hysterectomy for a select group of women.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM THE WORLD CONGRESS ON ENDOMETRIOSIS
ACT2: Noninvasive vagus nerve stimulation benefits episodic cluster headache
BOSTON – Noninvasive vagus nerve stimulation (nVNS) proved safe and effective for the treatment of episodic cluster headaches in the pivotal, multicenter ACT2 study.
The findings confirmed those of the ACT1 study – and together, the results led to the April 18 approval by the Food and Drug Administration of the gammaCore stimulation device for the treatment of episodic cluster headaches (eCH).
In ACT2, nVNS was used to treat 495 cluster headache attacks in 50 patients randomized to the treatment group, and a sham treatment was used for 400 attacks in 52 patients. The proportion of patients who achieved pain freedom within 15 minutes (responders) was 13.5% with stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Stimulation led to pain freedom within 15 minutes in 47.5% of 101 attacks in 14 patients with eCH, compared with 6.2% of 81 attacks in eCH patients in the sham treatment group (OR, 9.19), said Dr. Goadsby of King’s College, London. Conversely, the proportion of responders was only 4.8% with stimulation for 394 attacks in 34 patients with cCH, compared with 12.9% in 319 attacks in 31 patients in the sham treatment group (OR, 0.41).
Further, the proportion of patients with any type of cluster headache who achieved responder status for at least 50% of attacks was 39.5% with stimulation vs. 13.6% with sham. Among those with eCH, the proportions were 64.3% and 15.4%, respectively, and with cCH they were 29.4% and 12.9%, respectively.
Study patients were adults with eCH or cCH who were enrolled from nine tertiary care centers in four European countries. Patients agreed to not start any new treatment and to not change the dose of any existing treatment during a 1-week run-in period and during a 2-week double-blind period.
Vagus nerve stimulation was self administered using the gammaCore study device at the onset of a cluster headache attack. Three consecutive 120-second stimulations were administered, and if pain freedom was not achieved by 9 minutes, three additional stimulations could be administered.
Patients were asked to refrain from use of rescue treatments for 15 minutes after beginning stimulation (use of rescue treatments constituted a treatment failure), and an initial assessment of pain intensity was conducted at 15 minutes. All patients were eligible for nVNS during a 2-week open-label period after the double-blind period. Patients recorded cluster headache attack data in diaries.
Treatment was safe and well tolerated. A total of 20 and 14 patients in the treatment and sham groups experienced adverse events in the double-blind period (total number of events, 65 and 39, respectively); and 9 and 10 in the groups, respectively, experienced adverse drug events. The adverse events occurring more often in the treatment group included application-site irritation in two patients, application-site paresthesia in two patients, and skin irritation in two patients.
Vagus nerve stimulation is a well-established neuromodulation therapy for epilepsy and medication-resistant depression. The gammaCore device used in the ACT1 and ACT2 studies delivers treatment to the cervical branch of the vagus nerve transcutaneously, whereas prior methods involved surgically implanted devices, which are more prone to cause infection and other complications and costs.
The current study’s findings demonstrate the superiority of nVNS over sham therapy for the acute treatment of attacks in patients with eCH, Dr. Goadsby noted. The lack of benefit in those with cCH likely affected the results for the total population, he added.
The findings indicate the nVNS can be safely and easily incorporated into existing therapeutic regimens, Dr. Goadsby concluded.
The ACT1 and ACT2 studies were sponsored by electroCore, the maker of gammaCore. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
BOSTON – Noninvasive vagus nerve stimulation (nVNS) proved safe and effective for the treatment of episodic cluster headaches in the pivotal, multicenter ACT2 study.
The findings confirmed those of the ACT1 study – and together, the results led to the April 18 approval by the Food and Drug Administration of the gammaCore stimulation device for the treatment of episodic cluster headaches (eCH).
In ACT2, nVNS was used to treat 495 cluster headache attacks in 50 patients randomized to the treatment group, and a sham treatment was used for 400 attacks in 52 patients. The proportion of patients who achieved pain freedom within 15 minutes (responders) was 13.5% with stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Stimulation led to pain freedom within 15 minutes in 47.5% of 101 attacks in 14 patients with eCH, compared with 6.2% of 81 attacks in eCH patients in the sham treatment group (OR, 9.19), said Dr. Goadsby of King’s College, London. Conversely, the proportion of responders was only 4.8% with stimulation for 394 attacks in 34 patients with cCH, compared with 12.9% in 319 attacks in 31 patients in the sham treatment group (OR, 0.41).
Further, the proportion of patients with any type of cluster headache who achieved responder status for at least 50% of attacks was 39.5% with stimulation vs. 13.6% with sham. Among those with eCH, the proportions were 64.3% and 15.4%, respectively, and with cCH they were 29.4% and 12.9%, respectively.
Study patients were adults with eCH or cCH who were enrolled from nine tertiary care centers in four European countries. Patients agreed to not start any new treatment and to not change the dose of any existing treatment during a 1-week run-in period and during a 2-week double-blind period.
Vagus nerve stimulation was self administered using the gammaCore study device at the onset of a cluster headache attack. Three consecutive 120-second stimulations were administered, and if pain freedom was not achieved by 9 minutes, three additional stimulations could be administered.
Patients were asked to refrain from use of rescue treatments for 15 minutes after beginning stimulation (use of rescue treatments constituted a treatment failure), and an initial assessment of pain intensity was conducted at 15 minutes. All patients were eligible for nVNS during a 2-week open-label period after the double-blind period. Patients recorded cluster headache attack data in diaries.
Treatment was safe and well tolerated. A total of 20 and 14 patients in the treatment and sham groups experienced adverse events in the double-blind period (total number of events, 65 and 39, respectively); and 9 and 10 in the groups, respectively, experienced adverse drug events. The adverse events occurring more often in the treatment group included application-site irritation in two patients, application-site paresthesia in two patients, and skin irritation in two patients.
Vagus nerve stimulation is a well-established neuromodulation therapy for epilepsy and medication-resistant depression. The gammaCore device used in the ACT1 and ACT2 studies delivers treatment to the cervical branch of the vagus nerve transcutaneously, whereas prior methods involved surgically implanted devices, which are more prone to cause infection and other complications and costs.
The current study’s findings demonstrate the superiority of nVNS over sham therapy for the acute treatment of attacks in patients with eCH, Dr. Goadsby noted. The lack of benefit in those with cCH likely affected the results for the total population, he added.
The findings indicate the nVNS can be safely and easily incorporated into existing therapeutic regimens, Dr. Goadsby concluded.
The ACT1 and ACT2 studies were sponsored by electroCore, the maker of gammaCore. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
BOSTON – Noninvasive vagus nerve stimulation (nVNS) proved safe and effective for the treatment of episodic cluster headaches in the pivotal, multicenter ACT2 study.
The findings confirmed those of the ACT1 study – and together, the results led to the April 18 approval by the Food and Drug Administration of the gammaCore stimulation device for the treatment of episodic cluster headaches (eCH).
In ACT2, nVNS was used to treat 495 cluster headache attacks in 50 patients randomized to the treatment group, and a sham treatment was used for 400 attacks in 52 patients. The proportion of patients who achieved pain freedom within 15 minutes (responders) was 13.5% with stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Stimulation led to pain freedom within 15 minutes in 47.5% of 101 attacks in 14 patients with eCH, compared with 6.2% of 81 attacks in eCH patients in the sham treatment group (OR, 9.19), said Dr. Goadsby of King’s College, London. Conversely, the proportion of responders was only 4.8% with stimulation for 394 attacks in 34 patients with cCH, compared with 12.9% in 319 attacks in 31 patients in the sham treatment group (OR, 0.41).
Further, the proportion of patients with any type of cluster headache who achieved responder status for at least 50% of attacks was 39.5% with stimulation vs. 13.6% with sham. Among those with eCH, the proportions were 64.3% and 15.4%, respectively, and with cCH they were 29.4% and 12.9%, respectively.
Study patients were adults with eCH or cCH who were enrolled from nine tertiary care centers in four European countries. Patients agreed to not start any new treatment and to not change the dose of any existing treatment during a 1-week run-in period and during a 2-week double-blind period.
Vagus nerve stimulation was self administered using the gammaCore study device at the onset of a cluster headache attack. Three consecutive 120-second stimulations were administered, and if pain freedom was not achieved by 9 minutes, three additional stimulations could be administered.
Patients were asked to refrain from use of rescue treatments for 15 minutes after beginning stimulation (use of rescue treatments constituted a treatment failure), and an initial assessment of pain intensity was conducted at 15 minutes. All patients were eligible for nVNS during a 2-week open-label period after the double-blind period. Patients recorded cluster headache attack data in diaries.
Treatment was safe and well tolerated. A total of 20 and 14 patients in the treatment and sham groups experienced adverse events in the double-blind period (total number of events, 65 and 39, respectively); and 9 and 10 in the groups, respectively, experienced adverse drug events. The adverse events occurring more often in the treatment group included application-site irritation in two patients, application-site paresthesia in two patients, and skin irritation in two patients.
Vagus nerve stimulation is a well-established neuromodulation therapy for epilepsy and medication-resistant depression. The gammaCore device used in the ACT1 and ACT2 studies delivers treatment to the cervical branch of the vagus nerve transcutaneously, whereas prior methods involved surgically implanted devices, which are more prone to cause infection and other complications and costs.
The current study’s findings demonstrate the superiority of nVNS over sham therapy for the acute treatment of attacks in patients with eCH, Dr. Goadsby noted. The lack of benefit in those with cCH likely affected the results for the total population, he added.
The findings indicate the nVNS can be safely and easily incorporated into existing therapeutic regimens, Dr. Goadsby concluded.
The ACT1 and ACT2 studies were sponsored by electroCore, the maker of gammaCore. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
AT AAN 2017
Key clinical point:
Major finding: The proportion of patients who achieved pain freedom within 15 minutes was 13.5% with noninvasive vagus nerve stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Data source: The randomized, sham-controlled, multicenter ACT2 study of 102 patients.
Disclosures: The ACT1 and ACT2 studies were sponsored by electroCore, the maker of the gammaCore device. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
VIDEO: Wedge resection offers higher survival for NSCLC
BOSTON – High quality wedge resection results in higher survival for patients with early stage non–small cell lung cancer when compared with stereotactic body radiation therapy, according to new research.
The analysis, reported at the annual meeting of the American Association for Thoracic Surgery, evaluated the treatment of 7,337 patients in the National Cancer Database with clinical T1-T2, N0, M0 non–small cell lung cancer who were treated with either wedge resection or stereotactic body radiation therapy from 2005 to 2012.
In this video, Varun Puri, MD, of Washington University, St. Louis, discusses the study and the significance of the findings.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @legal_med
BOSTON – High quality wedge resection results in higher survival for patients with early stage non–small cell lung cancer when compared with stereotactic body radiation therapy, according to new research.
The analysis, reported at the annual meeting of the American Association for Thoracic Surgery, evaluated the treatment of 7,337 patients in the National Cancer Database with clinical T1-T2, N0, M0 non–small cell lung cancer who were treated with either wedge resection or stereotactic body radiation therapy from 2005 to 2012.
In this video, Varun Puri, MD, of Washington University, St. Louis, discusses the study and the significance of the findings.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @legal_med
BOSTON – High quality wedge resection results in higher survival for patients with early stage non–small cell lung cancer when compared with stereotactic body radiation therapy, according to new research.
The analysis, reported at the annual meeting of the American Association for Thoracic Surgery, evaluated the treatment of 7,337 patients in the National Cancer Database with clinical T1-T2, N0, M0 non–small cell lung cancer who were treated with either wedge resection or stereotactic body radiation therapy from 2005 to 2012.
In this video, Varun Puri, MD, of Washington University, St. Louis, discusses the study and the significance of the findings.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @legal_med
AT THE AATS ANNUAL MEETING
Why Do Patients Discontinue Botulinum Toxin for Dystonia?
A Potent Neurotoxin
The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.
Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.
Blepharospasm
Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.
The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.
Cervical Dystonia Registries
CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”
Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.
A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”
Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.
Limb Dystonia
In limb dystonia, mostly occupational dystonias have been studied, including writer’s cramp and musician’s dystonia. The most frequent adverse event with botulinum toxin is weakness, which may lead to discontinuation. In a 2007 study of abobotulinumtoxinA for writer’s cramp that used continuation of treatment as the primary outcome, 70% of patients who received active treatment continued treatment, compared with 32% of patients in the placebo group. Hand weakness occurred in about 90% of patients in the active treatment group, however, compared with 25% of patients in the placebo group, and 25% of patients in the active treatment group discontinued because of hand weakness.
Neurologists adjust a patient’s injections based on the patient’s response to the previous treatment, so treatment may become more beneficial as neurologists optimize the injection pattern and dosing.
Why Might Treatment Fail?
Injection of botulinum toxin into the wrong muscle may be a common reason for lack of efficacy. Stress-induced exacerbation or inadequate dose may be other reasons for treatment failure. Uncommon reasons for lack of efficacy include change in dystonia and immunoresistance. In addition, patients may discontinue treatment because of the expense or inconvenience, Dr. Comella said.
Neurologists should help set realistic expectations for treatment. “We must manage patient expectations. It is not a cure. This may not restore you to perfect movement,” Dr. Comella said. “Too often we tell them how well they are going to do without giving them a more realistic view.”
Future Directions
Neurologists need better long-term outcome data to understand the effects of botulinum toxin in dystonia, and telemedicine may be an ideal way to assess the treatment’s long-term efficacy, Dr. Comella said. Remote evaluations could supplement in-person evaluations and avoid reliance on patients’ retrospective reports.
An investigational formulation of botulinum toxin, daxibotulinumtoxinA, is being developed by Revance Pharmaceuticals. It contains a peptide excipient that is designed to produce a longer treatment effect. A phase II open-label study is evaluating the formulation in patients with cervical dystonia, said Dr. Comella, who is one of the study investigators. One cohort of 12 patients received between 100 units and 200 units of the neurotoxin. The patients’ mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score change from baseline was 33% at 24 weeks. Investigators observed a clinically meaningful benefit by Week 2. The preliminary results are promising, but “we have much more work to do before this [formulation] could be available to us,” Dr. Comella said.
—Jake Remaly
Suggested Reading
Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23(10):1353-1360.
Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848.
Evidente VG, Truong D, Jankovic J, et al. IncobotulinumtoxinA (Xeomin) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated. J Neurol Sci. 2014;346(1-2):116-120.
Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93.
Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, et al. Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry. 2007;78(3):264-270.
Martinez-Ramirez D, Giugni JC, Hastings E, et al. Comparable botulinum toxin outcomes between primary and secondary blepharospasm: A retrospective analysis. Tremor Other Hyperkinet Mov (NY). 2014;4:286.
Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423.
Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.
Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826.
A Potent Neurotoxin
The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.
Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.
Blepharospasm
Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.
The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.
Cervical Dystonia Registries
CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”
Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.
A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”
Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.
Limb Dystonia
In limb dystonia, mostly occupational dystonias have been studied, including writer’s cramp and musician’s dystonia. The most frequent adverse event with botulinum toxin is weakness, which may lead to discontinuation. In a 2007 study of abobotulinumtoxinA for writer’s cramp that used continuation of treatment as the primary outcome, 70% of patients who received active treatment continued treatment, compared with 32% of patients in the placebo group. Hand weakness occurred in about 90% of patients in the active treatment group, however, compared with 25% of patients in the placebo group, and 25% of patients in the active treatment group discontinued because of hand weakness.
Neurologists adjust a patient’s injections based on the patient’s response to the previous treatment, so treatment may become more beneficial as neurologists optimize the injection pattern and dosing.
Why Might Treatment Fail?
Injection of botulinum toxin into the wrong muscle may be a common reason for lack of efficacy. Stress-induced exacerbation or inadequate dose may be other reasons for treatment failure. Uncommon reasons for lack of efficacy include change in dystonia and immunoresistance. In addition, patients may discontinue treatment because of the expense or inconvenience, Dr. Comella said.
Neurologists should help set realistic expectations for treatment. “We must manage patient expectations. It is not a cure. This may not restore you to perfect movement,” Dr. Comella said. “Too often we tell them how well they are going to do without giving them a more realistic view.”
Future Directions
Neurologists need better long-term outcome data to understand the effects of botulinum toxin in dystonia, and telemedicine may be an ideal way to assess the treatment’s long-term efficacy, Dr. Comella said. Remote evaluations could supplement in-person evaluations and avoid reliance on patients’ retrospective reports.
An investigational formulation of botulinum toxin, daxibotulinumtoxinA, is being developed by Revance Pharmaceuticals. It contains a peptide excipient that is designed to produce a longer treatment effect. A phase II open-label study is evaluating the formulation in patients with cervical dystonia, said Dr. Comella, who is one of the study investigators. One cohort of 12 patients received between 100 units and 200 units of the neurotoxin. The patients’ mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score change from baseline was 33% at 24 weeks. Investigators observed a clinically meaningful benefit by Week 2. The preliminary results are promising, but “we have much more work to do before this [formulation] could be available to us,” Dr. Comella said.
—Jake Remaly
Suggested Reading
Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23(10):1353-1360.
Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848.
Evidente VG, Truong D, Jankovic J, et al. IncobotulinumtoxinA (Xeomin) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated. J Neurol Sci. 2014;346(1-2):116-120.
Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93.
Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, et al. Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry. 2007;78(3):264-270.
Martinez-Ramirez D, Giugni JC, Hastings E, et al. Comparable botulinum toxin outcomes between primary and secondary blepharospasm: A retrospective analysis. Tremor Other Hyperkinet Mov (NY). 2014;4:286.
Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423.
Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.
Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826.
A Potent Neurotoxin
The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.
Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.
Blepharospasm
Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.
The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.
Cervical Dystonia Registries
CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”
Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.
A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”
Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.
Limb Dystonia
In limb dystonia, mostly occupational dystonias have been studied, including writer’s cramp and musician’s dystonia. The most frequent adverse event with botulinum toxin is weakness, which may lead to discontinuation. In a 2007 study of abobotulinumtoxinA for writer’s cramp that used continuation of treatment as the primary outcome, 70% of patients who received active treatment continued treatment, compared with 32% of patients in the placebo group. Hand weakness occurred in about 90% of patients in the active treatment group, however, compared with 25% of patients in the placebo group, and 25% of patients in the active treatment group discontinued because of hand weakness.
Neurologists adjust a patient’s injections based on the patient’s response to the previous treatment, so treatment may become more beneficial as neurologists optimize the injection pattern and dosing.
Why Might Treatment Fail?
Injection of botulinum toxin into the wrong muscle may be a common reason for lack of efficacy. Stress-induced exacerbation or inadequate dose may be other reasons for treatment failure. Uncommon reasons for lack of efficacy include change in dystonia and immunoresistance. In addition, patients may discontinue treatment because of the expense or inconvenience, Dr. Comella said.
Neurologists should help set realistic expectations for treatment. “We must manage patient expectations. It is not a cure. This may not restore you to perfect movement,” Dr. Comella said. “Too often we tell them how well they are going to do without giving them a more realistic view.”
Future Directions
Neurologists need better long-term outcome data to understand the effects of botulinum toxin in dystonia, and telemedicine may be an ideal way to assess the treatment’s long-term efficacy, Dr. Comella said. Remote evaluations could supplement in-person evaluations and avoid reliance on patients’ retrospective reports.
An investigational formulation of botulinum toxin, daxibotulinumtoxinA, is being developed by Revance Pharmaceuticals. It contains a peptide excipient that is designed to produce a longer treatment effect. A phase II open-label study is evaluating the formulation in patients with cervical dystonia, said Dr. Comella, who is one of the study investigators. One cohort of 12 patients received between 100 units and 200 units of the neurotoxin. The patients’ mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score change from baseline was 33% at 24 weeks. Investigators observed a clinically meaningful benefit by Week 2. The preliminary results are promising, but “we have much more work to do before this [formulation] could be available to us,” Dr. Comella said.
—Jake Remaly
Suggested Reading
Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23(10):1353-1360.
Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848.
Evidente VG, Truong D, Jankovic J, et al. IncobotulinumtoxinA (Xeomin) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated. J Neurol Sci. 2014;346(1-2):116-120.
Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93.
Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, et al. Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry. 2007;78(3):264-270.
Martinez-Ramirez D, Giugni JC, Hastings E, et al. Comparable botulinum toxin outcomes between primary and secondary blepharospasm: A retrospective analysis. Tremor Other Hyperkinet Mov (NY). 2014;4:286.
Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423.
Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.
Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826.
Truncal Vagotomy May Reduce the Risk of Parkinson’s Disease
Truncal vagotomy may be associated with a reduced risk of incident Parkinson’s disease, according to data published online ahead of print April 26 in Neurology. Selective vagotomy, however, is not associated with risk of Parkinson’s disease. These findings provide support for the theory that Parkinson’s disease begins in the gut and spreads to the brain via the vagus nerve, according to the authors.
Braak et al have hypothesized that Lewy pathology in Parkinson’s disease may start in peripheral nerves, such as the enteric nervous system, and spread to the CNS in a way similar to the propagation of prions. Researchers have found Lewy-type deposition in the gut of people with prodromal Parkinson’s disease. In addition, resection of the vagus nerve before administration of rotenone, which prompts alpha-synuclein accumulation, stopped the spread of parkinsonian pathology in mice. 
To examine whether vagotomy decreases the risk of Parkinson’s disease, Bojing Liu, a doctoral student at the Karolinska Institutet in Stockholm, and colleagues conducted a matched-cohort study using data from nationwide Swedish registers. The investigators identified 9,430 patients who underwent vagotomy (3,445 truncal, 5,978 selective, and seven unknown) between 1970 and 2010. Eligible participants were born before 1970 and lived in Sweden without a diagnosis of Parkinson’s disease before vagotomy. To each of these patients, the researchers individually matched 377,200 reference individuals from the general population by sex and year of birth in a 40:1 ratio. Participants were followed up from the date of vagotomy until Parkinson’s disease diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first.
Participants’ mean age at index date was 54. The investigators identified 4,930 cases of Parkinson’s disease during follow-up, and mean age at diagnosis was 76. Although the study groups were otherwise well balanced, proportionally more patients who underwent vagotomy were born outside Sweden, compared with controls. Participants who underwent truncal vagotomy were older than those who underwent selective vagotomy and older than controls.
Ms. Liu and colleagues did not find an association between vagotomy and Parkinson’s disease overall. They did, however, observe a lower risk of Parkinson’s disease more than five years after truncal vagotomy (hazard ratio [HR], 0.59) and more than 10 years after truncal vagotomy (HR, 0.62). Selective vagotomy was not associated with Parkinson’s disease risk in any of the analyses.
“Our observation of the temporal relationship is consistent with the possibility that Parkinson’s disease pathology may start at multiple sites of the peripheral nervous system. Therefore, even truncal vagotomy may delay rather than eliminate the risk for Parkinson’s disease,” said Ms. Liu and colleagues. She acknowledged that she and her colleagues were unable to control for potential individual confounders such as smoking, coffee consumption, or genetic factors.
“If the observed association is confirmed and proven to be biologic, we expect the results could be generalized to populations in other parts of the world,” Ms. Liu continued. “These data provide preliminary and indirect support for the Braak and prion-like hypotheses for Parkinson’s disease prodromal development.”
—Erik Greb
Suggested Reading
Liu B, Fang F, Pedersen NL, et al. Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study. Neurology. 2017 Apr 26 [Epub ahead of print].
Truncal vagotomy may be associated with a reduced risk of incident Parkinson’s disease, according to data published online ahead of print April 26 in Neurology. Selective vagotomy, however, is not associated with risk of Parkinson’s disease. These findings provide support for the theory that Parkinson’s disease begins in the gut and spreads to the brain via the vagus nerve, according to the authors.
Braak et al have hypothesized that Lewy pathology in Parkinson’s disease may start in peripheral nerves, such as the enteric nervous system, and spread to the CNS in a way similar to the propagation of prions. Researchers have found Lewy-type deposition in the gut of people with prodromal Parkinson’s disease. In addition, resection of the vagus nerve before administration of rotenone, which prompts alpha-synuclein accumulation, stopped the spread of parkinsonian pathology in mice.
To examine whether vagotomy decreases the risk of Parkinson’s disease, Bojing Liu, a doctoral student at the Karolinska Institutet in Stockholm, and colleagues conducted a matched-cohort study using data from nationwide Swedish registers. The investigators identified 9,430 patients who underwent vagotomy (3,445 truncal, 5,978 selective, and seven unknown) between 1970 and 2010. Eligible participants were born before 1970 and lived in Sweden without a diagnosis of Parkinson’s disease before vagotomy. To each of these patients, the researchers individually matched 377,200 reference individuals from the general population by sex and year of birth in a 40:1 ratio. Participants were followed up from the date of vagotomy until Parkinson’s disease diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first.
Participants’ mean age at index date was 54. The investigators identified 4,930 cases of Parkinson’s disease during follow-up, and mean age at diagnosis was 76. Although the study groups were otherwise well balanced, proportionally more patients who underwent vagotomy were born outside Sweden, compared with controls. Participants who underwent truncal vagotomy were older than those who underwent selective vagotomy and older than controls.
Ms. Liu and colleagues did not find an association between vagotomy and Parkinson’s disease overall. They did, however, observe a lower risk of Parkinson’s disease more than five years after truncal vagotomy (hazard ratio [HR], 0.59) and more than 10 years after truncal vagotomy (HR, 0.62). Selective vagotomy was not associated with Parkinson’s disease risk in any of the analyses.
“Our observation of the temporal relationship is consistent with the possibility that Parkinson’s disease pathology may start at multiple sites of the peripheral nervous system. Therefore, even truncal vagotomy may delay rather than eliminate the risk for Parkinson’s disease,” said Ms. Liu and colleagues. She acknowledged that she and her colleagues were unable to control for potential individual confounders such as smoking, coffee consumption, or genetic factors.
“If the observed association is confirmed and proven to be biologic, we expect the results could be generalized to populations in other parts of the world,” Ms. Liu continued. “These data provide preliminary and indirect support for the Braak and prion-like hypotheses for Parkinson’s disease prodromal development.”
—Erik Greb
Suggested Reading
Liu B, Fang F, Pedersen NL, et al. Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study. Neurology. 2017 Apr 26 [Epub ahead of print].
Truncal vagotomy may be associated with a reduced risk of incident Parkinson’s disease, according to data published online ahead of print April 26 in Neurology. Selective vagotomy, however, is not associated with risk of Parkinson’s disease. These findings provide support for the theory that Parkinson’s disease begins in the gut and spreads to the brain via the vagus nerve, according to the authors.
Braak et al have hypothesized that Lewy pathology in Parkinson’s disease may start in peripheral nerves, such as the enteric nervous system, and spread to the CNS in a way similar to the propagation of prions. Researchers have found Lewy-type deposition in the gut of people with prodromal Parkinson’s disease. In addition, resection of the vagus nerve before administration of rotenone, which prompts alpha-synuclein accumulation, stopped the spread of parkinsonian pathology in mice.
To examine whether vagotomy decreases the risk of Parkinson’s disease, Bojing Liu, a doctoral student at the Karolinska Institutet in Stockholm, and colleagues conducted a matched-cohort study using data from nationwide Swedish registers. The investigators identified 9,430 patients who underwent vagotomy (3,445 truncal, 5,978 selective, and seven unknown) between 1970 and 2010. Eligible participants were born before 1970 and lived in Sweden without a diagnosis of Parkinson’s disease before vagotomy. To each of these patients, the researchers individually matched 377,200 reference individuals from the general population by sex and year of birth in a 40:1 ratio. Participants were followed up from the date of vagotomy until Parkinson’s disease diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first.
Participants’ mean age at index date was 54. The investigators identified 4,930 cases of Parkinson’s disease during follow-up, and mean age at diagnosis was 76. Although the study groups were otherwise well balanced, proportionally more patients who underwent vagotomy were born outside Sweden, compared with controls. Participants who underwent truncal vagotomy were older than those who underwent selective vagotomy and older than controls.
Ms. Liu and colleagues did not find an association between vagotomy and Parkinson’s disease overall. They did, however, observe a lower risk of Parkinson’s disease more than five years after truncal vagotomy (hazard ratio [HR], 0.59) and more than 10 years after truncal vagotomy (HR, 0.62). Selective vagotomy was not associated with Parkinson’s disease risk in any of the analyses.
“Our observation of the temporal relationship is consistent with the possibility that Parkinson’s disease pathology may start at multiple sites of the peripheral nervous system. Therefore, even truncal vagotomy may delay rather than eliminate the risk for Parkinson’s disease,” said Ms. Liu and colleagues. She acknowledged that she and her colleagues were unable to control for potential individual confounders such as smoking, coffee consumption, or genetic factors.
“If the observed association is confirmed and proven to be biologic, we expect the results could be generalized to populations in other parts of the world,” Ms. Liu continued. “These data provide preliminary and indirect support for the Braak and prion-like hypotheses for Parkinson’s disease prodromal development.”
—Erik Greb
Suggested Reading
Liu B, Fang F, Pedersen NL, et al. Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study. Neurology. 2017 Apr 26 [Epub ahead of print].