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CMT1A neuropathy improves with investigational drug PXT3003
AUSTIN, TEX. – , according to new research.
“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”
The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.
The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.
The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).
The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.
Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).
Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).
Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.
Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.
Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.
SOURCE: Thomas F et al. AANEM 2019, Abstract 92.
AUSTIN, TEX. – , according to new research.
“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”
The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.
The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.
The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).
The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.
Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).
Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).
Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.
Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.
Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.
SOURCE: Thomas F et al. AANEM 2019, Abstract 92.
AUSTIN, TEX. – , according to new research.
“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”
The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.
The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.
The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).
The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.
Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).
Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).
Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.
Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.
Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.
SOURCE: Thomas F et al. AANEM 2019, Abstract 92.
REPORTING FROM AANEM 2019
The time is now for physicians to ride the digital disruption wave
CHICAGO – “The health care milieu is ripe for digital disruption,” said Anton Decker, MD. Speaking at the American Gastroenterological Association Partners in Value meeting, which was developed in partnership with the Digestive Health Physicians Association, he said that physicians need to become part of the disruption before it’s too late.
There’s no sign of improvement in worrisome trends in reimbursement, said Dr. Decker, president, international, at the Mayo Clinic, Rochester, Minn. The megamerger trend that is bringing together ever-larger payers, pharmacy benefit managers, and hospital groups is just one manifestation of the trend toward consolidation that’s also seen in the airline industry, in financial services, and in telecommunications, he said.
“The math is not good on the payer and health systems side,” but for physicians, “There are ways to survive trends like this if we can move ourselves higher in the food chain.”
Other players in the health care space are figuring it out, he said. For example, the state of Ohio has five Medicaid plans; in 2018, aggregate profits for these plans were approximately 400 million dollars. Laying this profit figure against the backdrop of Medicare reimbursement rates for physician services makes it clear that “we have to figure out ways to survive this game,” he said.
“Health systems keep their lights on because of the hospital reimbursements – that pays for everything else,” said Dr. Decker, adding that payments from commercial insurers fill the coffers that, in turn, pay physicians who are employed by health systems. However, there’s a sea change underway in the sites in which care is delivered: “There’s enormous pressure to get people out of the hospital and out of the emergency rooms,” said Dr. Decker, “And that’s not always better for patients.”
That shift to delivering care outside of the four walls of the hospital represents an opportunity for digitally savvy companies, many of whom may actually have little experience with health care delivery.
“Digital disruption is a sleeping giant that is easy to ignore, but you do that at your own peril. It’s happening in front of your eyes. My message today is: Figure out how you can move yourself further down the line.”
Chronic diseases, said Dr. Decker, “represent an opportunity for providers and health systems to leverage digital disruption.”
Overall, health care services contribute only to 10% of a patient’s health, said Dr. Decker, and are far overshadowed by individual health behaviors and social determinants of health. Is there a role for physicians to move beyond the clinic and hospital as partners in the digital disruption of health care? Yes, said Dr. Decker: “We’re not part of that aspect of a person’s life, and we need to be. ... I believe that providers have the right to be involved in other aspects of peoples’ lives to make them better, and yes, also to survive financially.”
said Dr. Decker. “Sixty percent of this country has a chronic disease. We as health care providers need to think differently about that.”
Changes are already well underway, with score upon score of startup companies developing apps that utilize smartphones and wearable devices to offer coaching, health education, and remote monitoring to consumers. “The barrier to entry is really low,” said Dr. Decker, with Silicon Valley already partnering with patients and payers to achieve digital monitoring and care delivery. But relatively few of these partnerships have actually involved physicians in building and executing the solutions they offer. “And that’s our fault, for not making sure we are part of this disruption,” he said.
Further, the evidence base for much of this monitoring and intervention is low. “There are some scathing articles on the level of evidence that these apps have – or don’t have,” said Dr. Becker. Physicians who get on board at the early stages of technology development could make a real difference, he said. “We could help them build the real evidence.”
Looping back to the current payer model, Dr. Decker asked, “Which pool of money is this coming from?” From the same pool of money that pays physicians, he said: “It’s coming off our backs.”
This isn’t a time when physicians can afford to wait and see how the digital health care landscape evolves, stressed Dr. Decker, making the subtle but important point that it’s hard to discern when you’re in the middle of disruptive change. Though the curve may appear relatively flat at the moment, he assured attendees that exponential growth in digital health care is already well underway.
Here is where early entry and user adoption are key: “Why do you think Facebook bought WhatsApp?” he asked. Though the messaging app, which has more than a billion users worldwide, is free now, eventual plans to charge WhatsApp users a dollar – or even less – per year will net Facebook staggering sums in the end, he said. Companies like Facebook “have figured out...the strength of exponential growth in a digital world,” he said.
All the building blocks are in place for physicians to begin contributing to health care’s digital disruption, said Dr. Decker. The Centers for Medicare and Medicaid already have reimbursement codes for remote patient monitoring, for example. “Providers are being left out, and I think it’s our own fault.”
Dr. Decker reported that he had no relevant conflicts of interest.
CHICAGO – “The health care milieu is ripe for digital disruption,” said Anton Decker, MD. Speaking at the American Gastroenterological Association Partners in Value meeting, which was developed in partnership with the Digestive Health Physicians Association, he said that physicians need to become part of the disruption before it’s too late.
There’s no sign of improvement in worrisome trends in reimbursement, said Dr. Decker, president, international, at the Mayo Clinic, Rochester, Minn. The megamerger trend that is bringing together ever-larger payers, pharmacy benefit managers, and hospital groups is just one manifestation of the trend toward consolidation that’s also seen in the airline industry, in financial services, and in telecommunications, he said.
“The math is not good on the payer and health systems side,” but for physicians, “There are ways to survive trends like this if we can move ourselves higher in the food chain.”
Other players in the health care space are figuring it out, he said. For example, the state of Ohio has five Medicaid plans; in 2018, aggregate profits for these plans were approximately 400 million dollars. Laying this profit figure against the backdrop of Medicare reimbursement rates for physician services makes it clear that “we have to figure out ways to survive this game,” he said.
“Health systems keep their lights on because of the hospital reimbursements – that pays for everything else,” said Dr. Decker, adding that payments from commercial insurers fill the coffers that, in turn, pay physicians who are employed by health systems. However, there’s a sea change underway in the sites in which care is delivered: “There’s enormous pressure to get people out of the hospital and out of the emergency rooms,” said Dr. Decker, “And that’s not always better for patients.”
That shift to delivering care outside of the four walls of the hospital represents an opportunity for digitally savvy companies, many of whom may actually have little experience with health care delivery.
“Digital disruption is a sleeping giant that is easy to ignore, but you do that at your own peril. It’s happening in front of your eyes. My message today is: Figure out how you can move yourself further down the line.”
Chronic diseases, said Dr. Decker, “represent an opportunity for providers and health systems to leverage digital disruption.”
Overall, health care services contribute only to 10% of a patient’s health, said Dr. Decker, and are far overshadowed by individual health behaviors and social determinants of health. Is there a role for physicians to move beyond the clinic and hospital as partners in the digital disruption of health care? Yes, said Dr. Decker: “We’re not part of that aspect of a person’s life, and we need to be. ... I believe that providers have the right to be involved in other aspects of peoples’ lives to make them better, and yes, also to survive financially.”
said Dr. Decker. “Sixty percent of this country has a chronic disease. We as health care providers need to think differently about that.”
Changes are already well underway, with score upon score of startup companies developing apps that utilize smartphones and wearable devices to offer coaching, health education, and remote monitoring to consumers. “The barrier to entry is really low,” said Dr. Decker, with Silicon Valley already partnering with patients and payers to achieve digital monitoring and care delivery. But relatively few of these partnerships have actually involved physicians in building and executing the solutions they offer. “And that’s our fault, for not making sure we are part of this disruption,” he said.
Further, the evidence base for much of this monitoring and intervention is low. “There are some scathing articles on the level of evidence that these apps have – or don’t have,” said Dr. Becker. Physicians who get on board at the early stages of technology development could make a real difference, he said. “We could help them build the real evidence.”
Looping back to the current payer model, Dr. Decker asked, “Which pool of money is this coming from?” From the same pool of money that pays physicians, he said: “It’s coming off our backs.”
This isn’t a time when physicians can afford to wait and see how the digital health care landscape evolves, stressed Dr. Decker, making the subtle but important point that it’s hard to discern when you’re in the middle of disruptive change. Though the curve may appear relatively flat at the moment, he assured attendees that exponential growth in digital health care is already well underway.
Here is where early entry and user adoption are key: “Why do you think Facebook bought WhatsApp?” he asked. Though the messaging app, which has more than a billion users worldwide, is free now, eventual plans to charge WhatsApp users a dollar – or even less – per year will net Facebook staggering sums in the end, he said. Companies like Facebook “have figured out...the strength of exponential growth in a digital world,” he said.
All the building blocks are in place for physicians to begin contributing to health care’s digital disruption, said Dr. Decker. The Centers for Medicare and Medicaid already have reimbursement codes for remote patient monitoring, for example. “Providers are being left out, and I think it’s our own fault.”
Dr. Decker reported that he had no relevant conflicts of interest.
CHICAGO – “The health care milieu is ripe for digital disruption,” said Anton Decker, MD. Speaking at the American Gastroenterological Association Partners in Value meeting, which was developed in partnership with the Digestive Health Physicians Association, he said that physicians need to become part of the disruption before it’s too late.
There’s no sign of improvement in worrisome trends in reimbursement, said Dr. Decker, president, international, at the Mayo Clinic, Rochester, Minn. The megamerger trend that is bringing together ever-larger payers, pharmacy benefit managers, and hospital groups is just one manifestation of the trend toward consolidation that’s also seen in the airline industry, in financial services, and in telecommunications, he said.
“The math is not good on the payer and health systems side,” but for physicians, “There are ways to survive trends like this if we can move ourselves higher in the food chain.”
Other players in the health care space are figuring it out, he said. For example, the state of Ohio has five Medicaid plans; in 2018, aggregate profits for these plans were approximately 400 million dollars. Laying this profit figure against the backdrop of Medicare reimbursement rates for physician services makes it clear that “we have to figure out ways to survive this game,” he said.
“Health systems keep their lights on because of the hospital reimbursements – that pays for everything else,” said Dr. Decker, adding that payments from commercial insurers fill the coffers that, in turn, pay physicians who are employed by health systems. However, there’s a sea change underway in the sites in which care is delivered: “There’s enormous pressure to get people out of the hospital and out of the emergency rooms,” said Dr. Decker, “And that’s not always better for patients.”
That shift to delivering care outside of the four walls of the hospital represents an opportunity for digitally savvy companies, many of whom may actually have little experience with health care delivery.
“Digital disruption is a sleeping giant that is easy to ignore, but you do that at your own peril. It’s happening in front of your eyes. My message today is: Figure out how you can move yourself further down the line.”
Chronic diseases, said Dr. Decker, “represent an opportunity for providers and health systems to leverage digital disruption.”
Overall, health care services contribute only to 10% of a patient’s health, said Dr. Decker, and are far overshadowed by individual health behaviors and social determinants of health. Is there a role for physicians to move beyond the clinic and hospital as partners in the digital disruption of health care? Yes, said Dr. Decker: “We’re not part of that aspect of a person’s life, and we need to be. ... I believe that providers have the right to be involved in other aspects of peoples’ lives to make them better, and yes, also to survive financially.”
said Dr. Decker. “Sixty percent of this country has a chronic disease. We as health care providers need to think differently about that.”
Changes are already well underway, with score upon score of startup companies developing apps that utilize smartphones and wearable devices to offer coaching, health education, and remote monitoring to consumers. “The barrier to entry is really low,” said Dr. Decker, with Silicon Valley already partnering with patients and payers to achieve digital monitoring and care delivery. But relatively few of these partnerships have actually involved physicians in building and executing the solutions they offer. “And that’s our fault, for not making sure we are part of this disruption,” he said.
Further, the evidence base for much of this monitoring and intervention is low. “There are some scathing articles on the level of evidence that these apps have – or don’t have,” said Dr. Becker. Physicians who get on board at the early stages of technology development could make a real difference, he said. “We could help them build the real evidence.”
Looping back to the current payer model, Dr. Decker asked, “Which pool of money is this coming from?” From the same pool of money that pays physicians, he said: “It’s coming off our backs.”
This isn’t a time when physicians can afford to wait and see how the digital health care landscape evolves, stressed Dr. Decker, making the subtle but important point that it’s hard to discern when you’re in the middle of disruptive change. Though the curve may appear relatively flat at the moment, he assured attendees that exponential growth in digital health care is already well underway.
Here is where early entry and user adoption are key: “Why do you think Facebook bought WhatsApp?” he asked. Though the messaging app, which has more than a billion users worldwide, is free now, eventual plans to charge WhatsApp users a dollar – or even less – per year will net Facebook staggering sums in the end, he said. Companies like Facebook “have figured out...the strength of exponential growth in a digital world,” he said.
All the building blocks are in place for physicians to begin contributing to health care’s digital disruption, said Dr. Decker. The Centers for Medicare and Medicaid already have reimbursement codes for remote patient monitoring, for example. “Providers are being left out, and I think it’s our own fault.”
Dr. Decker reported that he had no relevant conflicts of interest.
EXPERT ANALYSIS FROM AGA PARTNERS IN VALUE MEETING
‘Time lost is brain lost’
Question: Which of the following statements regarding “common knowledge” is correct?
A. In any negligence action absent common knowledge, expert testimony is then required to prove requisite standard of care and causation.
B.
C. An expert is needed in the first place to establish whether something constitutes common knowledge.
D. The jury is the one who determines whether a plaintiff can invoke the common knowledge exception.
E. An example of common knowledge in malpractice law is where a delay in stroke diagnosis results in loss of brain function.
Answer: B. The judge, not the jury or anyone else, makes the decision regarding res ipsa loquitur (the thing speaks for itself) or common knowledge, which exempts a plaintiff from producing an expert witness to testify as to the standard of care and causation. However, this is only true in actions arising out of professional negligence such as medical malpractice, whereas most common negligence actions – for example, slips and falls – do not require expert testimony.
Only a professional, duly qualified by the court as an expert witness, is allowed to offer medical testimony, while the plaintiff will typically be disqualified from playing this role because of the complexity of issues involved unless there is common knowledge. In general, courts are reluctant to grant this exception, which favors the plaintiff.
The best example of res ipsa loquitur is where a surgeon inadvertently leaves behind a sponge or instrument inside a body cavity. Other successfully litigated examples include cardiac arrest in the operating room, hypoxia in the recovery room, burns to the buttock, gangrene after the accidental injection of penicillin into an artery, air trapped subcutaneously from a displaced needle, and a pierced eyeball during a procedure. The factual circumstances of each case are critical to its outcome. For example, in a 2013 New York case, the plaintiff was barred from using the res doctrine.1 The defendant doctor had left a guide wire in the plaintiff’s chest following a biopsy and retrieved it 2 months later. The plaintiff did not call any expert witness, relying instead on the “foreign object” basis for invoking the res doctrine. However, the Court of Appeals reasoned that the object was left behind deliberately, not unintentionally, and that under the circumstances of the case, an expert witness was needed to set out the applicable standard of care, without which a jury could not determine whether the doctor’s professional judgment breached the requisite standard.
The Supreme Court of Kentucky recently rejected the use of common knowledge in a stroke case.2 In 2010, David Shackelford’s rheumatologist referred him to Paul Lewis, MD, an interventional radiologist, for a four-vessel cerebral angiogram to assist with diagnosing the cause of Mr. Shackelford’s chronic headaches. The procedure itself was uneventful, but while in the recovery room, Mr. Shackelford reported a frontal headache and scotoma, which resolved on its own. The headache improved with medication, and the patient experienced no other symptoms. There were no other visual changes, weakness, slurred speech, or facial palsies. Mr. Shackelford was discharged but had to return to the hospital the next morning via ambulance after becoming disoriented at his home. An MRI indicated multiple scattered small infarcts, and he was left with residual short-term memory loss and visual problems.
There was no allegation that the stroke itself was caused by negligence; rather, Mr. Shackelford alleged that the failure to examine and diagnose the stroke after the angiogram was negligent and caused injury greater than that which the stroke would have caused with earlier intervention. To support his claims, Mr. Shackelford’s expert, Michael David Khoury, MD, a vascular surgeon, criticized Dr. Lewis’s failure to examine Mr. Shackelford when his symptoms were consistent with a stroke. However, Dr. Khoury did not opine that Dr. Lewis could have limited the effects of the stroke through earlier intervention. When asked specifically whether he could state within a reasonable degree of medical probability that Dr. Lewis’s postprocedure care was a substantial factor in causing harm to Mr. Shackelford, Dr. Khoury responded that it was “impossible to tell.”
Based largely upon Dr. Khoury’s deposition testimony, the defendants successfully moved for summary judgment on the basis that the expert had failed to opine that the alleged negligence caused any injury to Mr. Shackelford. As a result, Mr. Shackelford could not prove an essential element of his medical malpractice claim. Defense expert Peter J. Pema, MD, a neuroradiologist, acknowledged the general proposition that strokes require timely diagnosis and treatment but did not provide an opinion on causation under the specific facts of this case. Another defense expert, Gregory Postal, MD, opined that Mr. Shackelford began to present symptoms of a stroke after leaving the hospital.
Notwithstanding the lower court’s ruling to summarily dismiss the case, the Court of Appeals found that, in this case, the issue of causation did not require expert medical testimony. It explained that given the ubiquity of information regarding stroke symptom identification and the necessity of prompt treatment, it had become common knowledge that “time lost is brain lost” as to timely medical intervention. In other words, a jury of laymen with this general knowledge could resolve the causation issue without the aid of expert testimony.
However, the Supreme Court of Kentucky held otherwise, writing: “We disagree with the Court of Appeals’ analysis. Although public service campaigns have increased public awareness and knowledge about stroke symptoms and timely intervention, that general information cannot provide the medical expertise necessary to evaluate this particular claim of medical malpractice. In other words, the question is not simply whether ‘time lost is brain lost.’ Rather, the specific facts and circumstances of this case play a significant role in determining whether the alleged negligent conduct was a substantial factor in Shackelford’s injuries, and to what extent. For example, as Dr. Lewis’s deposition testimony illustrates, a variety of factors influenced his diagnosis and treatment of Shackelford, including Shackelford’s medical history and history of cluster headaches; the common side effects of the angiogram procedure, including headache and scotoma; and the manner in which Shackelford’s headache and scotoma presented, as well as their timing. The complexities of these factors and how they affected Dr. Lewis’s evaluation of Shackelford may have also influenced the severity of the injury. These matters are clearly relevant to the determination of an alleged breach of the standard of care. Despite public perception about timely intervention, the average layperson cannot properly weigh such complex medical evidence without the aid of expert opinion. … To conclude otherwise is to drastically expand the res ipsa loquitor exception and to virtually eliminate the need for expert opinion evidence in similar medical malpractice actions that involve common or highly publicized conditions (e.g., stroke, heart attack, and even some cancers).”
Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical or legal advice. The author published an earlier version of this topic in the April 19, 2016, issue of Internal Medicine News, available at https://www.mdedge.com/internalmedicine/law-medicine. For additional information, readers may contact the author at [email protected].
References
1. James v. Wormuth, 997 N.E.2d 133 (N.Y. 2013).
2. Lewis/Ashland Hospital v. Shackelford, Supreme Court of Kentucky, Opinion of the Court by Justice Keller, rendered August 29, 2019.
Question: Which of the following statements regarding “common knowledge” is correct?
A. In any negligence action absent common knowledge, expert testimony is then required to prove requisite standard of care and causation.
B.
C. An expert is needed in the first place to establish whether something constitutes common knowledge.
D. The jury is the one who determines whether a plaintiff can invoke the common knowledge exception.
E. An example of common knowledge in malpractice law is where a delay in stroke diagnosis results in loss of brain function.
Answer: B. The judge, not the jury or anyone else, makes the decision regarding res ipsa loquitur (the thing speaks for itself) or common knowledge, which exempts a plaintiff from producing an expert witness to testify as to the standard of care and causation. However, this is only true in actions arising out of professional negligence such as medical malpractice, whereas most common negligence actions – for example, slips and falls – do not require expert testimony.
Only a professional, duly qualified by the court as an expert witness, is allowed to offer medical testimony, while the plaintiff will typically be disqualified from playing this role because of the complexity of issues involved unless there is common knowledge. In general, courts are reluctant to grant this exception, which favors the plaintiff.
The best example of res ipsa loquitur is where a surgeon inadvertently leaves behind a sponge or instrument inside a body cavity. Other successfully litigated examples include cardiac arrest in the operating room, hypoxia in the recovery room, burns to the buttock, gangrene after the accidental injection of penicillin into an artery, air trapped subcutaneously from a displaced needle, and a pierced eyeball during a procedure. The factual circumstances of each case are critical to its outcome. For example, in a 2013 New York case, the plaintiff was barred from using the res doctrine.1 The defendant doctor had left a guide wire in the plaintiff’s chest following a biopsy and retrieved it 2 months later. The plaintiff did not call any expert witness, relying instead on the “foreign object” basis for invoking the res doctrine. However, the Court of Appeals reasoned that the object was left behind deliberately, not unintentionally, and that under the circumstances of the case, an expert witness was needed to set out the applicable standard of care, without which a jury could not determine whether the doctor’s professional judgment breached the requisite standard.
The Supreme Court of Kentucky recently rejected the use of common knowledge in a stroke case.2 In 2010, David Shackelford’s rheumatologist referred him to Paul Lewis, MD, an interventional radiologist, for a four-vessel cerebral angiogram to assist with diagnosing the cause of Mr. Shackelford’s chronic headaches. The procedure itself was uneventful, but while in the recovery room, Mr. Shackelford reported a frontal headache and scotoma, which resolved on its own. The headache improved with medication, and the patient experienced no other symptoms. There were no other visual changes, weakness, slurred speech, or facial palsies. Mr. Shackelford was discharged but had to return to the hospital the next morning via ambulance after becoming disoriented at his home. An MRI indicated multiple scattered small infarcts, and he was left with residual short-term memory loss and visual problems.
There was no allegation that the stroke itself was caused by negligence; rather, Mr. Shackelford alleged that the failure to examine and diagnose the stroke after the angiogram was negligent and caused injury greater than that which the stroke would have caused with earlier intervention. To support his claims, Mr. Shackelford’s expert, Michael David Khoury, MD, a vascular surgeon, criticized Dr. Lewis’s failure to examine Mr. Shackelford when his symptoms were consistent with a stroke. However, Dr. Khoury did not opine that Dr. Lewis could have limited the effects of the stroke through earlier intervention. When asked specifically whether he could state within a reasonable degree of medical probability that Dr. Lewis’s postprocedure care was a substantial factor in causing harm to Mr. Shackelford, Dr. Khoury responded that it was “impossible to tell.”
Based largely upon Dr. Khoury’s deposition testimony, the defendants successfully moved for summary judgment on the basis that the expert had failed to opine that the alleged negligence caused any injury to Mr. Shackelford. As a result, Mr. Shackelford could not prove an essential element of his medical malpractice claim. Defense expert Peter J. Pema, MD, a neuroradiologist, acknowledged the general proposition that strokes require timely diagnosis and treatment but did not provide an opinion on causation under the specific facts of this case. Another defense expert, Gregory Postal, MD, opined that Mr. Shackelford began to present symptoms of a stroke after leaving the hospital.
Notwithstanding the lower court’s ruling to summarily dismiss the case, the Court of Appeals found that, in this case, the issue of causation did not require expert medical testimony. It explained that given the ubiquity of information regarding stroke symptom identification and the necessity of prompt treatment, it had become common knowledge that “time lost is brain lost” as to timely medical intervention. In other words, a jury of laymen with this general knowledge could resolve the causation issue without the aid of expert testimony.
However, the Supreme Court of Kentucky held otherwise, writing: “We disagree with the Court of Appeals’ analysis. Although public service campaigns have increased public awareness and knowledge about stroke symptoms and timely intervention, that general information cannot provide the medical expertise necessary to evaluate this particular claim of medical malpractice. In other words, the question is not simply whether ‘time lost is brain lost.’ Rather, the specific facts and circumstances of this case play a significant role in determining whether the alleged negligent conduct was a substantial factor in Shackelford’s injuries, and to what extent. For example, as Dr. Lewis’s deposition testimony illustrates, a variety of factors influenced his diagnosis and treatment of Shackelford, including Shackelford’s medical history and history of cluster headaches; the common side effects of the angiogram procedure, including headache and scotoma; and the manner in which Shackelford’s headache and scotoma presented, as well as their timing. The complexities of these factors and how they affected Dr. Lewis’s evaluation of Shackelford may have also influenced the severity of the injury. These matters are clearly relevant to the determination of an alleged breach of the standard of care. Despite public perception about timely intervention, the average layperson cannot properly weigh such complex medical evidence without the aid of expert opinion. … To conclude otherwise is to drastically expand the res ipsa loquitor exception and to virtually eliminate the need for expert opinion evidence in similar medical malpractice actions that involve common or highly publicized conditions (e.g., stroke, heart attack, and even some cancers).”
Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical or legal advice. The author published an earlier version of this topic in the April 19, 2016, issue of Internal Medicine News, available at https://www.mdedge.com/internalmedicine/law-medicine. For additional information, readers may contact the author at [email protected].
References
1. James v. Wormuth, 997 N.E.2d 133 (N.Y. 2013).
2. Lewis/Ashland Hospital v. Shackelford, Supreme Court of Kentucky, Opinion of the Court by Justice Keller, rendered August 29, 2019.
Question: Which of the following statements regarding “common knowledge” is correct?
A. In any negligence action absent common knowledge, expert testimony is then required to prove requisite standard of care and causation.
B.
C. An expert is needed in the first place to establish whether something constitutes common knowledge.
D. The jury is the one who determines whether a plaintiff can invoke the common knowledge exception.
E. An example of common knowledge in malpractice law is where a delay in stroke diagnosis results in loss of brain function.
Answer: B. The judge, not the jury or anyone else, makes the decision regarding res ipsa loquitur (the thing speaks for itself) or common knowledge, which exempts a plaintiff from producing an expert witness to testify as to the standard of care and causation. However, this is only true in actions arising out of professional negligence such as medical malpractice, whereas most common negligence actions – for example, slips and falls – do not require expert testimony.
Only a professional, duly qualified by the court as an expert witness, is allowed to offer medical testimony, while the plaintiff will typically be disqualified from playing this role because of the complexity of issues involved unless there is common knowledge. In general, courts are reluctant to grant this exception, which favors the plaintiff.
The best example of res ipsa loquitur is where a surgeon inadvertently leaves behind a sponge or instrument inside a body cavity. Other successfully litigated examples include cardiac arrest in the operating room, hypoxia in the recovery room, burns to the buttock, gangrene after the accidental injection of penicillin into an artery, air trapped subcutaneously from a displaced needle, and a pierced eyeball during a procedure. The factual circumstances of each case are critical to its outcome. For example, in a 2013 New York case, the plaintiff was barred from using the res doctrine.1 The defendant doctor had left a guide wire in the plaintiff’s chest following a biopsy and retrieved it 2 months later. The plaintiff did not call any expert witness, relying instead on the “foreign object” basis for invoking the res doctrine. However, the Court of Appeals reasoned that the object was left behind deliberately, not unintentionally, and that under the circumstances of the case, an expert witness was needed to set out the applicable standard of care, without which a jury could not determine whether the doctor’s professional judgment breached the requisite standard.
The Supreme Court of Kentucky recently rejected the use of common knowledge in a stroke case.2 In 2010, David Shackelford’s rheumatologist referred him to Paul Lewis, MD, an interventional radiologist, for a four-vessel cerebral angiogram to assist with diagnosing the cause of Mr. Shackelford’s chronic headaches. The procedure itself was uneventful, but while in the recovery room, Mr. Shackelford reported a frontal headache and scotoma, which resolved on its own. The headache improved with medication, and the patient experienced no other symptoms. There were no other visual changes, weakness, slurred speech, or facial palsies. Mr. Shackelford was discharged but had to return to the hospital the next morning via ambulance after becoming disoriented at his home. An MRI indicated multiple scattered small infarcts, and he was left with residual short-term memory loss and visual problems.
There was no allegation that the stroke itself was caused by negligence; rather, Mr. Shackelford alleged that the failure to examine and diagnose the stroke after the angiogram was negligent and caused injury greater than that which the stroke would have caused with earlier intervention. To support his claims, Mr. Shackelford’s expert, Michael David Khoury, MD, a vascular surgeon, criticized Dr. Lewis’s failure to examine Mr. Shackelford when his symptoms were consistent with a stroke. However, Dr. Khoury did not opine that Dr. Lewis could have limited the effects of the stroke through earlier intervention. When asked specifically whether he could state within a reasonable degree of medical probability that Dr. Lewis’s postprocedure care was a substantial factor in causing harm to Mr. Shackelford, Dr. Khoury responded that it was “impossible to tell.”
Based largely upon Dr. Khoury’s deposition testimony, the defendants successfully moved for summary judgment on the basis that the expert had failed to opine that the alleged negligence caused any injury to Mr. Shackelford. As a result, Mr. Shackelford could not prove an essential element of his medical malpractice claim. Defense expert Peter J. Pema, MD, a neuroradiologist, acknowledged the general proposition that strokes require timely diagnosis and treatment but did not provide an opinion on causation under the specific facts of this case. Another defense expert, Gregory Postal, MD, opined that Mr. Shackelford began to present symptoms of a stroke after leaving the hospital.
Notwithstanding the lower court’s ruling to summarily dismiss the case, the Court of Appeals found that, in this case, the issue of causation did not require expert medical testimony. It explained that given the ubiquity of information regarding stroke symptom identification and the necessity of prompt treatment, it had become common knowledge that “time lost is brain lost” as to timely medical intervention. In other words, a jury of laymen with this general knowledge could resolve the causation issue without the aid of expert testimony.
However, the Supreme Court of Kentucky held otherwise, writing: “We disagree with the Court of Appeals’ analysis. Although public service campaigns have increased public awareness and knowledge about stroke symptoms and timely intervention, that general information cannot provide the medical expertise necessary to evaluate this particular claim of medical malpractice. In other words, the question is not simply whether ‘time lost is brain lost.’ Rather, the specific facts and circumstances of this case play a significant role in determining whether the alleged negligent conduct was a substantial factor in Shackelford’s injuries, and to what extent. For example, as Dr. Lewis’s deposition testimony illustrates, a variety of factors influenced his diagnosis and treatment of Shackelford, including Shackelford’s medical history and history of cluster headaches; the common side effects of the angiogram procedure, including headache and scotoma; and the manner in which Shackelford’s headache and scotoma presented, as well as their timing. The complexities of these factors and how they affected Dr. Lewis’s evaluation of Shackelford may have also influenced the severity of the injury. These matters are clearly relevant to the determination of an alleged breach of the standard of care. Despite public perception about timely intervention, the average layperson cannot properly weigh such complex medical evidence without the aid of expert opinion. … To conclude otherwise is to drastically expand the res ipsa loquitor exception and to virtually eliminate the need for expert opinion evidence in similar medical malpractice actions that involve common or highly publicized conditions (e.g., stroke, heart attack, and even some cancers).”
Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical or legal advice. The author published an earlier version of this topic in the April 19, 2016, issue of Internal Medicine News, available at https://www.mdedge.com/internalmedicine/law-medicine. For additional information, readers may contact the author at [email protected].
References
1. James v. Wormuth, 997 N.E.2d 133 (N.Y. 2013).
2. Lewis/Ashland Hospital v. Shackelford, Supreme Court of Kentucky, Opinion of the Court by Justice Keller, rendered August 29, 2019.
Evidence lacking for using cannabinoids to treat mental disorders
Systematic review and meta-analysis concluded more ‘high-quality studies’ needed
Scant evidence exists to recommend medical cannabinoids and derivatives such as tetrahydrocannabinol and cannabidiol to patients with depressive disorders, anxiety, or other mental disorders, suggested research in a recent systematic review and meta-analysis published in The Lancet Psychiatry.
In their review, Nicola Black, PhD, Emily Stockings, PhD,and colleagues performed a search of the MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Clinical Trials, and Cochrane Database of Systematic Reviews and identified 83 studies between January 1980 and April 2018 in which adult patients were treated with a medical cannabinoid for primary or secondary depression, anxiety, ADHD, Tourette syndrome, PTSD, or psychosis.
The researchers examined symptom changes, symptom remission, and the safety of medicinal cannabinoids in each study. Overall, there were 3,067 participants across the 83 studies, including 42 trials for depression, 31 trials for anxiety, 11 for psychosis, 8 for Tourette syndrome, 3 for ADHD, and 12 trials for PTSD. Of those, 23 were randomized controlled trials (RCTs) for depression (2,551 participants), 17 were RCTs for anxiety (605 participants), and six were RCTs for psychosis (281 participants). In addition, one RCT was for Tourette syndrome (36 participants), one RCT was for ADHD (30 participants), and one RCT was for PTSD (10 participants), reported Dr. Black and Dr. Stockings, both of the National Drug and Alcohol Research Centre (NDARC) at the University of New South Wales in Sydney and colleagues.
In patients with anxiety in seven RCTs (252 participants), there was a “very low” evidence assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach that pharmaceutical tetrahydrocannabinol (THC) with and without cannabidiol (CBD) in standardized mean differences in symptoms (SMD, –0.25; 95% confidence interval, –0.49 to –0.01); however, researchers noted that most patients in this study had other medical conditions, such as noncancer pain and multiple sclerosis, which might have affected results. Patients with psychosis in one study (24 participants) had significantly worse outcomes after use of pharmaceutical THC with and without CBD (SMD, 0.36; 95% CI, 0.10-0.62).
In 10 studies (1,495 participants), a pooled analysis across all mental disorders showed pharmaceutical THC with and without CBD did not improve the primary outcome and was associated with significantly increased adverse events, compared with placebo (odds ratio, 1.99; 95% CI, 1.20-3.29). It led to study withdrawal from adverse events (OR, 2.78; 95% CI, 1.59-4.86) in 11 studies (1,621 participants), compared with placebo. While there were not many RCTs that examined adverse events after use of pharmaceutical CBD or medicinal cannabis, the studies that did examine the association did not find an increased risk of adverse events or adverse events leading to study withdrawal, compared with placebo.
“Our findings have important implications in countries where cannabis and cannabinoids are being made available for medical use,” one of the authors, Louisa Degenhardt, PhD, said in a press release. “There is a notable absence of high-quality evidence to properly assess the effectiveness and safety of medicinal cannabinoids, compared with placebo, and until evidence from randomized, controlled trials is available, clinical guidelines cannot be drawn up around their use in mental health disorders.”
“In countries where medicinal cannabinoids are already legal, doctors and patients must be aware of the limitations of existing evidence and the risks of cannabinoids,” said Dr. Degenhardt, who also is with NDARC. “These must be weighed when considering use to treat symptoms of common mental health disorders. Those who decide to proceed should be carefully monitored for positive and negative mental health effects of using medicinal cannabinoids.”
Among the limitations cited by investigators were the small amount of medical data. More “high-quality studies” are needed, they wrote.
The study was supported in part by funding from the Health Products Regulation Group, research fellowship grants from the National Health and Medical Research Council, and a grant from the National Institutes of Health National Institute on Drug Abuse. Two authors reported serving as investigators for studies funded by Indivior, Reckitt Benckiser, Mundipharma, and Seqirus; another also reported being an investigator for studies funded by Indivior. The remaining authors reported no relevant conflicts of interest.
SOURCE: Black N et al. Lancet Psychiatry. 2019. doi: 10.1016/S2215-0355(19)30401-8.
The results from Black et al. demonstrate that use of cannabinoids is unsupported for treating ADHD, PTSD, Tourette syndrome, psychosis, and depressive and anxiety disorders and symptoms, especially given that other approved medications for these conditions already exist, Deepak D’Souza, MBBS, MD, wrote in a related editorial.
“In light of the paucity of evidence, the absence of good quality evidence for efficacy, and the known risk of cannabinoids, their use as treatments for psychiatric disorders cannot be justified at present,” said Dr. D’Souza.
In addition, the conditions examined in the systematic review by Dr. Black, Dr. Stockings, and colleagues are distinct, and it is unclear how cannabinoids could treat these various conditions unless cannabinoids’ effects are similar to those of benzodiazepines, Dr. D’Souza noted. Another issue is that information on safety and efficacy of cannabinoids is also unknown, and factors such as optimal dosing, treatment duration, and tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio must also be established to begin trials. Finally, cannabinoids are also subject to tolerance issues with long-term exposure and would need to be considered for use with chronic psychiatric disorders.
“With cannabinoids, it seems that the cart (use) is before the horse (evidence),” Dr. D’Souza concluded. “If cannabinoids are to be used in the treatment of psychiatric disorders, they should first be tested in randomized controlled trials and subjected to the same regulatory approval process as other prescription medications.”
Dr. D’Souza is affiliated with the department of psychiatry at Yale University in New Haven, Conn. He reported receiving grants from the National Institutes of Health, Veterans Health Administration Office of Research and Development, Heffter Foundation, Wallace Foundation, and Takeda. He also reported serving on the physicians advisory board of the medical marijuana program for the state of Connecticut.
Systematic review and meta-analysis concluded more ‘high-quality studies’ needed
Systematic review and meta-analysis concluded more ‘high-quality studies’ needed
The results from Black et al. demonstrate that use of cannabinoids is unsupported for treating ADHD, PTSD, Tourette syndrome, psychosis, and depressive and anxiety disorders and symptoms, especially given that other approved medications for these conditions already exist, Deepak D’Souza, MBBS, MD, wrote in a related editorial.
“In light of the paucity of evidence, the absence of good quality evidence for efficacy, and the known risk of cannabinoids, their use as treatments for psychiatric disorders cannot be justified at present,” said Dr. D’Souza.
In addition, the conditions examined in the systematic review by Dr. Black, Dr. Stockings, and colleagues are distinct, and it is unclear how cannabinoids could treat these various conditions unless cannabinoids’ effects are similar to those of benzodiazepines, Dr. D’Souza noted. Another issue is that information on safety and efficacy of cannabinoids is also unknown, and factors such as optimal dosing, treatment duration, and tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio must also be established to begin trials. Finally, cannabinoids are also subject to tolerance issues with long-term exposure and would need to be considered for use with chronic psychiatric disorders.
“With cannabinoids, it seems that the cart (use) is before the horse (evidence),” Dr. D’Souza concluded. “If cannabinoids are to be used in the treatment of psychiatric disorders, they should first be tested in randomized controlled trials and subjected to the same regulatory approval process as other prescription medications.”
Dr. D’Souza is affiliated with the department of psychiatry at Yale University in New Haven, Conn. He reported receiving grants from the National Institutes of Health, Veterans Health Administration Office of Research and Development, Heffter Foundation, Wallace Foundation, and Takeda. He also reported serving on the physicians advisory board of the medical marijuana program for the state of Connecticut.
The results from Black et al. demonstrate that use of cannabinoids is unsupported for treating ADHD, PTSD, Tourette syndrome, psychosis, and depressive and anxiety disorders and symptoms, especially given that other approved medications for these conditions already exist, Deepak D’Souza, MBBS, MD, wrote in a related editorial.
“In light of the paucity of evidence, the absence of good quality evidence for efficacy, and the known risk of cannabinoids, their use as treatments for psychiatric disorders cannot be justified at present,” said Dr. D’Souza.
In addition, the conditions examined in the systematic review by Dr. Black, Dr. Stockings, and colleagues are distinct, and it is unclear how cannabinoids could treat these various conditions unless cannabinoids’ effects are similar to those of benzodiazepines, Dr. D’Souza noted. Another issue is that information on safety and efficacy of cannabinoids is also unknown, and factors such as optimal dosing, treatment duration, and tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio must also be established to begin trials. Finally, cannabinoids are also subject to tolerance issues with long-term exposure and would need to be considered for use with chronic psychiatric disorders.
“With cannabinoids, it seems that the cart (use) is before the horse (evidence),” Dr. D’Souza concluded. “If cannabinoids are to be used in the treatment of psychiatric disorders, they should first be tested in randomized controlled trials and subjected to the same regulatory approval process as other prescription medications.”
Dr. D’Souza is affiliated with the department of psychiatry at Yale University in New Haven, Conn. He reported receiving grants from the National Institutes of Health, Veterans Health Administration Office of Research and Development, Heffter Foundation, Wallace Foundation, and Takeda. He also reported serving on the physicians advisory board of the medical marijuana program for the state of Connecticut.
Scant evidence exists to recommend medical cannabinoids and derivatives such as tetrahydrocannabinol and cannabidiol to patients with depressive disorders, anxiety, or other mental disorders, suggested research in a recent systematic review and meta-analysis published in The Lancet Psychiatry.
In their review, Nicola Black, PhD, Emily Stockings, PhD,and colleagues performed a search of the MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Clinical Trials, and Cochrane Database of Systematic Reviews and identified 83 studies between January 1980 and April 2018 in which adult patients were treated with a medical cannabinoid for primary or secondary depression, anxiety, ADHD, Tourette syndrome, PTSD, or psychosis.
The researchers examined symptom changes, symptom remission, and the safety of medicinal cannabinoids in each study. Overall, there were 3,067 participants across the 83 studies, including 42 trials for depression, 31 trials for anxiety, 11 for psychosis, 8 for Tourette syndrome, 3 for ADHD, and 12 trials for PTSD. Of those, 23 were randomized controlled trials (RCTs) for depression (2,551 participants), 17 were RCTs for anxiety (605 participants), and six were RCTs for psychosis (281 participants). In addition, one RCT was for Tourette syndrome (36 participants), one RCT was for ADHD (30 participants), and one RCT was for PTSD (10 participants), reported Dr. Black and Dr. Stockings, both of the National Drug and Alcohol Research Centre (NDARC) at the University of New South Wales in Sydney and colleagues.
In patients with anxiety in seven RCTs (252 participants), there was a “very low” evidence assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach that pharmaceutical tetrahydrocannabinol (THC) with and without cannabidiol (CBD) in standardized mean differences in symptoms (SMD, –0.25; 95% confidence interval, –0.49 to –0.01); however, researchers noted that most patients in this study had other medical conditions, such as noncancer pain and multiple sclerosis, which might have affected results. Patients with psychosis in one study (24 participants) had significantly worse outcomes after use of pharmaceutical THC with and without CBD (SMD, 0.36; 95% CI, 0.10-0.62).
In 10 studies (1,495 participants), a pooled analysis across all mental disorders showed pharmaceutical THC with and without CBD did not improve the primary outcome and was associated with significantly increased adverse events, compared with placebo (odds ratio, 1.99; 95% CI, 1.20-3.29). It led to study withdrawal from adverse events (OR, 2.78; 95% CI, 1.59-4.86) in 11 studies (1,621 participants), compared with placebo. While there were not many RCTs that examined adverse events after use of pharmaceutical CBD or medicinal cannabis, the studies that did examine the association did not find an increased risk of adverse events or adverse events leading to study withdrawal, compared with placebo.
“Our findings have important implications in countries where cannabis and cannabinoids are being made available for medical use,” one of the authors, Louisa Degenhardt, PhD, said in a press release. “There is a notable absence of high-quality evidence to properly assess the effectiveness and safety of medicinal cannabinoids, compared with placebo, and until evidence from randomized, controlled trials is available, clinical guidelines cannot be drawn up around their use in mental health disorders.”
“In countries where medicinal cannabinoids are already legal, doctors and patients must be aware of the limitations of existing evidence and the risks of cannabinoids,” said Dr. Degenhardt, who also is with NDARC. “These must be weighed when considering use to treat symptoms of common mental health disorders. Those who decide to proceed should be carefully monitored for positive and negative mental health effects of using medicinal cannabinoids.”
Among the limitations cited by investigators were the small amount of medical data. More “high-quality studies” are needed, they wrote.
The study was supported in part by funding from the Health Products Regulation Group, research fellowship grants from the National Health and Medical Research Council, and a grant from the National Institutes of Health National Institute on Drug Abuse. Two authors reported serving as investigators for studies funded by Indivior, Reckitt Benckiser, Mundipharma, and Seqirus; another also reported being an investigator for studies funded by Indivior. The remaining authors reported no relevant conflicts of interest.
SOURCE: Black N et al. Lancet Psychiatry. 2019. doi: 10.1016/S2215-0355(19)30401-8.
Scant evidence exists to recommend medical cannabinoids and derivatives such as tetrahydrocannabinol and cannabidiol to patients with depressive disorders, anxiety, or other mental disorders, suggested research in a recent systematic review and meta-analysis published in The Lancet Psychiatry.
In their review, Nicola Black, PhD, Emily Stockings, PhD,and colleagues performed a search of the MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Clinical Trials, and Cochrane Database of Systematic Reviews and identified 83 studies between January 1980 and April 2018 in which adult patients were treated with a medical cannabinoid for primary or secondary depression, anxiety, ADHD, Tourette syndrome, PTSD, or psychosis.
The researchers examined symptom changes, symptom remission, and the safety of medicinal cannabinoids in each study. Overall, there were 3,067 participants across the 83 studies, including 42 trials for depression, 31 trials for anxiety, 11 for psychosis, 8 for Tourette syndrome, 3 for ADHD, and 12 trials for PTSD. Of those, 23 were randomized controlled trials (RCTs) for depression (2,551 participants), 17 were RCTs for anxiety (605 participants), and six were RCTs for psychosis (281 participants). In addition, one RCT was for Tourette syndrome (36 participants), one RCT was for ADHD (30 participants), and one RCT was for PTSD (10 participants), reported Dr. Black and Dr. Stockings, both of the National Drug and Alcohol Research Centre (NDARC) at the University of New South Wales in Sydney and colleagues.
In patients with anxiety in seven RCTs (252 participants), there was a “very low” evidence assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach that pharmaceutical tetrahydrocannabinol (THC) with and without cannabidiol (CBD) in standardized mean differences in symptoms (SMD, –0.25; 95% confidence interval, –0.49 to –0.01); however, researchers noted that most patients in this study had other medical conditions, such as noncancer pain and multiple sclerosis, which might have affected results. Patients with psychosis in one study (24 participants) had significantly worse outcomes after use of pharmaceutical THC with and without CBD (SMD, 0.36; 95% CI, 0.10-0.62).
In 10 studies (1,495 participants), a pooled analysis across all mental disorders showed pharmaceutical THC with and without CBD did not improve the primary outcome and was associated with significantly increased adverse events, compared with placebo (odds ratio, 1.99; 95% CI, 1.20-3.29). It led to study withdrawal from adverse events (OR, 2.78; 95% CI, 1.59-4.86) in 11 studies (1,621 participants), compared with placebo. While there were not many RCTs that examined adverse events after use of pharmaceutical CBD or medicinal cannabis, the studies that did examine the association did not find an increased risk of adverse events or adverse events leading to study withdrawal, compared with placebo.
“Our findings have important implications in countries where cannabis and cannabinoids are being made available for medical use,” one of the authors, Louisa Degenhardt, PhD, said in a press release. “There is a notable absence of high-quality evidence to properly assess the effectiveness and safety of medicinal cannabinoids, compared with placebo, and until evidence from randomized, controlled trials is available, clinical guidelines cannot be drawn up around their use in mental health disorders.”
“In countries where medicinal cannabinoids are already legal, doctors and patients must be aware of the limitations of existing evidence and the risks of cannabinoids,” said Dr. Degenhardt, who also is with NDARC. “These must be weighed when considering use to treat symptoms of common mental health disorders. Those who decide to proceed should be carefully monitored for positive and negative mental health effects of using medicinal cannabinoids.”
Among the limitations cited by investigators were the small amount of medical data. More “high-quality studies” are needed, they wrote.
The study was supported in part by funding from the Health Products Regulation Group, research fellowship grants from the National Health and Medical Research Council, and a grant from the National Institutes of Health National Institute on Drug Abuse. Two authors reported serving as investigators for studies funded by Indivior, Reckitt Benckiser, Mundipharma, and Seqirus; another also reported being an investigator for studies funded by Indivior. The remaining authors reported no relevant conflicts of interest.
SOURCE: Black N et al. Lancet Psychiatry. 2019. doi: 10.1016/S2215-0355(19)30401-8.
FROM THE LANCET PSYCHIATRY
Key clinical point: There is a low level of evidence to recommend use of medical cannabinoids or derivatives for the treatment of primary or secondary mental disorders.
Major finding: A pooled analysis across all mental disorders showed pharmaceutical tetrahydrocannabinol (THC) with and without cannabidiol (CBD) did not improve the primary outcome, and it was associated with significantly increased adverse events, compared with placebo (odds ratio, 1.99; 95% confidence interval, 1.20-3.29), and it led to study withdrawal because of adverse events (OR, 2.78; 95% CI, 1.59-4.86) in 11 studies (1,621 participants), compared with placebo.
Study details: A systematic review and meta-analysis of 83 trials with 3,067 participants who received medical cannabinoids or derivatives for treatment of primary or secondary mental disorders between January 1980 and April 2018.
Disclosures: Black N et al. Lancet Psychiatry. 2019 Oct 28. doi: 10.1016/S2215-0366(19)30401-8.
Source: This study was supported in part by funding from the Health Products Regulation Group, research fellowship grants from the National Health and Medical Research Council, and a grant from the National Institutes of Health National Institute on Drug Abuse. Two authors reported being investigators for studies funded by Indivior, Reckitt Benckiser, Mundipharma, and Seqirus; another author also reported being an investigator for studies funded by Indivior. The remaining authors reported no relevant conflicts of interest.
Edasalonexent may slow progression of Duchenne muscular dystrophy
CHARLOTTE, N.C. – presented at the annual meeting of the Child Neurology Society.
The NF-kB pathway is “fundamental to the pathogenesis and biology of DMD,” said Richard Finkel, MD, chief of neurology at Nemours Children’s Health System in Orlando and principal investigator for the phase 2 study, known as MoveDMD.
A lack of dystrophin, combined with the mechanical stress of muscle contraction, activates the NF-kB pathway and inhibits muscle regeneration. “It is known that there is inflammation and fibrosis and release of cytokines early in life” in patients with DMD, Dr. Finkel said.
Independent of mutation
Edasalonexent is an NF-kB inhibitor that is being developed by Catabasis as a therapy for patients with DMD regardless of the genetic mutation that is causing the disease. It may be used as monotherapy or with other dystrophin-targeted treatments, Dr. Finkel said.
In a mouse model of DMD, an analog of the drug reduced muscle inflammation and increased the force of diaphragm muscle. To assess edasalonexent’s safety, pharmacokinetics, and effects on functional measures and MRI in patients with DMD, Dr. Finkel and colleagues conducted the MoveDMD trial. Investigators enrolled boys aged 4 years to younger than 8 years who were not receiving treatment with corticosteroids.
Researchers first examined drug safety and pharmacokinetics in 17 boys who received the treatment for 1 week. The investigators then followed 16 of these patients off treatment for as long as 6 months. This off-treatment period was followed by a phase 2, placebo-controlled period, during which the 16 patients and another 15 patients received edasalonexent 67 mg/kg/day, edasalonexent 100 mg/kg/day, or placebo for 12 weeks. Patients subsequently entered an open-label extension study.
Dr. Finkel presented a comparison of outcomes during the off-treatment period with outcomes during the open-label extension. “We used these boys as their own internal control, if you wish,” he said.
Creatine kinase levels decreased soon after treatment, as did other markers of muscle disease. The drug “seems to have an early and sustained biomarker response,” Dr. Finkel said.
Annualized rate of change on lower leg muscle MRI-T2 decreased. “There is a relative reduction and stabilization from week 12 all the way out through the open-label extension to 72 weeks,” he said. “It suggests that there is an early and sustained response in stabilization of the MRI as a biomarker.”
Timed function tests
A comparison of the annualized rates of change on timed function tests – including the 10-meter walk/run, time-to-stand, and four-stair-climb, and the North Star Ambulatory Assessment – during the off-treatment and on-treatment periods indicated slowing of disease progression with treatment. “Shortly after starting on drug ... there was a relative stabilization in each of these measures,” Dr. Finkel said.
In addition, the researchers observed an early signal of possible cardiac benefit. Mean heart rate at baseline was 99 bpm. On treatment, it decreased to 92 bpm. “Boys with DMD die typically of cardiomyopathy, so it is important to try to address the cardiac status,” he said.
The drug was safe and well tolerated. Most participants experienced mild gastrointestinal issues, which typically were transient. One serious adverse event during the trial occurred in a patient receiving placebo. Patients tended to have a stable body mass index during treatment, Dr. Finkel said.
During the open-label extension, patients had “clinically meaningful slowing of disease progression on edasalonexent,” relative to the off-treatment period, Dr. Finkel said. Investigators plan to further study edasalonexent for the treatment of DMD in a phase 3 trial. The phase 3 study, PolarisDMD, recently completed enrollment at 40 sites. Results could be available in about a year, Dr. Finkel said.
The study was sponsored by Catabasis. Dr. Finkel disclosed consulting work and grants or research support from Catabasis and other companies.
SOURCE: Finkel R et al. CNS 2019. Abstract PL1-3.
CHARLOTTE, N.C. – presented at the annual meeting of the Child Neurology Society.
The NF-kB pathway is “fundamental to the pathogenesis and biology of DMD,” said Richard Finkel, MD, chief of neurology at Nemours Children’s Health System in Orlando and principal investigator for the phase 2 study, known as MoveDMD.
A lack of dystrophin, combined with the mechanical stress of muscle contraction, activates the NF-kB pathway and inhibits muscle regeneration. “It is known that there is inflammation and fibrosis and release of cytokines early in life” in patients with DMD, Dr. Finkel said.
Independent of mutation
Edasalonexent is an NF-kB inhibitor that is being developed by Catabasis as a therapy for patients with DMD regardless of the genetic mutation that is causing the disease. It may be used as monotherapy or with other dystrophin-targeted treatments, Dr. Finkel said.
In a mouse model of DMD, an analog of the drug reduced muscle inflammation and increased the force of diaphragm muscle. To assess edasalonexent’s safety, pharmacokinetics, and effects on functional measures and MRI in patients with DMD, Dr. Finkel and colleagues conducted the MoveDMD trial. Investigators enrolled boys aged 4 years to younger than 8 years who were not receiving treatment with corticosteroids.
Researchers first examined drug safety and pharmacokinetics in 17 boys who received the treatment for 1 week. The investigators then followed 16 of these patients off treatment for as long as 6 months. This off-treatment period was followed by a phase 2, placebo-controlled period, during which the 16 patients and another 15 patients received edasalonexent 67 mg/kg/day, edasalonexent 100 mg/kg/day, or placebo for 12 weeks. Patients subsequently entered an open-label extension study.
Dr. Finkel presented a comparison of outcomes during the off-treatment period with outcomes during the open-label extension. “We used these boys as their own internal control, if you wish,” he said.
Creatine kinase levels decreased soon after treatment, as did other markers of muscle disease. The drug “seems to have an early and sustained biomarker response,” Dr. Finkel said.
Annualized rate of change on lower leg muscle MRI-T2 decreased. “There is a relative reduction and stabilization from week 12 all the way out through the open-label extension to 72 weeks,” he said. “It suggests that there is an early and sustained response in stabilization of the MRI as a biomarker.”
Timed function tests
A comparison of the annualized rates of change on timed function tests – including the 10-meter walk/run, time-to-stand, and four-stair-climb, and the North Star Ambulatory Assessment – during the off-treatment and on-treatment periods indicated slowing of disease progression with treatment. “Shortly after starting on drug ... there was a relative stabilization in each of these measures,” Dr. Finkel said.
In addition, the researchers observed an early signal of possible cardiac benefit. Mean heart rate at baseline was 99 bpm. On treatment, it decreased to 92 bpm. “Boys with DMD die typically of cardiomyopathy, so it is important to try to address the cardiac status,” he said.
The drug was safe and well tolerated. Most participants experienced mild gastrointestinal issues, which typically were transient. One serious adverse event during the trial occurred in a patient receiving placebo. Patients tended to have a stable body mass index during treatment, Dr. Finkel said.
During the open-label extension, patients had “clinically meaningful slowing of disease progression on edasalonexent,” relative to the off-treatment period, Dr. Finkel said. Investigators plan to further study edasalonexent for the treatment of DMD in a phase 3 trial. The phase 3 study, PolarisDMD, recently completed enrollment at 40 sites. Results could be available in about a year, Dr. Finkel said.
The study was sponsored by Catabasis. Dr. Finkel disclosed consulting work and grants or research support from Catabasis and other companies.
SOURCE: Finkel R et al. CNS 2019. Abstract PL1-3.
CHARLOTTE, N.C. – presented at the annual meeting of the Child Neurology Society.
The NF-kB pathway is “fundamental to the pathogenesis and biology of DMD,” said Richard Finkel, MD, chief of neurology at Nemours Children’s Health System in Orlando and principal investigator for the phase 2 study, known as MoveDMD.
A lack of dystrophin, combined with the mechanical stress of muscle contraction, activates the NF-kB pathway and inhibits muscle regeneration. “It is known that there is inflammation and fibrosis and release of cytokines early in life” in patients with DMD, Dr. Finkel said.
Independent of mutation
Edasalonexent is an NF-kB inhibitor that is being developed by Catabasis as a therapy for patients with DMD regardless of the genetic mutation that is causing the disease. It may be used as monotherapy or with other dystrophin-targeted treatments, Dr. Finkel said.
In a mouse model of DMD, an analog of the drug reduced muscle inflammation and increased the force of diaphragm muscle. To assess edasalonexent’s safety, pharmacokinetics, and effects on functional measures and MRI in patients with DMD, Dr. Finkel and colleagues conducted the MoveDMD trial. Investigators enrolled boys aged 4 years to younger than 8 years who were not receiving treatment with corticosteroids.
Researchers first examined drug safety and pharmacokinetics in 17 boys who received the treatment for 1 week. The investigators then followed 16 of these patients off treatment for as long as 6 months. This off-treatment period was followed by a phase 2, placebo-controlled period, during which the 16 patients and another 15 patients received edasalonexent 67 mg/kg/day, edasalonexent 100 mg/kg/day, or placebo for 12 weeks. Patients subsequently entered an open-label extension study.
Dr. Finkel presented a comparison of outcomes during the off-treatment period with outcomes during the open-label extension. “We used these boys as their own internal control, if you wish,” he said.
Creatine kinase levels decreased soon after treatment, as did other markers of muscle disease. The drug “seems to have an early and sustained biomarker response,” Dr. Finkel said.
Annualized rate of change on lower leg muscle MRI-T2 decreased. “There is a relative reduction and stabilization from week 12 all the way out through the open-label extension to 72 weeks,” he said. “It suggests that there is an early and sustained response in stabilization of the MRI as a biomarker.”
Timed function tests
A comparison of the annualized rates of change on timed function tests – including the 10-meter walk/run, time-to-stand, and four-stair-climb, and the North Star Ambulatory Assessment – during the off-treatment and on-treatment periods indicated slowing of disease progression with treatment. “Shortly after starting on drug ... there was a relative stabilization in each of these measures,” Dr. Finkel said.
In addition, the researchers observed an early signal of possible cardiac benefit. Mean heart rate at baseline was 99 bpm. On treatment, it decreased to 92 bpm. “Boys with DMD die typically of cardiomyopathy, so it is important to try to address the cardiac status,” he said.
The drug was safe and well tolerated. Most participants experienced mild gastrointestinal issues, which typically were transient. One serious adverse event during the trial occurred in a patient receiving placebo. Patients tended to have a stable body mass index during treatment, Dr. Finkel said.
During the open-label extension, patients had “clinically meaningful slowing of disease progression on edasalonexent,” relative to the off-treatment period, Dr. Finkel said. Investigators plan to further study edasalonexent for the treatment of DMD in a phase 3 trial. The phase 3 study, PolarisDMD, recently completed enrollment at 40 sites. Results could be available in about a year, Dr. Finkel said.
The study was sponsored by Catabasis. Dr. Finkel disclosed consulting work and grants or research support from Catabasis and other companies.
SOURCE: Finkel R et al. CNS 2019. Abstract PL1-3.
REPORTING FROM CNS 2019
SUSTAIN 10: Weight loss, glycemic control better with semaglutide than liraglutide
BARCELONA – Patients with type 2 diabetes who were treated with semaglutide achieved greater reductions in glycated hemoglobin (HbA1c) levels and body weight, compared with those receiving liraglutide, according to results presented at the annual meeting of the European Association for the Study of Diabetes.
In the phase 3b SUSTAIN 10 trial, conducted in 11 European countries, mean glycated hemoglobin at 30 weeks decreased by 1.7% with once-weekly semaglutide and 1.0% for once-daily liraglutide, from the overall baseline level of 8.2%. The estimated treatment difference (ETD) between the two treatments was –0.69 percentage points (95% confidence interval, –0.82 to –0.56; P less than .0001).
Mean body weight decreased during the same period by 5.8 kg with semaglutide and 1.9 kg with liraglutide, from a baseline of 96.9 kg. The ETD was 3.83 kg (95% CI, –4.57 to –3.09; P less than .0001).
The doses of semaglutide and liraglutide used in the study were 1.0 mg and 1.2 mg, respectively, the latter being the dose that is used most commonly in clinical practice, study investigator Matthew Capehorn, MB, CAB, explained in an interview at the meeting.
“We know that at a dose of 1.8 mg, liraglutide is more effective than 1.2 mg, but it’s about whether it is deemed more cost effective,” said Dr. Capehorn, who is clinical manager at Rotherham (England) Institute for Obesity, Clifton Medical Centre. “Certainly, in the United Kingdom, we’re encouraged to use the 1.2-mg dose” according to guidance from the National Institute for Heath and Care Excellence, and “other European countries are the same.”
Dr. Capehorn noted that studies are being done with a higher dose of semaglutide to see if it has potential as a weight loss drug in its own right in patients who do not have type 2 diabetes. “I care as much about obesity and cardiovascular disease as I do about chasing the HbA1c level and getting that reduced, so I would rather pick an agent that covers all three [components], than just looking at the HbA1c,” he said.
In SUSTAIN 10,577 adults with type 2 diabetes and an HbA1c level of between 7.0% and 11.0% who were on stable doses of one to three oral antidiabetic drugs were randomized to receive semaglutide (n = 290) or liraglutide (n = 287) for 30 weeks.
The primary endpoint was the change in HbA1c from baseline to week 30, and the secondary confirmatory endpoint was change in body weight over the same period.
In presenting the findings, which were simultaneously published in Diabetes & Metabolism, Dr. Capehorn noted that the efficacy results were consistent with those of other SUSTAIN trials that compared semaglutide with other glucagonlike peptide–1 receptor antagonists, notably SUSTAIN 3 (with exenatide extended release) and SUSTAIN 7 (with dulaglutide).
Other efficacy findings from SUSTAIN 10 were that semaglutide produced greater mean changes than did liraglutide in both fasting plasma glucose and in a 7-point, self-monitoring of blood glucose profile.
A greater percentage of people treated with semaglutide, compared with liraglutide, also achieved their glycemic targets of less than 7.0% (80% vs. 46%, respectively) and of 6.5% or less (58% vs. 25%), and their weight loss targets of 5% or more (56% vs. 18%) and 10% or more (19% vs. 4%).
In addition, more semaglutide- than liraglutide-treated patients achieved an HbA1c target of less than 7.0% without severe or blood glucose–confirmed symptomatic hypoglycemia, with or without weight gain (76% vs. 37%; P less than .0001). There were also more semaglutide patients who achieved an HbA1c reduction of 1% or more and a weight loss reduction of 10% or more (17% vs. 4% for liraglutide, P less than .0001).
The safety profiles were similar for semaglutide and liraglutide, Dr. Capehorn noted, but gastrointestinal adverse events were more prevalent in patients receiving semaglutide, compared with liraglutide (43.9% vs. 38.3%), and more patients receiving semaglutide discontinued treatment prematurely because of those adverse events (11.4% vs. 6.6% for liraglutide).
Novo Nordisk sponsored the study. Dr. Capehorn reported receiving research funding from, providing advisory board support to, and speaker fees from Novo Nordisk and from several other companies.
SOURCE: Capehorn M et al. EASD 2019, Oral Presentation 53; Capehorn M et al. Diabetes Metab. 2019 Sep 17. doi: 10.1016/j.diabet.2019.101117.
BARCELONA – Patients with type 2 diabetes who were treated with semaglutide achieved greater reductions in glycated hemoglobin (HbA1c) levels and body weight, compared with those receiving liraglutide, according to results presented at the annual meeting of the European Association for the Study of Diabetes.
In the phase 3b SUSTAIN 10 trial, conducted in 11 European countries, mean glycated hemoglobin at 30 weeks decreased by 1.7% with once-weekly semaglutide and 1.0% for once-daily liraglutide, from the overall baseline level of 8.2%. The estimated treatment difference (ETD) between the two treatments was –0.69 percentage points (95% confidence interval, –0.82 to –0.56; P less than .0001).
Mean body weight decreased during the same period by 5.8 kg with semaglutide and 1.9 kg with liraglutide, from a baseline of 96.9 kg. The ETD was 3.83 kg (95% CI, –4.57 to –3.09; P less than .0001).
The doses of semaglutide and liraglutide used in the study were 1.0 mg and 1.2 mg, respectively, the latter being the dose that is used most commonly in clinical practice, study investigator Matthew Capehorn, MB, CAB, explained in an interview at the meeting.
“We know that at a dose of 1.8 mg, liraglutide is more effective than 1.2 mg, but it’s about whether it is deemed more cost effective,” said Dr. Capehorn, who is clinical manager at Rotherham (England) Institute for Obesity, Clifton Medical Centre. “Certainly, in the United Kingdom, we’re encouraged to use the 1.2-mg dose” according to guidance from the National Institute for Heath and Care Excellence, and “other European countries are the same.”
Dr. Capehorn noted that studies are being done with a higher dose of semaglutide to see if it has potential as a weight loss drug in its own right in patients who do not have type 2 diabetes. “I care as much about obesity and cardiovascular disease as I do about chasing the HbA1c level and getting that reduced, so I would rather pick an agent that covers all three [components], than just looking at the HbA1c,” he said.
In SUSTAIN 10,577 adults with type 2 diabetes and an HbA1c level of between 7.0% and 11.0% who were on stable doses of one to three oral antidiabetic drugs were randomized to receive semaglutide (n = 290) or liraglutide (n = 287) for 30 weeks.
The primary endpoint was the change in HbA1c from baseline to week 30, and the secondary confirmatory endpoint was change in body weight over the same period.
In presenting the findings, which were simultaneously published in Diabetes & Metabolism, Dr. Capehorn noted that the efficacy results were consistent with those of other SUSTAIN trials that compared semaglutide with other glucagonlike peptide–1 receptor antagonists, notably SUSTAIN 3 (with exenatide extended release) and SUSTAIN 7 (with dulaglutide).
Other efficacy findings from SUSTAIN 10 were that semaglutide produced greater mean changes than did liraglutide in both fasting plasma glucose and in a 7-point, self-monitoring of blood glucose profile.
A greater percentage of people treated with semaglutide, compared with liraglutide, also achieved their glycemic targets of less than 7.0% (80% vs. 46%, respectively) and of 6.5% or less (58% vs. 25%), and their weight loss targets of 5% or more (56% vs. 18%) and 10% or more (19% vs. 4%).
In addition, more semaglutide- than liraglutide-treated patients achieved an HbA1c target of less than 7.0% without severe or blood glucose–confirmed symptomatic hypoglycemia, with or without weight gain (76% vs. 37%; P less than .0001). There were also more semaglutide patients who achieved an HbA1c reduction of 1% or more and a weight loss reduction of 10% or more (17% vs. 4% for liraglutide, P less than .0001).
The safety profiles were similar for semaglutide and liraglutide, Dr. Capehorn noted, but gastrointestinal adverse events were more prevalent in patients receiving semaglutide, compared with liraglutide (43.9% vs. 38.3%), and more patients receiving semaglutide discontinued treatment prematurely because of those adverse events (11.4% vs. 6.6% for liraglutide).
Novo Nordisk sponsored the study. Dr. Capehorn reported receiving research funding from, providing advisory board support to, and speaker fees from Novo Nordisk and from several other companies.
SOURCE: Capehorn M et al. EASD 2019, Oral Presentation 53; Capehorn M et al. Diabetes Metab. 2019 Sep 17. doi: 10.1016/j.diabet.2019.101117.
BARCELONA – Patients with type 2 diabetes who were treated with semaglutide achieved greater reductions in glycated hemoglobin (HbA1c) levels and body weight, compared with those receiving liraglutide, according to results presented at the annual meeting of the European Association for the Study of Diabetes.
In the phase 3b SUSTAIN 10 trial, conducted in 11 European countries, mean glycated hemoglobin at 30 weeks decreased by 1.7% with once-weekly semaglutide and 1.0% for once-daily liraglutide, from the overall baseline level of 8.2%. The estimated treatment difference (ETD) between the two treatments was –0.69 percentage points (95% confidence interval, –0.82 to –0.56; P less than .0001).
Mean body weight decreased during the same period by 5.8 kg with semaglutide and 1.9 kg with liraglutide, from a baseline of 96.9 kg. The ETD was 3.83 kg (95% CI, –4.57 to –3.09; P less than .0001).
The doses of semaglutide and liraglutide used in the study were 1.0 mg and 1.2 mg, respectively, the latter being the dose that is used most commonly in clinical practice, study investigator Matthew Capehorn, MB, CAB, explained in an interview at the meeting.
“We know that at a dose of 1.8 mg, liraglutide is more effective than 1.2 mg, but it’s about whether it is deemed more cost effective,” said Dr. Capehorn, who is clinical manager at Rotherham (England) Institute for Obesity, Clifton Medical Centre. “Certainly, in the United Kingdom, we’re encouraged to use the 1.2-mg dose” according to guidance from the National Institute for Heath and Care Excellence, and “other European countries are the same.”
Dr. Capehorn noted that studies are being done with a higher dose of semaglutide to see if it has potential as a weight loss drug in its own right in patients who do not have type 2 diabetes. “I care as much about obesity and cardiovascular disease as I do about chasing the HbA1c level and getting that reduced, so I would rather pick an agent that covers all three [components], than just looking at the HbA1c,” he said.
In SUSTAIN 10,577 adults with type 2 diabetes and an HbA1c level of between 7.0% and 11.0% who were on stable doses of one to three oral antidiabetic drugs were randomized to receive semaglutide (n = 290) or liraglutide (n = 287) for 30 weeks.
The primary endpoint was the change in HbA1c from baseline to week 30, and the secondary confirmatory endpoint was change in body weight over the same period.
In presenting the findings, which were simultaneously published in Diabetes & Metabolism, Dr. Capehorn noted that the efficacy results were consistent with those of other SUSTAIN trials that compared semaglutide with other glucagonlike peptide–1 receptor antagonists, notably SUSTAIN 3 (with exenatide extended release) and SUSTAIN 7 (with dulaglutide).
Other efficacy findings from SUSTAIN 10 were that semaglutide produced greater mean changes than did liraglutide in both fasting plasma glucose and in a 7-point, self-monitoring of blood glucose profile.
A greater percentage of people treated with semaglutide, compared with liraglutide, also achieved their glycemic targets of less than 7.0% (80% vs. 46%, respectively) and of 6.5% or less (58% vs. 25%), and their weight loss targets of 5% or more (56% vs. 18%) and 10% or more (19% vs. 4%).
In addition, more semaglutide- than liraglutide-treated patients achieved an HbA1c target of less than 7.0% without severe or blood glucose–confirmed symptomatic hypoglycemia, with or without weight gain (76% vs. 37%; P less than .0001). There were also more semaglutide patients who achieved an HbA1c reduction of 1% or more and a weight loss reduction of 10% or more (17% vs. 4% for liraglutide, P less than .0001).
The safety profiles were similar for semaglutide and liraglutide, Dr. Capehorn noted, but gastrointestinal adverse events were more prevalent in patients receiving semaglutide, compared with liraglutide (43.9% vs. 38.3%), and more patients receiving semaglutide discontinued treatment prematurely because of those adverse events (11.4% vs. 6.6% for liraglutide).
Novo Nordisk sponsored the study. Dr. Capehorn reported receiving research funding from, providing advisory board support to, and speaker fees from Novo Nordisk and from several other companies.
SOURCE: Capehorn M et al. EASD 2019, Oral Presentation 53; Capehorn M et al. Diabetes Metab. 2019 Sep 17. doi: 10.1016/j.diabet.2019.101117.
REPORTING FROM EASD 2019
Blood test might rival PET scan for detecting brain amyloidosis
ST. LOUIS – according to a report at the annual meeting of the American Neurological Association. The research was also published in Neurology (2019 Oct 22;93[17]:e1647-59).
Investigators at Washington University, St. Louis, found that, among 158 mostly cognitively normal people in their 60s and 70s, the plasma ratio of amyloid-beta 42 peptide to amyloid-beta 40 peptide identified people who were PET positive and PET negative for amyloid with an area under the curve of 0.88 (95% confidence interval, 0.82-0.93) and climbed to 0.94 when combined with age and Apolipoprotein E epsilon 4 status (95% CI, 0.90-0.97), “which is really quite spectacular for a blood test,” said study lead Suzanne Schindler, MD, PhD, who is affiliated with the university.
People who had a positive blood test – a ratio below .1281 – but a negative PET scan were 15 times more likely to convert to a positive scan at an average of 4 years than subjects with a negative test. “The blood test [detected] brain changes of Alzheimer’s disease before the amyloid PET scan,” Dr. Schindler said.
Amyloid-beta 42 – the number refers to how many amino acids are in the peptide chain – is much stickier and more prone to aggregate in plaques than amyloid-beta 40. The ratio of the two falls as the 42 form is sequestered preferentially into amyloid plaques while the level of amyloid-beta 40 remains more constant, she explained at the meeting.
The team concluded that the test accurately “predicts current and future brain amyloidosis” and “could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.”
“We are really excited about it. I think there’s been recognition for a long time that a blood test would really be a game changer. We still have a little bit more work to do, but I don’t think it’s that far away,” Dr. Schindler said in an interview after her presentation.
The goal of Alzheimer’s research is to slow, reverse, or even prevent brain pathology before symptoms set in, at which point damage is likely irreversible. For that to happen, plaques need to be detected early.
Currently there are two ways to do that, both with difficulties: PET scans, which are expensive, expose people to radiation, and of limited availability, and spinal fluid analysis, which involves a lumbar puncture that “not many people want to undergo.” The problems slow down enrollment for prevention trials, Dr. Schindler said.
The blood test, which the Food and Drug Administration granted breakthrough status in January 2019, could offer a much easier and less expensive way to identify subjects and monitor outcomes. It could “really speed up enrollment and help us get to effective drugs faster,” she said.
Beyond that, clinicians could use it to help figure out what’s going on in older people with cognitive issues. If a drug or some other way is ever found to prevent Alzheimer’s, there’s even the possibility of screening patients for amyloidosis during routine exams. Potentially, “I think the market is huge,” she said.
The test is being developed by a company, C2N diagnostics, founded by Dr. Schindler’s colleagues at the university, and could be available commercially in 2-3 years. It involves high precision immunoprecipitation and liquid chromatography/mass spectrometry, so “it isn’t something your general lab is going to do. It’s probably going to be a couple centers that have this test, and everybody mails their samples in, which we do for a lot of different tests,” she said.
Several companies are working on similar assays.
Dr. Schindler said she has no financial stake in the blood test.
SOURCE: Schindler S et al. Neurology. 2019 Oct 22;93(17):e1647-59.
ST. LOUIS – according to a report at the annual meeting of the American Neurological Association. The research was also published in Neurology (2019 Oct 22;93[17]:e1647-59).
Investigators at Washington University, St. Louis, found that, among 158 mostly cognitively normal people in their 60s and 70s, the plasma ratio of amyloid-beta 42 peptide to amyloid-beta 40 peptide identified people who were PET positive and PET negative for amyloid with an area under the curve of 0.88 (95% confidence interval, 0.82-0.93) and climbed to 0.94 when combined with age and Apolipoprotein E epsilon 4 status (95% CI, 0.90-0.97), “which is really quite spectacular for a blood test,” said study lead Suzanne Schindler, MD, PhD, who is affiliated with the university.
People who had a positive blood test – a ratio below .1281 – but a negative PET scan were 15 times more likely to convert to a positive scan at an average of 4 years than subjects with a negative test. “The blood test [detected] brain changes of Alzheimer’s disease before the amyloid PET scan,” Dr. Schindler said.
Amyloid-beta 42 – the number refers to how many amino acids are in the peptide chain – is much stickier and more prone to aggregate in plaques than amyloid-beta 40. The ratio of the two falls as the 42 form is sequestered preferentially into amyloid plaques while the level of amyloid-beta 40 remains more constant, she explained at the meeting.
The team concluded that the test accurately “predicts current and future brain amyloidosis” and “could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.”
“We are really excited about it. I think there’s been recognition for a long time that a blood test would really be a game changer. We still have a little bit more work to do, but I don’t think it’s that far away,” Dr. Schindler said in an interview after her presentation.
The goal of Alzheimer’s research is to slow, reverse, or even prevent brain pathology before symptoms set in, at which point damage is likely irreversible. For that to happen, plaques need to be detected early.
Currently there are two ways to do that, both with difficulties: PET scans, which are expensive, expose people to radiation, and of limited availability, and spinal fluid analysis, which involves a lumbar puncture that “not many people want to undergo.” The problems slow down enrollment for prevention trials, Dr. Schindler said.
The blood test, which the Food and Drug Administration granted breakthrough status in January 2019, could offer a much easier and less expensive way to identify subjects and monitor outcomes. It could “really speed up enrollment and help us get to effective drugs faster,” she said.
Beyond that, clinicians could use it to help figure out what’s going on in older people with cognitive issues. If a drug or some other way is ever found to prevent Alzheimer’s, there’s even the possibility of screening patients for amyloidosis during routine exams. Potentially, “I think the market is huge,” she said.
The test is being developed by a company, C2N diagnostics, founded by Dr. Schindler’s colleagues at the university, and could be available commercially in 2-3 years. It involves high precision immunoprecipitation and liquid chromatography/mass spectrometry, so “it isn’t something your general lab is going to do. It’s probably going to be a couple centers that have this test, and everybody mails their samples in, which we do for a lot of different tests,” she said.
Several companies are working on similar assays.
Dr. Schindler said she has no financial stake in the blood test.
SOURCE: Schindler S et al. Neurology. 2019 Oct 22;93(17):e1647-59.
ST. LOUIS – according to a report at the annual meeting of the American Neurological Association. The research was also published in Neurology (2019 Oct 22;93[17]:e1647-59).
Investigators at Washington University, St. Louis, found that, among 158 mostly cognitively normal people in their 60s and 70s, the plasma ratio of amyloid-beta 42 peptide to amyloid-beta 40 peptide identified people who were PET positive and PET negative for amyloid with an area under the curve of 0.88 (95% confidence interval, 0.82-0.93) and climbed to 0.94 when combined with age and Apolipoprotein E epsilon 4 status (95% CI, 0.90-0.97), “which is really quite spectacular for a blood test,” said study lead Suzanne Schindler, MD, PhD, who is affiliated with the university.
People who had a positive blood test – a ratio below .1281 – but a negative PET scan were 15 times more likely to convert to a positive scan at an average of 4 years than subjects with a negative test. “The blood test [detected] brain changes of Alzheimer’s disease before the amyloid PET scan,” Dr. Schindler said.
Amyloid-beta 42 – the number refers to how many amino acids are in the peptide chain – is much stickier and more prone to aggregate in plaques than amyloid-beta 40. The ratio of the two falls as the 42 form is sequestered preferentially into amyloid plaques while the level of amyloid-beta 40 remains more constant, she explained at the meeting.
The team concluded that the test accurately “predicts current and future brain amyloidosis” and “could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.”
“We are really excited about it. I think there’s been recognition for a long time that a blood test would really be a game changer. We still have a little bit more work to do, but I don’t think it’s that far away,” Dr. Schindler said in an interview after her presentation.
The goal of Alzheimer’s research is to slow, reverse, or even prevent brain pathology before symptoms set in, at which point damage is likely irreversible. For that to happen, plaques need to be detected early.
Currently there are two ways to do that, both with difficulties: PET scans, which are expensive, expose people to radiation, and of limited availability, and spinal fluid analysis, which involves a lumbar puncture that “not many people want to undergo.” The problems slow down enrollment for prevention trials, Dr. Schindler said.
The blood test, which the Food and Drug Administration granted breakthrough status in January 2019, could offer a much easier and less expensive way to identify subjects and monitor outcomes. It could “really speed up enrollment and help us get to effective drugs faster,” she said.
Beyond that, clinicians could use it to help figure out what’s going on in older people with cognitive issues. If a drug or some other way is ever found to prevent Alzheimer’s, there’s even the possibility of screening patients for amyloidosis during routine exams. Potentially, “I think the market is huge,” she said.
The test is being developed by a company, C2N diagnostics, founded by Dr. Schindler’s colleagues at the university, and could be available commercially in 2-3 years. It involves high precision immunoprecipitation and liquid chromatography/mass spectrometry, so “it isn’t something your general lab is going to do. It’s probably going to be a couple centers that have this test, and everybody mails their samples in, which we do for a lot of different tests,” she said.
Several companies are working on similar assays.
Dr. Schindler said she has no financial stake in the blood test.
SOURCE: Schindler S et al. Neurology. 2019 Oct 22;93(17):e1647-59.
REPORTING FROM ANA 2019
MMS linked with better survival in early-stage melanoma
according to a retrospective cohort study.
In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.
“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.
The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.
In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.
After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).
“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.
The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.
“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.
While controversial historically, evidence showing benefit for Mohs micrographic surgery (MMS) in patients with melanoma has been reported. The findings from the current study add to the body of retrospective data suggesting improved survival for those with early-stage disease.
The survival benefit found by Cheraghlou et al., “although relatively novel,” is not surprising. Previous population-based and database studies have demonstrated a nonsignificant trend toward a survival advantage in patients with early-stage melanoma. In addition, no survival disadvantages have been reported in any other stage of malignancy.
The primary advantage of MMS is the ability of the surgery to allow for full tumor resection. Reducing the likelihood of recurrence and ensuring local control is maximized remain key strategies to ensuring survival in patients with melanoma.
Database studies have limitations, and care should be taken not to overinterpret the results of a study with two groups of patients that are disproportionate in size. As the authors of the study note, their results support the need for prospective studies to compare surgical melanoma treatments. And until those studies can be done, “the weight of existing evidence suggests that MMS is a safe and effective treatment for melanoma.”
These comments are adapted from an accompanying editorial (JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2622) by Ian Maher, MD, professor and director of dermatologic surgery at the University of Minnesota, Minneapolis. He reported having no conflicts of interest.
While controversial historically, evidence showing benefit for Mohs micrographic surgery (MMS) in patients with melanoma has been reported. The findings from the current study add to the body of retrospective data suggesting improved survival for those with early-stage disease.
The survival benefit found by Cheraghlou et al., “although relatively novel,” is not surprising. Previous population-based and database studies have demonstrated a nonsignificant trend toward a survival advantage in patients with early-stage melanoma. In addition, no survival disadvantages have been reported in any other stage of malignancy.
The primary advantage of MMS is the ability of the surgery to allow for full tumor resection. Reducing the likelihood of recurrence and ensuring local control is maximized remain key strategies to ensuring survival in patients with melanoma.
Database studies have limitations, and care should be taken not to overinterpret the results of a study with two groups of patients that are disproportionate in size. As the authors of the study note, their results support the need for prospective studies to compare surgical melanoma treatments. And until those studies can be done, “the weight of existing evidence suggests that MMS is a safe and effective treatment for melanoma.”
These comments are adapted from an accompanying editorial (JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2622) by Ian Maher, MD, professor and director of dermatologic surgery at the University of Minnesota, Minneapolis. He reported having no conflicts of interest.
While controversial historically, evidence showing benefit for Mohs micrographic surgery (MMS) in patients with melanoma has been reported. The findings from the current study add to the body of retrospective data suggesting improved survival for those with early-stage disease.
The survival benefit found by Cheraghlou et al., “although relatively novel,” is not surprising. Previous population-based and database studies have demonstrated a nonsignificant trend toward a survival advantage in patients with early-stage melanoma. In addition, no survival disadvantages have been reported in any other stage of malignancy.
The primary advantage of MMS is the ability of the surgery to allow for full tumor resection. Reducing the likelihood of recurrence and ensuring local control is maximized remain key strategies to ensuring survival in patients with melanoma.
Database studies have limitations, and care should be taken not to overinterpret the results of a study with two groups of patients that are disproportionate in size. As the authors of the study note, their results support the need for prospective studies to compare surgical melanoma treatments. And until those studies can be done, “the weight of existing evidence suggests that MMS is a safe and effective treatment for melanoma.”
These comments are adapted from an accompanying editorial (JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2622) by Ian Maher, MD, professor and director of dermatologic surgery at the University of Minnesota, Minneapolis. He reported having no conflicts of interest.
according to a retrospective cohort study.
In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.
“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.
The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.
In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.
After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).
“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.
The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.
“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.
according to a retrospective cohort study.
In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.
“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.
The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.
In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.
After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).
“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.
The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.
“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.
FROM JAMA DERMATOLOGY
Severe hypoglycemia, poor glycemic control fuels fracture risk in older diabetic patients
Patients with type 2 diabetes and poor glycemic control or severe hypoglycemia may be at greater risk for fracture, according to recent research from a Japanese cohort of older men and postmenopausal women.
“The impacts of severe hypoglycemia and poor glycemic control on fractures appeared to be independent,” noted Yuji Komorita, MD, PhD, of the department of medicine and clinical science, Graduate School of Medical Sciences at Kyushu University, and colleagues. “This study suggests that the glycemic target to prevent fractures may be HbA1c <75 mmol/mol, which is far higher than that used to prevent microvascular complications, and higher than that for older adults with type 2 diabetes.”
Dr. Komorita and colleagues performed a prospective analysis of fracture incidence for 2,755 men and 1,951 postmenopausal women with type 2 diabetes in the Fukuoka Diabetes Registry who were mean 66 years old between April 2008 and October 2010. At the start of the study, the researchers assessed patient diabetes duration, previous fracture history, physical activity, alcohol and smoking status, whether patients were treated for diabetic retinopathy with laser photocoagulation, and their history of coronary artery disease or stroke. Patients were followed for a median 5.3 years, during which fractures were assessed through an annual self-administered questionnaire, with the results stratified by glycemic control and hypoglycemia.
Overall, there were 249 men and 413 women who experienced fractures during the study period, with a follow-up rate of 97.6%. In a multivariate analysis, patients with a higher risk of fracture included those with two or more episodes of severe hypoglycemia (hazard ratio, 2.25; 95% confidence interval, 1.57-3.22) and one episode of severe hypoglycemia (HR, 1.57; 95% CI, 1.11-2.20). In patients without severe hypoglycemic episodes, there was an increased risk of fracture in those with baseline hemoglobin A1c (HbA1c) level of 53 to less than 64 mmol/mol (7% to less than 8%; HR, 1.14; 0.94-1.39), 64 to less than 75 mmol/mol (8% to less than 9%; HR, 1.11; 95% CI, 0.86-1.43), and at least 75 mmol/mol (at least 9%; HR, 1.45; 95% CI, 1.06-1.98).
Compared with postmenopausal women, the unadjusted risk of fracture was higher in men with multiple severe hypoglycemic episodes (HR, 3.46; 95% CI, 2.05-5.85) and one episode of hypoglycemia (HR, 2.81; 95% CI, 1.74-4.56). These higher risks in older men persisted after adjustment for age, multivariate factors, and HbA1c.
“The association between severe hypoglycemia, poor glycemic control, and fracture risk at any anatomic site seems to be stronger in men than in postmenopausal women, although the interaction between men and postmenopausal women for fracture risk was not significant,” the researchers said. “The higher incidence rate of fractures in postmenopausal women, compared with men, was attributed to drastic changes in sex hormones after menopause, which may reduce the apparent impacts of hyperglycemia and severe hypoglycemia on postmenopausal women.”
Researchers said they did not consider potential external factors for fracture incidence, nor did they measure incident falls or other markers of bone health, such as bone mineral density and 25-hydroxyvitamin D levels. They also noted among the limitations of the study the self-reported nature of fracture reporting, and the lack of generalizability of the results.
This study was funded in part by grants from The Japan Society for the Promotion of Science KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Junior Scientist Development Grant supported by the Japan Diabetes Society; and the Lilly Research Grant Program for Bone & Mineral Research. The authors reported no relevant conflicts of interest.
SOURCE: Komorita Y et al. Diabet Med. 2019 Sep 25. doi: 10.1111/dme.14142.
Patients with type 2 diabetes and poor glycemic control or severe hypoglycemia may be at greater risk for fracture, according to recent research from a Japanese cohort of older men and postmenopausal women.
“The impacts of severe hypoglycemia and poor glycemic control on fractures appeared to be independent,” noted Yuji Komorita, MD, PhD, of the department of medicine and clinical science, Graduate School of Medical Sciences at Kyushu University, and colleagues. “This study suggests that the glycemic target to prevent fractures may be HbA1c <75 mmol/mol, which is far higher than that used to prevent microvascular complications, and higher than that for older adults with type 2 diabetes.”
Dr. Komorita and colleagues performed a prospective analysis of fracture incidence for 2,755 men and 1,951 postmenopausal women with type 2 diabetes in the Fukuoka Diabetes Registry who were mean 66 years old between April 2008 and October 2010. At the start of the study, the researchers assessed patient diabetes duration, previous fracture history, physical activity, alcohol and smoking status, whether patients were treated for diabetic retinopathy with laser photocoagulation, and their history of coronary artery disease or stroke. Patients were followed for a median 5.3 years, during which fractures were assessed through an annual self-administered questionnaire, with the results stratified by glycemic control and hypoglycemia.
Overall, there were 249 men and 413 women who experienced fractures during the study period, with a follow-up rate of 97.6%. In a multivariate analysis, patients with a higher risk of fracture included those with two or more episodes of severe hypoglycemia (hazard ratio, 2.25; 95% confidence interval, 1.57-3.22) and one episode of severe hypoglycemia (HR, 1.57; 95% CI, 1.11-2.20). In patients without severe hypoglycemic episodes, there was an increased risk of fracture in those with baseline hemoglobin A1c (HbA1c) level of 53 to less than 64 mmol/mol (7% to less than 8%; HR, 1.14; 0.94-1.39), 64 to less than 75 mmol/mol (8% to less than 9%; HR, 1.11; 95% CI, 0.86-1.43), and at least 75 mmol/mol (at least 9%; HR, 1.45; 95% CI, 1.06-1.98).
Compared with postmenopausal women, the unadjusted risk of fracture was higher in men with multiple severe hypoglycemic episodes (HR, 3.46; 95% CI, 2.05-5.85) and one episode of hypoglycemia (HR, 2.81; 95% CI, 1.74-4.56). These higher risks in older men persisted after adjustment for age, multivariate factors, and HbA1c.
“The association between severe hypoglycemia, poor glycemic control, and fracture risk at any anatomic site seems to be stronger in men than in postmenopausal women, although the interaction between men and postmenopausal women for fracture risk was not significant,” the researchers said. “The higher incidence rate of fractures in postmenopausal women, compared with men, was attributed to drastic changes in sex hormones after menopause, which may reduce the apparent impacts of hyperglycemia and severe hypoglycemia on postmenopausal women.”
Researchers said they did not consider potential external factors for fracture incidence, nor did they measure incident falls or other markers of bone health, such as bone mineral density and 25-hydroxyvitamin D levels. They also noted among the limitations of the study the self-reported nature of fracture reporting, and the lack of generalizability of the results.
This study was funded in part by grants from The Japan Society for the Promotion of Science KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Junior Scientist Development Grant supported by the Japan Diabetes Society; and the Lilly Research Grant Program for Bone & Mineral Research. The authors reported no relevant conflicts of interest.
SOURCE: Komorita Y et al. Diabet Med. 2019 Sep 25. doi: 10.1111/dme.14142.
Patients with type 2 diabetes and poor glycemic control or severe hypoglycemia may be at greater risk for fracture, according to recent research from a Japanese cohort of older men and postmenopausal women.
“The impacts of severe hypoglycemia and poor glycemic control on fractures appeared to be independent,” noted Yuji Komorita, MD, PhD, of the department of medicine and clinical science, Graduate School of Medical Sciences at Kyushu University, and colleagues. “This study suggests that the glycemic target to prevent fractures may be HbA1c <75 mmol/mol, which is far higher than that used to prevent microvascular complications, and higher than that for older adults with type 2 diabetes.”
Dr. Komorita and colleagues performed a prospective analysis of fracture incidence for 2,755 men and 1,951 postmenopausal women with type 2 diabetes in the Fukuoka Diabetes Registry who were mean 66 years old between April 2008 and October 2010. At the start of the study, the researchers assessed patient diabetes duration, previous fracture history, physical activity, alcohol and smoking status, whether patients were treated for diabetic retinopathy with laser photocoagulation, and their history of coronary artery disease or stroke. Patients were followed for a median 5.3 years, during which fractures were assessed through an annual self-administered questionnaire, with the results stratified by glycemic control and hypoglycemia.
Overall, there were 249 men and 413 women who experienced fractures during the study period, with a follow-up rate of 97.6%. In a multivariate analysis, patients with a higher risk of fracture included those with two or more episodes of severe hypoglycemia (hazard ratio, 2.25; 95% confidence interval, 1.57-3.22) and one episode of severe hypoglycemia (HR, 1.57; 95% CI, 1.11-2.20). In patients without severe hypoglycemic episodes, there was an increased risk of fracture in those with baseline hemoglobin A1c (HbA1c) level of 53 to less than 64 mmol/mol (7% to less than 8%; HR, 1.14; 0.94-1.39), 64 to less than 75 mmol/mol (8% to less than 9%; HR, 1.11; 95% CI, 0.86-1.43), and at least 75 mmol/mol (at least 9%; HR, 1.45; 95% CI, 1.06-1.98).
Compared with postmenopausal women, the unadjusted risk of fracture was higher in men with multiple severe hypoglycemic episodes (HR, 3.46; 95% CI, 2.05-5.85) and one episode of hypoglycemia (HR, 2.81; 95% CI, 1.74-4.56). These higher risks in older men persisted after adjustment for age, multivariate factors, and HbA1c.
“The association between severe hypoglycemia, poor glycemic control, and fracture risk at any anatomic site seems to be stronger in men than in postmenopausal women, although the interaction between men and postmenopausal women for fracture risk was not significant,” the researchers said. “The higher incidence rate of fractures in postmenopausal women, compared with men, was attributed to drastic changes in sex hormones after menopause, which may reduce the apparent impacts of hyperglycemia and severe hypoglycemia on postmenopausal women.”
Researchers said they did not consider potential external factors for fracture incidence, nor did they measure incident falls or other markers of bone health, such as bone mineral density and 25-hydroxyvitamin D levels. They also noted among the limitations of the study the self-reported nature of fracture reporting, and the lack of generalizability of the results.
This study was funded in part by grants from The Japan Society for the Promotion of Science KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Junior Scientist Development Grant supported by the Japan Diabetes Society; and the Lilly Research Grant Program for Bone & Mineral Research. The authors reported no relevant conflicts of interest.
SOURCE: Komorita Y et al. Diabet Med. 2019 Sep 25. doi: 10.1111/dme.14142.
FROM DIABETIC MEDICINE
THC use reported in majority of vaping-related illnesses
(EVALI), according to the Centers for Disease Control and Prevention.
In the largest analysis to date, exclusive use of THC-containing products was reported for 34% of the 1,378 patients with confirmed or probable EVALI as of Oct. 15, 2019. Among those who died, 63% had been using THC exclusively during the 3 months preceding symptom onset, Erin D. Moritz, PhD, and associates said Oct. 28 in the Morbidity and Mortality Weekly Report.
Almost two-thirds (64%) of all EVALI patients had used nicotine-containing products at some time in the 3 months before symptom onset, and nicotine use was exclusive for 11%. Any nicotine use was reported for 37% of EVALI-related deaths, with exclusive use at 16%, the investigators reported.
“The data presented here suggest that THC-containing products are playing an important role in this outbreak,” they wrote, but “to date, no single compound or ingredient has emerged as the cause of EVALI, and there might be more than one cause.”
Dr. Moritz and associates also noted that many “patients likely did not know the content of the e-cigarette, or vaping, products they used,” which may have led to misclassification of substances.
SOURCE: Moritz ED et al. MMWR. Morbidity and mortality weekly report 2019 Oct 28;68(early release):1-4.
(EVALI), according to the Centers for Disease Control and Prevention.
In the largest analysis to date, exclusive use of THC-containing products was reported for 34% of the 1,378 patients with confirmed or probable EVALI as of Oct. 15, 2019. Among those who died, 63% had been using THC exclusively during the 3 months preceding symptom onset, Erin D. Moritz, PhD, and associates said Oct. 28 in the Morbidity and Mortality Weekly Report.
Almost two-thirds (64%) of all EVALI patients had used nicotine-containing products at some time in the 3 months before symptom onset, and nicotine use was exclusive for 11%. Any nicotine use was reported for 37% of EVALI-related deaths, with exclusive use at 16%, the investigators reported.
“The data presented here suggest that THC-containing products are playing an important role in this outbreak,” they wrote, but “to date, no single compound or ingredient has emerged as the cause of EVALI, and there might be more than one cause.”
Dr. Moritz and associates also noted that many “patients likely did not know the content of the e-cigarette, or vaping, products they used,” which may have led to misclassification of substances.
SOURCE: Moritz ED et al. MMWR. Morbidity and mortality weekly report 2019 Oct 28;68(early release):1-4.
(EVALI), according to the Centers for Disease Control and Prevention.
In the largest analysis to date, exclusive use of THC-containing products was reported for 34% of the 1,378 patients with confirmed or probable EVALI as of Oct. 15, 2019. Among those who died, 63% had been using THC exclusively during the 3 months preceding symptom onset, Erin D. Moritz, PhD, and associates said Oct. 28 in the Morbidity and Mortality Weekly Report.
Almost two-thirds (64%) of all EVALI patients had used nicotine-containing products at some time in the 3 months before symptom onset, and nicotine use was exclusive for 11%. Any nicotine use was reported for 37% of EVALI-related deaths, with exclusive use at 16%, the investigators reported.
“The data presented here suggest that THC-containing products are playing an important role in this outbreak,” they wrote, but “to date, no single compound or ingredient has emerged as the cause of EVALI, and there might be more than one cause.”
Dr. Moritz and associates also noted that many “patients likely did not know the content of the e-cigarette, or vaping, products they used,” which may have led to misclassification of substances.
SOURCE: Moritz ED et al. MMWR. Morbidity and mortality weekly report 2019 Oct 28;68(early release):1-4.
FROM MMWR