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Two immunologists receive Nobel Prize in medicine
Two immunologists have been awarded the Nobel Prize in Physiology or Medicine for discoveries that represent a “paradigmatic shift in the fight against cancer,” the Nobel committee said.
James P. Allison, PhD, of MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, shared the prize for their discovery of cancer therapies that work by inhibiting negative immune regulation.
Dr. Allison studied the protein CTLA-4 found on T cells, which acts as a T-cell brake, and Dr. Honjo discovered a protein on immune cells called PD-1 that also acts as a T-cell brake.
In addition to sharing the honor, the scientists will split the 9 million Swedish kronor ($1.01 million) that comes with the prize.
Drs. Allison and Honjo, working in parallel, pursued different strategies for inhibiting the brakes on the immune system. Both strategies produced effective checkpoint inhibitors in the treatment of cancer.
James P. Allison
Dr. Allison was one of several scientists during the 1990s who noticed that CTLA-4 functions as a brake on T cells. Unlike other scientists, however, he set out to investigate whether blocking CTLA-4 with an antibody he had already developed could release the brake on the immune system.
The antibody had “spectacular” effects in curing mice with cancer. Despite little interest from the pharmaceutical industry, Dr. Allison continued efforts to develop the antibody therapy for humans.
The antibody turned out to be ipilimumab, which was approved in 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.
Tasuko Honjo
A few years prior to Dr. Allison’s finding, Dr. Honjo discovered PD-1 and set out to determine its function. PD-1 also operates as a T-cell brake, but it uses a different mechanism than does CTLA-4.
Dr. Honjo and others demonstrated in animal experiments that PD-1 blockade could be an effective anticancer therapy. Over the years he demonstrated the efficacy of targeting PD-1 in different types of human cancers.
The first two PD-1 checkpoint inhibitors—pembrolizumab and nivolumab—were approved by the FDA in 2014 for the treatment of melanoma.
Nivolumab is also approved to treat classical Hodgkin lymphoma (HL), non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, and microsatellite instability-high or mismatch repair deficient colorectal cancer.
Pembrolizumab is also approved to treat primary mediastinal large B-cell lymphoma, advanced NSCLC, classical HL, advanced gastric cancer, advanced cervical cancer, head and neck squamous cell cancer, advanced urothelial bladder cancer, and microsatellite instability-high cancer.
And targeting both CTLA-4 and PD-1 in combination therapy together may prove to be even more effective in eliminating cancer cells than either strategy alone, as is being demonstrated in patients with melanoma.
The Nobel organization wrote in a press release, “Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”
Two immunologists have been awarded the Nobel Prize in Physiology or Medicine for discoveries that represent a “paradigmatic shift in the fight against cancer,” the Nobel committee said.
James P. Allison, PhD, of MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, shared the prize for their discovery of cancer therapies that work by inhibiting negative immune regulation.
Dr. Allison studied the protein CTLA-4 found on T cells, which acts as a T-cell brake, and Dr. Honjo discovered a protein on immune cells called PD-1 that also acts as a T-cell brake.
In addition to sharing the honor, the scientists will split the 9 million Swedish kronor ($1.01 million) that comes with the prize.
Drs. Allison and Honjo, working in parallel, pursued different strategies for inhibiting the brakes on the immune system. Both strategies produced effective checkpoint inhibitors in the treatment of cancer.
James P. Allison
Dr. Allison was one of several scientists during the 1990s who noticed that CTLA-4 functions as a brake on T cells. Unlike other scientists, however, he set out to investigate whether blocking CTLA-4 with an antibody he had already developed could release the brake on the immune system.
The antibody had “spectacular” effects in curing mice with cancer. Despite little interest from the pharmaceutical industry, Dr. Allison continued efforts to develop the antibody therapy for humans.
The antibody turned out to be ipilimumab, which was approved in 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.
Tasuko Honjo
A few years prior to Dr. Allison’s finding, Dr. Honjo discovered PD-1 and set out to determine its function. PD-1 also operates as a T-cell brake, but it uses a different mechanism than does CTLA-4.
Dr. Honjo and others demonstrated in animal experiments that PD-1 blockade could be an effective anticancer therapy. Over the years he demonstrated the efficacy of targeting PD-1 in different types of human cancers.
The first two PD-1 checkpoint inhibitors—pembrolizumab and nivolumab—were approved by the FDA in 2014 for the treatment of melanoma.
Nivolumab is also approved to treat classical Hodgkin lymphoma (HL), non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, and microsatellite instability-high or mismatch repair deficient colorectal cancer.
Pembrolizumab is also approved to treat primary mediastinal large B-cell lymphoma, advanced NSCLC, classical HL, advanced gastric cancer, advanced cervical cancer, head and neck squamous cell cancer, advanced urothelial bladder cancer, and microsatellite instability-high cancer.
And targeting both CTLA-4 and PD-1 in combination therapy together may prove to be even more effective in eliminating cancer cells than either strategy alone, as is being demonstrated in patients with melanoma.
The Nobel organization wrote in a press release, “Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”
Two immunologists have been awarded the Nobel Prize in Physiology or Medicine for discoveries that represent a “paradigmatic shift in the fight against cancer,” the Nobel committee said.
James P. Allison, PhD, of MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, shared the prize for their discovery of cancer therapies that work by inhibiting negative immune regulation.
Dr. Allison studied the protein CTLA-4 found on T cells, which acts as a T-cell brake, and Dr. Honjo discovered a protein on immune cells called PD-1 that also acts as a T-cell brake.
In addition to sharing the honor, the scientists will split the 9 million Swedish kronor ($1.01 million) that comes with the prize.
Drs. Allison and Honjo, working in parallel, pursued different strategies for inhibiting the brakes on the immune system. Both strategies produced effective checkpoint inhibitors in the treatment of cancer.
James P. Allison
Dr. Allison was one of several scientists during the 1990s who noticed that CTLA-4 functions as a brake on T cells. Unlike other scientists, however, he set out to investigate whether blocking CTLA-4 with an antibody he had already developed could release the brake on the immune system.
The antibody had “spectacular” effects in curing mice with cancer. Despite little interest from the pharmaceutical industry, Dr. Allison continued efforts to develop the antibody therapy for humans.
The antibody turned out to be ipilimumab, which was approved in 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.
Tasuko Honjo
A few years prior to Dr. Allison’s finding, Dr. Honjo discovered PD-1 and set out to determine its function. PD-1 also operates as a T-cell brake, but it uses a different mechanism than does CTLA-4.
Dr. Honjo and others demonstrated in animal experiments that PD-1 blockade could be an effective anticancer therapy. Over the years he demonstrated the efficacy of targeting PD-1 in different types of human cancers.
The first two PD-1 checkpoint inhibitors—pembrolizumab and nivolumab—were approved by the FDA in 2014 for the treatment of melanoma.
Nivolumab is also approved to treat classical Hodgkin lymphoma (HL), non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, and microsatellite instability-high or mismatch repair deficient colorectal cancer.
Pembrolizumab is also approved to treat primary mediastinal large B-cell lymphoma, advanced NSCLC, classical HL, advanced gastric cancer, advanced cervical cancer, head and neck squamous cell cancer, advanced urothelial bladder cancer, and microsatellite instability-high cancer.
And targeting both CTLA-4 and PD-1 in combination therapy together may prove to be even more effective in eliminating cancer cells than either strategy alone, as is being demonstrated in patients with melanoma.
The Nobel organization wrote in a press release, “Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”
Concurrent ‘never event’ prescribing may worsen dementia in Parkinson’s
Nearly half of Medicare beneficiaries with Parkinson’s disease were concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor, with higher rates of potential prescribing errors seen among women and Hispanic patients, according to a cross-sectional analysis of Centers for Medicare & Medicaid Services data published in JAMA Neurology.
“Coadministration of a drug with high anticholinergic activity and an [acetylcholinesterase inhibitor] represents a frank prescribing error because these drugs have opposing pharmacologic effects,” wrote Sneha Mantri, MD, of the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center, and her colleagues. “In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an [acetylcholinesterase inhibitor] and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability.”
Dr. Mantri and her colleagues analyzed the inpatient, outpatient, and prescription data of 268,407 Medicare beneficiaries with Parkinson’s, of whom 73,093 patients (27.2%) were prescribed a minimum of one antidementia medication fill. Patients were mean 78.9 years old, and the demographics of the Medicare beneficiaries were 50.1% male, 86.7% white, 5.5% black, 2.7% Hispanic, 2.7% Asian, and 0.7% Native American. The most common antidementia prescriptions were donepezil hydrochloride (63.0%), memantine hydrochloride (41.8%), and rivastigmine tartrate (26.4%). The researchers measured medications in cases of coprescription with potential anticholinergic (ACH) activity using the Anticholinergic Cognitive Burden Scale.
They found antidementia medication use was associated with patients who were black (adjusted odds ratio, 1.33; 95% confidence interval, 1.28-1.38) and Hispanic (aOR, 1.28; 95% CI, 1.22-1.35). Meanwhile, a negative association was found between Native American patients and antidementia medication use (aOR, 0.62; 95% CI, 0.51-0.74) compared with white patients and women (aOR, 0.85; 95% CI, 0.84-0.87) compared with men. The researchers noted that 28,495 patients (44.5%) were prescribed concurrently one high-potency anticholinergic and acetylcholinesterase inhibitors, with higher rates of prescribing seen for Hispanic (aOR, 1.11; 95% CI, 1.00-1.23) and women (aOR, 1.30; 95% CI, 1.25-1.35). High prevalence clusters of this type of prescribing were statistically high in the Southern and Midwestern states, they added.
Limitations included the study of a single year of data and the absence of conclusive data of dementia prevalence among Parkinson’s patients based on antidementia medication use alone and potential off-label use of antidementia medication analyzed in the study, the researchers said.
“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Dr. Mantri and her colleagues wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm.”
This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors report no relevant conflicts of interest.
SOURCE: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
Describing the prescribing patterns of antidementia medication for patients with Parkinson’s disease is useful, particularly with regard to black and Hispanic patients, but the analysis by Sneha Mantri, MD, and her colleagues has methodological issues that limit its impact, wrote Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, wrote in an editorial.
While the researchers used the Anticholinergic Cognitive Burden (ACB) Scale and graded acetylcholinesterase inhibitor and high anticholinergic (ACH) activity medication combinations with the highest ACB score (3 on a scale of 0 to 3) and labeled them as a prescribing error, the ACB scale score alone should not be the sole determination of whether a prescription combination is deemed an error, the authors said.
“A problem, however, arises in defining the coadministration of an antidementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances,” the authors wrote. “Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”
Further, medications such as clozapine and quetiapine fumarate are often prescribed for patients with Parkinson’s disease–related psychosis as a standard of care; those medications also have an ACB score of 3, which would label them as prescribing errors and never events under the study by Mantri et al., the authors continued.
“Variability in ACH activity scoring methods is an additional concern, as no criterion standard exists for ranking relative ACH activity and the scores for medications to treat Parkinson disease (such as quetiapine for Parkinson disease psychosis) can markedly differ between the scales commonly used (such as the ACB Scale),” they wrote.
Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, are affiliated with the Fixel Center for Neurological Diseases in the department of neurology at the University of Florida in Gainesville. These comments summarize their editorial (JAMA Neurol. 2018 Oct 1 doi: 10.1001/jamaneurol.2018.2826).They reported no relevant conflicts of interest.
Describing the prescribing patterns of antidementia medication for patients with Parkinson’s disease is useful, particularly with regard to black and Hispanic patients, but the analysis by Sneha Mantri, MD, and her colleagues has methodological issues that limit its impact, wrote Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, wrote in an editorial.
While the researchers used the Anticholinergic Cognitive Burden (ACB) Scale and graded acetylcholinesterase inhibitor and high anticholinergic (ACH) activity medication combinations with the highest ACB score (3 on a scale of 0 to 3) and labeled them as a prescribing error, the ACB scale score alone should not be the sole determination of whether a prescription combination is deemed an error, the authors said.
“A problem, however, arises in defining the coadministration of an antidementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances,” the authors wrote. “Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”
Further, medications such as clozapine and quetiapine fumarate are often prescribed for patients with Parkinson’s disease–related psychosis as a standard of care; those medications also have an ACB score of 3, which would label them as prescribing errors and never events under the study by Mantri et al., the authors continued.
“Variability in ACH activity scoring methods is an additional concern, as no criterion standard exists for ranking relative ACH activity and the scores for medications to treat Parkinson disease (such as quetiapine for Parkinson disease psychosis) can markedly differ between the scales commonly used (such as the ACB Scale),” they wrote.
Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, are affiliated with the Fixel Center for Neurological Diseases in the department of neurology at the University of Florida in Gainesville. These comments summarize their editorial (JAMA Neurol. 2018 Oct 1 doi: 10.1001/jamaneurol.2018.2826).They reported no relevant conflicts of interest.
Describing the prescribing patterns of antidementia medication for patients with Parkinson’s disease is useful, particularly with regard to black and Hispanic patients, but the analysis by Sneha Mantri, MD, and her colleagues has methodological issues that limit its impact, wrote Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, wrote in an editorial.
While the researchers used the Anticholinergic Cognitive Burden (ACB) Scale and graded acetylcholinesterase inhibitor and high anticholinergic (ACH) activity medication combinations with the highest ACB score (3 on a scale of 0 to 3) and labeled them as a prescribing error, the ACB scale score alone should not be the sole determination of whether a prescription combination is deemed an error, the authors said.
“A problem, however, arises in defining the coadministration of an antidementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances,” the authors wrote. “Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”
Further, medications such as clozapine and quetiapine fumarate are often prescribed for patients with Parkinson’s disease–related psychosis as a standard of care; those medications also have an ACB score of 3, which would label them as prescribing errors and never events under the study by Mantri et al., the authors continued.
“Variability in ACH activity scoring methods is an additional concern, as no criterion standard exists for ranking relative ACH activity and the scores for medications to treat Parkinson disease (such as quetiapine for Parkinson disease psychosis) can markedly differ between the scales commonly used (such as the ACB Scale),” they wrote.
Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, are affiliated with the Fixel Center for Neurological Diseases in the department of neurology at the University of Florida in Gainesville. These comments summarize their editorial (JAMA Neurol. 2018 Oct 1 doi: 10.1001/jamaneurol.2018.2826).They reported no relevant conflicts of interest.
Nearly half of Medicare beneficiaries with Parkinson’s disease were concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor, with higher rates of potential prescribing errors seen among women and Hispanic patients, according to a cross-sectional analysis of Centers for Medicare & Medicaid Services data published in JAMA Neurology.
“Coadministration of a drug with high anticholinergic activity and an [acetylcholinesterase inhibitor] represents a frank prescribing error because these drugs have opposing pharmacologic effects,” wrote Sneha Mantri, MD, of the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center, and her colleagues. “In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an [acetylcholinesterase inhibitor] and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability.”
Dr. Mantri and her colleagues analyzed the inpatient, outpatient, and prescription data of 268,407 Medicare beneficiaries with Parkinson’s, of whom 73,093 patients (27.2%) were prescribed a minimum of one antidementia medication fill. Patients were mean 78.9 years old, and the demographics of the Medicare beneficiaries were 50.1% male, 86.7% white, 5.5% black, 2.7% Hispanic, 2.7% Asian, and 0.7% Native American. The most common antidementia prescriptions were donepezil hydrochloride (63.0%), memantine hydrochloride (41.8%), and rivastigmine tartrate (26.4%). The researchers measured medications in cases of coprescription with potential anticholinergic (ACH) activity using the Anticholinergic Cognitive Burden Scale.
They found antidementia medication use was associated with patients who were black (adjusted odds ratio, 1.33; 95% confidence interval, 1.28-1.38) and Hispanic (aOR, 1.28; 95% CI, 1.22-1.35). Meanwhile, a negative association was found between Native American patients and antidementia medication use (aOR, 0.62; 95% CI, 0.51-0.74) compared with white patients and women (aOR, 0.85; 95% CI, 0.84-0.87) compared with men. The researchers noted that 28,495 patients (44.5%) were prescribed concurrently one high-potency anticholinergic and acetylcholinesterase inhibitors, with higher rates of prescribing seen for Hispanic (aOR, 1.11; 95% CI, 1.00-1.23) and women (aOR, 1.30; 95% CI, 1.25-1.35). High prevalence clusters of this type of prescribing were statistically high in the Southern and Midwestern states, they added.
Limitations included the study of a single year of data and the absence of conclusive data of dementia prevalence among Parkinson’s patients based on antidementia medication use alone and potential off-label use of antidementia medication analyzed in the study, the researchers said.
“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Dr. Mantri and her colleagues wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm.”
This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors report no relevant conflicts of interest.
SOURCE: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
Nearly half of Medicare beneficiaries with Parkinson’s disease were concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor, with higher rates of potential prescribing errors seen among women and Hispanic patients, according to a cross-sectional analysis of Centers for Medicare & Medicaid Services data published in JAMA Neurology.
“Coadministration of a drug with high anticholinergic activity and an [acetylcholinesterase inhibitor] represents a frank prescribing error because these drugs have opposing pharmacologic effects,” wrote Sneha Mantri, MD, of the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center, and her colleagues. “In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an [acetylcholinesterase inhibitor] and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability.”
Dr. Mantri and her colleagues analyzed the inpatient, outpatient, and prescription data of 268,407 Medicare beneficiaries with Parkinson’s, of whom 73,093 patients (27.2%) were prescribed a minimum of one antidementia medication fill. Patients were mean 78.9 years old, and the demographics of the Medicare beneficiaries were 50.1% male, 86.7% white, 5.5% black, 2.7% Hispanic, 2.7% Asian, and 0.7% Native American. The most common antidementia prescriptions were donepezil hydrochloride (63.0%), memantine hydrochloride (41.8%), and rivastigmine tartrate (26.4%). The researchers measured medications in cases of coprescription with potential anticholinergic (ACH) activity using the Anticholinergic Cognitive Burden Scale.
They found antidementia medication use was associated with patients who were black (adjusted odds ratio, 1.33; 95% confidence interval, 1.28-1.38) and Hispanic (aOR, 1.28; 95% CI, 1.22-1.35). Meanwhile, a negative association was found between Native American patients and antidementia medication use (aOR, 0.62; 95% CI, 0.51-0.74) compared with white patients and women (aOR, 0.85; 95% CI, 0.84-0.87) compared with men. The researchers noted that 28,495 patients (44.5%) were prescribed concurrently one high-potency anticholinergic and acetylcholinesterase inhibitors, with higher rates of prescribing seen for Hispanic (aOR, 1.11; 95% CI, 1.00-1.23) and women (aOR, 1.30; 95% CI, 1.25-1.35). High prevalence clusters of this type of prescribing were statistically high in the Southern and Midwestern states, they added.
Limitations included the study of a single year of data and the absence of conclusive data of dementia prevalence among Parkinson’s patients based on antidementia medication use alone and potential off-label use of antidementia medication analyzed in the study, the researchers said.
“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Dr. Mantri and her colleagues wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm.”
This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors report no relevant conflicts of interest.
SOURCE: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
FROM JAMA NEUROLOGY
Key clinical point: Medicare beneficiaries with Parkinson’s disease often are concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor.
Major finding: More than 44% of patients experienced at least one never event, with higher rates of potential prescribing errors seen in Hispanic patients (adjusted OR, 1.11) and women (adjusted OR, 1.30).
Study details: An analysis of inpatient, outpatient, and prescription data for 268,407 Medicare beneficiaries with Parkinson’s disease over 12 months.
Disclosures: This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors reported no relevant conflicts of interest.
Source: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
Low-dose ketamine controls pain from severe chest injury, while sparing opioid consumption
SAN DIEGO – while reducing opioid consumption.
The anesthetic didn’t make much difference in pain control or opioid use overall in a randomized study of 93 patients with thoracic injury Nathan Kugler, MD, said at the annual meeting of the American Association for the Surgery of Trauma. But among severely injured patients, it cut the opioid mean equivalency dose by about 164 mg over the 48-hour infusion and by 328 mg over a mean hospital stay while maintaining pain control, said Dr. Kugler, a surgical resident at the Medical College of Wisconsin, Milwaukee.
“With increasing focus on multimodal pain strategies, opioid-based regimens continue to be the backbone of pain control,” he said. “We have used ketamine effectively for failure of maximum therapy and demonstrated an opioid-sparing effect.” This new research shows that the drug can be an effective adjunct for acute pain control for severely injured patients in the emergency setting.
The study recruited 93 patients with thoracic injury; they had a mean of six broken ribs, mostly caused by motor vehicle accidents. Most of the patients were male (75%), and their mean age was 46 years. The mean Injury Severity Score was about 15; about 30% had flail chest.
All patients received a standardized acute pain medication regime comprising acetaminophen, nonsteroidal anti-inflammatories, methocarbamol (Robaxin), and intravenous opioids. Regional therapies included rib block with an epidural catheter. In addition, they were randomized to placebo infusions or to 48 hours of IV ketamine at 2.5 mcg/kg per minute. “To put this in perspective, for a 70-kg patient, that is a mean of 10.5 mg/hour,” Dr. Kugler said.
The primary endpoint was a reduction of at least 2 points on an 11-point pain scale. Secondary endpoints included opioid use in oral morphine equivalents (OME); respiratory complications; and psychoactive events. The primary outcome was assessed with an area under the curve model.
In the overall group, there was no significant between-group difference in pain score. Nor were there differences in the total OME at 12-24 hours (184 mg ketamine vs. 230 mg placebo), or at 48 hours (86 vs. 113 mg).
Dr. Kugler also looked at these outcomes in patients who had only rib fractures independent of other chest injury. He saw no significant differences in pain scores or OME at 24 or 48 hours.
However, significant differences did emerge in the group of severely injured patients with an Injury Severity Score of more than 15. There were no differences in pain scores at either time point. However, ketamine allowed patients to achieve the same level of pain control with significantly less opioid medication. The OME at 12-24 hours was 50.5 mg vs 94 mg. At 24-48 hours, it was 87 mg vs. 64 mg.
This worked out to a mean OME savings of 148 mg over a patient’s entire hospitalization.
“We saw a very nice separation of opioid consumption that began early and continued to separate over the 48-hour infusion and even after it was discontinued,” Dr. Kugler said.
This benefit was achieved without any additional adverse events, he added. There were no significant differences in confusion; epidural placement; length of stay; respiratory event, sedation, hallucinations, delusions or disturbing dreams; or unplanned transfers to the ICU.
Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, also of the Medical College of Wisconsin, Milwaukee, are both paid consultants for InnoVital Systems.
SAN DIEGO – while reducing opioid consumption.
The anesthetic didn’t make much difference in pain control or opioid use overall in a randomized study of 93 patients with thoracic injury Nathan Kugler, MD, said at the annual meeting of the American Association for the Surgery of Trauma. But among severely injured patients, it cut the opioid mean equivalency dose by about 164 mg over the 48-hour infusion and by 328 mg over a mean hospital stay while maintaining pain control, said Dr. Kugler, a surgical resident at the Medical College of Wisconsin, Milwaukee.
“With increasing focus on multimodal pain strategies, opioid-based regimens continue to be the backbone of pain control,” he said. “We have used ketamine effectively for failure of maximum therapy and demonstrated an opioid-sparing effect.” This new research shows that the drug can be an effective adjunct for acute pain control for severely injured patients in the emergency setting.
The study recruited 93 patients with thoracic injury; they had a mean of six broken ribs, mostly caused by motor vehicle accidents. Most of the patients were male (75%), and their mean age was 46 years. The mean Injury Severity Score was about 15; about 30% had flail chest.
All patients received a standardized acute pain medication regime comprising acetaminophen, nonsteroidal anti-inflammatories, methocarbamol (Robaxin), and intravenous opioids. Regional therapies included rib block with an epidural catheter. In addition, they were randomized to placebo infusions or to 48 hours of IV ketamine at 2.5 mcg/kg per minute. “To put this in perspective, for a 70-kg patient, that is a mean of 10.5 mg/hour,” Dr. Kugler said.
The primary endpoint was a reduction of at least 2 points on an 11-point pain scale. Secondary endpoints included opioid use in oral morphine equivalents (OME); respiratory complications; and psychoactive events. The primary outcome was assessed with an area under the curve model.
In the overall group, there was no significant between-group difference in pain score. Nor were there differences in the total OME at 12-24 hours (184 mg ketamine vs. 230 mg placebo), or at 48 hours (86 vs. 113 mg).
Dr. Kugler also looked at these outcomes in patients who had only rib fractures independent of other chest injury. He saw no significant differences in pain scores or OME at 24 or 48 hours.
However, significant differences did emerge in the group of severely injured patients with an Injury Severity Score of more than 15. There were no differences in pain scores at either time point. However, ketamine allowed patients to achieve the same level of pain control with significantly less opioid medication. The OME at 12-24 hours was 50.5 mg vs 94 mg. At 24-48 hours, it was 87 mg vs. 64 mg.
This worked out to a mean OME savings of 148 mg over a patient’s entire hospitalization.
“We saw a very nice separation of opioid consumption that began early and continued to separate over the 48-hour infusion and even after it was discontinued,” Dr. Kugler said.
This benefit was achieved without any additional adverse events, he added. There were no significant differences in confusion; epidural placement; length of stay; respiratory event, sedation, hallucinations, delusions or disturbing dreams; or unplanned transfers to the ICU.
Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, also of the Medical College of Wisconsin, Milwaukee, are both paid consultants for InnoVital Systems.
SAN DIEGO – while reducing opioid consumption.
The anesthetic didn’t make much difference in pain control or opioid use overall in a randomized study of 93 patients with thoracic injury Nathan Kugler, MD, said at the annual meeting of the American Association for the Surgery of Trauma. But among severely injured patients, it cut the opioid mean equivalency dose by about 164 mg over the 48-hour infusion and by 328 mg over a mean hospital stay while maintaining pain control, said Dr. Kugler, a surgical resident at the Medical College of Wisconsin, Milwaukee.
“With increasing focus on multimodal pain strategies, opioid-based regimens continue to be the backbone of pain control,” he said. “We have used ketamine effectively for failure of maximum therapy and demonstrated an opioid-sparing effect.” This new research shows that the drug can be an effective adjunct for acute pain control for severely injured patients in the emergency setting.
The study recruited 93 patients with thoracic injury; they had a mean of six broken ribs, mostly caused by motor vehicle accidents. Most of the patients were male (75%), and their mean age was 46 years. The mean Injury Severity Score was about 15; about 30% had flail chest.
All patients received a standardized acute pain medication regime comprising acetaminophen, nonsteroidal anti-inflammatories, methocarbamol (Robaxin), and intravenous opioids. Regional therapies included rib block with an epidural catheter. In addition, they were randomized to placebo infusions or to 48 hours of IV ketamine at 2.5 mcg/kg per minute. “To put this in perspective, for a 70-kg patient, that is a mean of 10.5 mg/hour,” Dr. Kugler said.
The primary endpoint was a reduction of at least 2 points on an 11-point pain scale. Secondary endpoints included opioid use in oral morphine equivalents (OME); respiratory complications; and psychoactive events. The primary outcome was assessed with an area under the curve model.
In the overall group, there was no significant between-group difference in pain score. Nor were there differences in the total OME at 12-24 hours (184 mg ketamine vs. 230 mg placebo), or at 48 hours (86 vs. 113 mg).
Dr. Kugler also looked at these outcomes in patients who had only rib fractures independent of other chest injury. He saw no significant differences in pain scores or OME at 24 or 48 hours.
However, significant differences did emerge in the group of severely injured patients with an Injury Severity Score of more than 15. There were no differences in pain scores at either time point. However, ketamine allowed patients to achieve the same level of pain control with significantly less opioid medication. The OME at 12-24 hours was 50.5 mg vs 94 mg. At 24-48 hours, it was 87 mg vs. 64 mg.
This worked out to a mean OME savings of 148 mg over a patient’s entire hospitalization.
“We saw a very nice separation of opioid consumption that began early and continued to separate over the 48-hour infusion and even after it was discontinued,” Dr. Kugler said.
This benefit was achieved without any additional adverse events, he added. There were no significant differences in confusion; epidural placement; length of stay; respiratory event, sedation, hallucinations, delusions or disturbing dreams; or unplanned transfers to the ICU.
Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, also of the Medical College of Wisconsin, Milwaukee, are both paid consultants for InnoVital Systems.
REPORTING FROM THE AAST ANNUAL MEETING
Key clinical point: Low-dose ketamine controlled pain while reducing opioid use among patients with severe thoracic injury.
Major finding: Compared with placebo, ketamine reduced opioids conferred OME savings of 148 mg over a patient’s entire hospitalization.
Study details: The randomized study comprised 93 patients with thoracic injury.
Disclosures: Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, are both paid consultants for InnoVital Systems.
Source: Carver T et al. AAST 2018, Oral abstract 2
October 2018 Question 2
Correct Answer: B
Rationale
This patient has large varices, which should be treated. In patients with cirrhosis and medium/large varices that have never bled, nonselective beta-blockers reduce the risk of first variceal hemorrhage by 50%. In high-quality randomized-controlled trials, endoscopic variceal ligation (EVL) is as effective as nonselective beta-blockers in preventing first variceal hemorrhage. Therefore, either of these therapies should be used for the prevention of first variceal bleeding. In this case, propranolol is not the best choice in the setting of diabetes, asthma as well as a blood pressure and pulse that are low already. Endoscopic variceal band ligation would be preferred in this patient. It is also more effective than sclerotherapy and is associated with fewer side effects. TIPS would be effective, but more invasive and not first-line for treatment of nonbleeding varices and comes with increased risk of hepatic encephalopathy and potentially mortality. The combination of nadolol and endoscopic variceal band ligation may have more side effects without a further reduction in the risk of first variceal hemorrhage beyond either therapy alone.
References
1. Gluud L.L., Klingenberg S., Nikolova D., Gluud C. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials. Am J Gastroenterol. 2007;102(12):2842-8.
2. Gluud L.L., Krag A. Banding ligation versus betablockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev. 2012;8:CD004544. doi: 10.1002/14651858. CD004544.
3. Villanueva C., Piqueras M., Aracil C., et al. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol. 2006;45(4):560-7.
Correct Answer: B
Rationale
This patient has large varices, which should be treated. In patients with cirrhosis and medium/large varices that have never bled, nonselective beta-blockers reduce the risk of first variceal hemorrhage by 50%. In high-quality randomized-controlled trials, endoscopic variceal ligation (EVL) is as effective as nonselective beta-blockers in preventing first variceal hemorrhage. Therefore, either of these therapies should be used for the prevention of first variceal bleeding. In this case, propranolol is not the best choice in the setting of diabetes, asthma as well as a blood pressure and pulse that are low already. Endoscopic variceal band ligation would be preferred in this patient. It is also more effective than sclerotherapy and is associated with fewer side effects. TIPS would be effective, but more invasive and not first-line for treatment of nonbleeding varices and comes with increased risk of hepatic encephalopathy and potentially mortality. The combination of nadolol and endoscopic variceal band ligation may have more side effects without a further reduction in the risk of first variceal hemorrhage beyond either therapy alone.
References
1. Gluud L.L., Klingenberg S., Nikolova D., Gluud C. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials. Am J Gastroenterol. 2007;102(12):2842-8.
2. Gluud L.L., Krag A. Banding ligation versus betablockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev. 2012;8:CD004544. doi: 10.1002/14651858. CD004544.
3. Villanueva C., Piqueras M., Aracil C., et al. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol. 2006;45(4):560-7.
Correct Answer: B
Rationale
This patient has large varices, which should be treated. In patients with cirrhosis and medium/large varices that have never bled, nonselective beta-blockers reduce the risk of first variceal hemorrhage by 50%. In high-quality randomized-controlled trials, endoscopic variceal ligation (EVL) is as effective as nonselective beta-blockers in preventing first variceal hemorrhage. Therefore, either of these therapies should be used for the prevention of first variceal bleeding. In this case, propranolol is not the best choice in the setting of diabetes, asthma as well as a blood pressure and pulse that are low already. Endoscopic variceal band ligation would be preferred in this patient. It is also more effective than sclerotherapy and is associated with fewer side effects. TIPS would be effective, but more invasive and not first-line for treatment of nonbleeding varices and comes with increased risk of hepatic encephalopathy and potentially mortality. The combination of nadolol and endoscopic variceal band ligation may have more side effects without a further reduction in the risk of first variceal hemorrhage beyond either therapy alone.
References
1. Gluud L.L., Klingenberg S., Nikolova D., Gluud C. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials. Am J Gastroenterol. 2007;102(12):2842-8.
2. Gluud L.L., Krag A. Banding ligation versus betablockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev. 2012;8:CD004544. doi: 10.1002/14651858. CD004544.
3. Villanueva C., Piqueras M., Aracil C., et al. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol. 2006;45(4):560-7.
A 59-year-old woman with a history of cirrhosis due to nonalcoholic steatohepatitis presents for endoscopic evaluation of varices. Her past medical history includes obesity, diabetes, hypertension, and mild asthma. She appears well and has no signs of decompensation. Her vitals are: temperature, 98.6 ºF; blood pressure, 90/51 mm Hg; heart rate, 58 beats/minute; O2 saturation, 98% on room air. Her endoscopy reveals mild portal hypertensive gastropathy, large esophageal varices, and no gastric varices.
Which is the best approach in the management of this patient?
October 2018 Question 1
Correct Answer: A
Rationale
This patient has an idiopathic, nonNSAID, non-H. pylori-associated ulcer and should be on daily PPI indefinitely. These patients have a high rate of recurrent bleeding (42%) and mortality when followed prospectively without being on antisecretory therapy. Although no randomized trials have assessed the benefit of medical cotherapy in this population, antiulcer therapy seems to reduce recurrent idiopathic ulcers.
References
1. Wong G.L.H., Wong V.W.S., Chan Y., et al. High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology. 2009;137:525-31.
2. Laine L., Jensen D.M. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345-60.
Correct Answer: A
Rationale
This patient has an idiopathic, nonNSAID, non-H. pylori-associated ulcer and should be on daily PPI indefinitely. These patients have a high rate of recurrent bleeding (42%) and mortality when followed prospectively without being on antisecretory therapy. Although no randomized trials have assessed the benefit of medical cotherapy in this population, antiulcer therapy seems to reduce recurrent idiopathic ulcers.
References
1. Wong G.L.H., Wong V.W.S., Chan Y., et al. High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology. 2009;137:525-31.
2. Laine L., Jensen D.M. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345-60.
Correct Answer: A
Rationale
This patient has an idiopathic, nonNSAID, non-H. pylori-associated ulcer and should be on daily PPI indefinitely. These patients have a high rate of recurrent bleeding (42%) and mortality when followed prospectively without being on antisecretory therapy. Although no randomized trials have assessed the benefit of medical cotherapy in this population, antiulcer therapy seems to reduce recurrent idiopathic ulcers.
References
1. Wong G.L.H., Wong V.W.S., Chan Y., et al. High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology. 2009;137:525-31.
2. Laine L., Jensen D.M. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345-60.
A 60-year-old woman is admitted to the hospital with an upper GI bleed and found to have a gastric ulcer. Biopsies from the ulcer show no malignancy. Gastric biopsies reveal no Helicobacter pylori and stool antigen for H. pylori is also negative. The patient denies any NSAID use. She is discharged home on twice-daily PPI. Two months later, she returns for a follow-up endoscopy, and the ulcer has healed.
What is your recommendation for this patient?
Palliative care consultations reduce hospital costs
Background: Health care costs are on the rise, and previous studies have found that PCC can reduce hospital costs. Timing of consultation and allocation of palliative care intervention to a certain population of patients may reveal a more significant cost reduction.
Study design: Meta-analysis.
Setting: English peer reviewed articles.
Synopsis: A systematic search was performed for articles that provided economic evaluation of PCC for adult inpatients in acute care hospitals. Patients were included if they had least one of seven conditions: cancer, heart failure, liver failure, kidney failure, chronic obstructive pulmonary disease, AIDS/HIV, or neurodegenerative conditions. Six data sets were reviewed, which included 133,118 patients altogether. There was a significant reduction in costs with PCC within 3 days of admission, regardless of the diagnosis (–$3,237; 95% confidence interval, –$3,581 to –$2,893). In the stratified analysis, the pooled meta-analysis suggested a statistically significant reduction in costs for both cancer (–$4,251; 95% CI, –$4,664 to –$3,837; P less than .001) and noncancer (–$2,105; 95% CI, –$2,698 to –$1,511; P less than .001) subsamples. In patients with cancer, the treatment effect was greater for patients with four or more comorbidities than it was for those with two or fewer.
Only six samples were evaluated, and causation could not be established because all samples had observational designs. There also was potential interpretation bias because the private investigator for each of the samples contributed to interpretation of the data and participated as an author. Overall evaluation of the economic value of PCC in this study was limited because analysis was focused to a single index hospital admission rather than including additional hospitalizations and outpatient costs.
Bottom line: Acute care hospitals might reduce hospital costs by increasing resources to allow palliative care consultations in patients with serious illnesses.
Citation: May P et al. Economics of palliative care for hospitalized adults with serious illness. JAMA Intern Med. 2018;178(6):820-9.
Dr. Libot is a hospitalist in the division of hospital medicine in the department of medicine at Loyola University Chicago, Maywood, Ill.
Background: Health care costs are on the rise, and previous studies have found that PCC can reduce hospital costs. Timing of consultation and allocation of palliative care intervention to a certain population of patients may reveal a more significant cost reduction.
Study design: Meta-analysis.
Setting: English peer reviewed articles.
Synopsis: A systematic search was performed for articles that provided economic evaluation of PCC for adult inpatients in acute care hospitals. Patients were included if they had least one of seven conditions: cancer, heart failure, liver failure, kidney failure, chronic obstructive pulmonary disease, AIDS/HIV, or neurodegenerative conditions. Six data sets were reviewed, which included 133,118 patients altogether. There was a significant reduction in costs with PCC within 3 days of admission, regardless of the diagnosis (–$3,237; 95% confidence interval, –$3,581 to –$2,893). In the stratified analysis, the pooled meta-analysis suggested a statistically significant reduction in costs for both cancer (–$4,251; 95% CI, –$4,664 to –$3,837; P less than .001) and noncancer (–$2,105; 95% CI, –$2,698 to –$1,511; P less than .001) subsamples. In patients with cancer, the treatment effect was greater for patients with four or more comorbidities than it was for those with two or fewer.
Only six samples were evaluated, and causation could not be established because all samples had observational designs. There also was potential interpretation bias because the private investigator for each of the samples contributed to interpretation of the data and participated as an author. Overall evaluation of the economic value of PCC in this study was limited because analysis was focused to a single index hospital admission rather than including additional hospitalizations and outpatient costs.
Bottom line: Acute care hospitals might reduce hospital costs by increasing resources to allow palliative care consultations in patients with serious illnesses.
Citation: May P et al. Economics of palliative care for hospitalized adults with serious illness. JAMA Intern Med. 2018;178(6):820-9.
Dr. Libot is a hospitalist in the division of hospital medicine in the department of medicine at Loyola University Chicago, Maywood, Ill.
Background: Health care costs are on the rise, and previous studies have found that PCC can reduce hospital costs. Timing of consultation and allocation of palliative care intervention to a certain population of patients may reveal a more significant cost reduction.
Study design: Meta-analysis.
Setting: English peer reviewed articles.
Synopsis: A systematic search was performed for articles that provided economic evaluation of PCC for adult inpatients in acute care hospitals. Patients were included if they had least one of seven conditions: cancer, heart failure, liver failure, kidney failure, chronic obstructive pulmonary disease, AIDS/HIV, or neurodegenerative conditions. Six data sets were reviewed, which included 133,118 patients altogether. There was a significant reduction in costs with PCC within 3 days of admission, regardless of the diagnosis (–$3,237; 95% confidence interval, –$3,581 to –$2,893). In the stratified analysis, the pooled meta-analysis suggested a statistically significant reduction in costs for both cancer (–$4,251; 95% CI, –$4,664 to –$3,837; P less than .001) and noncancer (–$2,105; 95% CI, –$2,698 to –$1,511; P less than .001) subsamples. In patients with cancer, the treatment effect was greater for patients with four or more comorbidities than it was for those with two or fewer.
Only six samples were evaluated, and causation could not be established because all samples had observational designs. There also was potential interpretation bias because the private investigator for each of the samples contributed to interpretation of the data and participated as an author. Overall evaluation of the economic value of PCC in this study was limited because analysis was focused to a single index hospital admission rather than including additional hospitalizations and outpatient costs.
Bottom line: Acute care hospitals might reduce hospital costs by increasing resources to allow palliative care consultations in patients with serious illnesses.
Citation: May P et al. Economics of palliative care for hospitalized adults with serious illness. JAMA Intern Med. 2018;178(6):820-9.
Dr. Libot is a hospitalist in the division of hospital medicine in the department of medicine at Loyola University Chicago, Maywood, Ill.
ALEX: Alectinib showed superior CNS efficacy in ALK+ NSCLC
For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.
Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.
The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.
ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.
Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.
The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.
“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.
Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”
F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.
SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.
The results of the phase 3 ALEX trial provide strong rationale for the first-line use of alectinib in patients with non–small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements.
Alectinib showed robust evidence of intracranial and extracranial efficacy, not only eliciting responses in existing brain metastases but also helping prevent new ones. These results likely translate into significant improvements in quality of life, function, and survival for patients, and reduce the well-documented health economic burden associated with the development of CNS metastases.
Newer-generation ALK inhibitors, such as brigatinib and lorlatinib, also show CNS activity and are currently in phase 3 trials. It will be important to assess their effects on brain metastases to help determine their role in managing patients with ALK-positive NSCLC.
Alesha A. Thai, MD, is with the Peter MacCallum Cancer Centre in Melbourne and Benjamin J. Solomon, MD, is with the University of Melbourne. Dr. Thai disclosed no conflicts of interest. Dr. Solomon disclosed advisory board relationships with Roche-Genentech, Pfizer, Novartis, AstraZeneca, Merck, and Bristol-Myers Squibb. These comments are from their editorial (Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy415).
The results of the phase 3 ALEX trial provide strong rationale for the first-line use of alectinib in patients with non–small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements.
Alectinib showed robust evidence of intracranial and extracranial efficacy, not only eliciting responses in existing brain metastases but also helping prevent new ones. These results likely translate into significant improvements in quality of life, function, and survival for patients, and reduce the well-documented health economic burden associated with the development of CNS metastases.
Newer-generation ALK inhibitors, such as brigatinib and lorlatinib, also show CNS activity and are currently in phase 3 trials. It will be important to assess their effects on brain metastases to help determine their role in managing patients with ALK-positive NSCLC.
Alesha A. Thai, MD, is with the Peter MacCallum Cancer Centre in Melbourne and Benjamin J. Solomon, MD, is with the University of Melbourne. Dr. Thai disclosed no conflicts of interest. Dr. Solomon disclosed advisory board relationships with Roche-Genentech, Pfizer, Novartis, AstraZeneca, Merck, and Bristol-Myers Squibb. These comments are from their editorial (Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy415).
The results of the phase 3 ALEX trial provide strong rationale for the first-line use of alectinib in patients with non–small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements.
Alectinib showed robust evidence of intracranial and extracranial efficacy, not only eliciting responses in existing brain metastases but also helping prevent new ones. These results likely translate into significant improvements in quality of life, function, and survival for patients, and reduce the well-documented health economic burden associated with the development of CNS metastases.
Newer-generation ALK inhibitors, such as brigatinib and lorlatinib, also show CNS activity and are currently in phase 3 trials. It will be important to assess their effects on brain metastases to help determine their role in managing patients with ALK-positive NSCLC.
Alesha A. Thai, MD, is with the Peter MacCallum Cancer Centre in Melbourne and Benjamin J. Solomon, MD, is with the University of Melbourne. Dr. Thai disclosed no conflicts of interest. Dr. Solomon disclosed advisory board relationships with Roche-Genentech, Pfizer, Novartis, AstraZeneca, Merck, and Bristol-Myers Squibb. These comments are from their editorial (Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy415).
For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.
Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.
The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.
ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.
Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.
The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.
“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.
Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”
F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.
SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.
For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.
Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.
The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.
ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.
Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.
The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.
“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.
Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”
F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.
SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.
FROM ANNALS OF ONCOLOGY
Key clinical point: Alectinib showed superior CNS activity and significantly delayed CNS progression over crizotinib in patients with treatment-naive anaplastic lymphoma kinase–positive non–small cell lung cancer.
Major finding: Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) and was comparable among patients with and without baseline CNS metastases or prior radiotherapy.
Study details: A phase 3 trial of 303 patients receiving alectinib (600 mg) or crizotinib (250 mg) twice daily.
Disclosures: F. Hoffman-La Roche funded the study. Dr. Gadgeel disclosed honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.
Source: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.
What’s the best VTE treatment for patients with cancer?
EVIDENCE SUMMARY
No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.
Long-term LMWH decreases VTE recurrence compared with VKA
Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE1-5).
The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.1
The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.3
Initial therapy with LMWH: A look at mortality
A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.4
The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.
Fondaparinux shows no advantage for initial therapy
The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.4 It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.
Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA
Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA: No differences
A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.2
A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).5 Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.
RECOMMENDATIONS
The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.6
1. Akl EA, Kahale L, Barba M, et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(7):CD006650.
2. Posch F, Königsbrügge O, Zielinski C, et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res. 2015;136:582-589.
3. Rojas-Hernandez CM, Oo TH, García-Perdomo HA. Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis. J Thromb Thrombolysis. 2017;43:233-240.
4. Akl EA, Kahale L, Neumann I, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(6):CD006649.
5. Sardar P, Chatterjee S, Herzog E, et al. New oral anticoagulants in patients with cancer: current state of evidence. Am J Ther. 2015;22:460-468.
6. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.
EVIDENCE SUMMARY
No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.
Long-term LMWH decreases VTE recurrence compared with VKA
Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE1-5).
The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.1
The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.3
Initial therapy with LMWH: A look at mortality
A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.4
The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.
Fondaparinux shows no advantage for initial therapy
The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.4 It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.
Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA
Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA: No differences
A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.2
A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).5 Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.
RECOMMENDATIONS
The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.6
EVIDENCE SUMMARY
No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.
Long-term LMWH decreases VTE recurrence compared with VKA
Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE1-5).
The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.1
The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.3
Initial therapy with LMWH: A look at mortality
A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.4
The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.
Fondaparinux shows no advantage for initial therapy
The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.4 It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.
Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA
Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA: No differences
A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.2
A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).5 Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.
RECOMMENDATIONS
The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.6
1. Akl EA, Kahale L, Barba M, et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(7):CD006650.
2. Posch F, Königsbrügge O, Zielinski C, et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res. 2015;136:582-589.
3. Rojas-Hernandez CM, Oo TH, García-Perdomo HA. Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis. J Thromb Thrombolysis. 2017;43:233-240.
4. Akl EA, Kahale L, Neumann I, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(6):CD006649.
5. Sardar P, Chatterjee S, Herzog E, et al. New oral anticoagulants in patients with cancer: current state of evidence. Am J Ther. 2015;22:460-468.
6. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.
1. Akl EA, Kahale L, Barba M, et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(7):CD006650.
2. Posch F, Königsbrügge O, Zielinski C, et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res. 2015;136:582-589.
3. Rojas-Hernandez CM, Oo TH, García-Perdomo HA. Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis. J Thromb Thrombolysis. 2017;43:233-240.
4. Akl EA, Kahale L, Neumann I, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(6):CD006649.
5. Sardar P, Chatterjee S, Herzog E, et al. New oral anticoagulants in patients with cancer: current state of evidence. Am J Ther. 2015;22:460-468.
6. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.
EVIDENCE-BASED ANSWER:
No head-to-head studies directly compare all the main treatments for venous thromboembolism (VTE) in cancer patients. Long-term treatment (3-12 months) with low-molecular-weight heparin (LMWH) reduces recurrence of VTE by 40% compared with vitamin K antagonists (VKA), but doesn’t change rates of mortality, major or minor bleeding, or intracranial hemorrhage in patients with solid or hematologic cancer at any stage or in any age group. Initial treatment with LMWH reduces mortality by 30% compared with unfractionated heparin (UFH) for 5 to 10 days followed by warfarin, but doesn’t alter recurrent VTE or bleeding. Non-vitamin K oral anticoagulants (NOACs) have risks of recurrent VTE or VTE-related death (composite outcome) and clinically significant bleeding comparable to VKA or LMWH/VKA (strength of recommendation [SOR]: B, meta-analyses of randomized controlled trials [RCTs], mostly of low quality).
Astonished by physician hourly rate calculation
Astonished by physician hourly rate calculation
I always enjoy the articles and incredible insights presented in OBG Management. Some very sophisticated, well-founded ideas are presented in the article on deciding on purchasing medical equipment. Then, however, you get to the calculations: $50 for 30 minutes of physician time!
My plumber charges me $100 for the first half hour of a visit (okay, there are lots of cliched jokes about this), but on average a physician assistant costs almost that much. It is a sad day in the business of medicine when experts value the time of highly educated physicians at $100 per hour. Maybe someday we can expect to be reasonably compensated for our efforts and training. When I advise my colleagues, I calculate their time, depending on their practice model, between $300 and $400 per hour.
Hamid Banooni, MD
Farmington Hills, Michigan
Dr. Kim responds
I thank Dr. Banooni for his comment. I agree that physicians are highly skilled and educated and that their time deserves to be valued at more than $100 per hour. In the article and the example provided, the values (revenues, costs, and so on) were not meant to be exactly representative of the marketplace, but instead were used merely as an example for understanding the calculation tools for purchasing medical equipment. That being said, I arrived at the $100 per hour cost for physician time (included in the variable cost in the Figure, “Breakeven analysis for hysteroscope purchase for use in tubal sterilization”) for 2 primary reasons. First, to simplify the calculation, and second, to use an equivalent universal hourly salary ($100 per hour) for a physician’s comparative labor cost in the marketplace. Currently, the median hourly compensation for an ObGyn laborist is $110 per hour.1 To simplify, I rounded down to $100. I wholeheartedly agree with Dr. Banooni, however, that a physician’s time should be valued higher in society.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Society of Ob/Gyn Hospitalists. SOGH 2016 hospitalist employment and salary survey. 2016. https://www.societyofobgynhospitalists.org/assets/SOGH%202016%20Salary%20%20Employment%20Survey.pdf. Accessed September 24, 2018.
Astonished by physician hourly rate calculation
I always enjoy the articles and incredible insights presented in OBG Management. Some very sophisticated, well-founded ideas are presented in the article on deciding on purchasing medical equipment. Then, however, you get to the calculations: $50 for 30 minutes of physician time!
My plumber charges me $100 for the first half hour of a visit (okay, there are lots of cliched jokes about this), but on average a physician assistant costs almost that much. It is a sad day in the business of medicine when experts value the time of highly educated physicians at $100 per hour. Maybe someday we can expect to be reasonably compensated for our efforts and training. When I advise my colleagues, I calculate their time, depending on their practice model, between $300 and $400 per hour.
Hamid Banooni, MD
Farmington Hills, Michigan
Dr. Kim responds
I thank Dr. Banooni for his comment. I agree that physicians are highly skilled and educated and that their time deserves to be valued at more than $100 per hour. In the article and the example provided, the values (revenues, costs, and so on) were not meant to be exactly representative of the marketplace, but instead were used merely as an example for understanding the calculation tools for purchasing medical equipment. That being said, I arrived at the $100 per hour cost for physician time (included in the variable cost in the Figure, “Breakeven analysis for hysteroscope purchase for use in tubal sterilization”) for 2 primary reasons. First, to simplify the calculation, and second, to use an equivalent universal hourly salary ($100 per hour) for a physician’s comparative labor cost in the marketplace. Currently, the median hourly compensation for an ObGyn laborist is $110 per hour.1 To simplify, I rounded down to $100. I wholeheartedly agree with Dr. Banooni, however, that a physician’s time should be valued higher in society.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Astonished by physician hourly rate calculation
I always enjoy the articles and incredible insights presented in OBG Management. Some very sophisticated, well-founded ideas are presented in the article on deciding on purchasing medical equipment. Then, however, you get to the calculations: $50 for 30 minutes of physician time!
My plumber charges me $100 for the first half hour of a visit (okay, there are lots of cliched jokes about this), but on average a physician assistant costs almost that much. It is a sad day in the business of medicine when experts value the time of highly educated physicians at $100 per hour. Maybe someday we can expect to be reasonably compensated for our efforts and training. When I advise my colleagues, I calculate their time, depending on their practice model, between $300 and $400 per hour.
Hamid Banooni, MD
Farmington Hills, Michigan
Dr. Kim responds
I thank Dr. Banooni for his comment. I agree that physicians are highly skilled and educated and that their time deserves to be valued at more than $100 per hour. In the article and the example provided, the values (revenues, costs, and so on) were not meant to be exactly representative of the marketplace, but instead were used merely as an example for understanding the calculation tools for purchasing medical equipment. That being said, I arrived at the $100 per hour cost for physician time (included in the variable cost in the Figure, “Breakeven analysis for hysteroscope purchase for use in tubal sterilization”) for 2 primary reasons. First, to simplify the calculation, and second, to use an equivalent universal hourly salary ($100 per hour) for a physician’s comparative labor cost in the marketplace. Currently, the median hourly compensation for an ObGyn laborist is $110 per hour.1 To simplify, I rounded down to $100. I wholeheartedly agree with Dr. Banooni, however, that a physician’s time should be valued higher in society.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Society of Ob/Gyn Hospitalists. SOGH 2016 hospitalist employment and salary survey. 2016. https://www.societyofobgynhospitalists.org/assets/SOGH%202016%20Salary%20%20Employment%20Survey.pdf. Accessed September 24, 2018.
- Society of Ob/Gyn Hospitalists. SOGH 2016 hospitalist employment and salary survey. 2016. https://www.societyofobgynhospitalists.org/assets/SOGH%202016%20Salary%20%20Employment%20Survey.pdf. Accessed September 24, 2018.
How effectively do ACE inhibitors and ARBs prevent migraines?
EVIDENCE SUMMARY
A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine1 headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE1). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.
Lisinopril reduces hours, days with headache and days with migraine
The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.2 Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.
Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).
Candesartan also decreases headaches and migraine
The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.3 It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.
Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.
Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).
Continue to: Overall both drugs have a significant effect on number of headaches
Overall both drugs have a significant effect on number of headaches
Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).1 (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).1
RECOMMENDATIONS
In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.4 The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”
1. Jackson JL, Cogbil E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One. 2015;10:e0130733.
2. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo controlled, crossover study. BMJ. 2001;322:19-22.
3. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
EVIDENCE SUMMARY
A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine1 headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE1). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.
Lisinopril reduces hours, days with headache and days with migraine
The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.2 Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.
Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).
Candesartan also decreases headaches and migraine
The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.3 It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.
Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.
Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).
Continue to: Overall both drugs have a significant effect on number of headaches
Overall both drugs have a significant effect on number of headaches
Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).1 (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).1
RECOMMENDATIONS
In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.4 The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”
EVIDENCE SUMMARY
A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine1 headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE1). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.
Lisinopril reduces hours, days with headache and days with migraine
The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.2 Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.
Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).
Candesartan also decreases headaches and migraine
The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.3 It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.
Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.
Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).
Continue to: Overall both drugs have a significant effect on number of headaches
Overall both drugs have a significant effect on number of headaches
Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).1 (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).1
RECOMMENDATIONS
In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.4 The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”
1. Jackson JL, Cogbil E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One. 2015;10:e0130733.
2. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo controlled, crossover study. BMJ. 2001;322:19-22.
3. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
1. Jackson JL, Cogbil E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One. 2015;10:e0130733.
2. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo controlled, crossover study. BMJ. 2001;322:19-22.
3. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
EVIDENCE-BASED ANSWER:
The angiotensin-converting enzyme (ACE) inhibitor lisinopril reduces the number of migraines by about 1.5 per month in patients experiencing 2 to 6 migraines monthly (strength of recommendation [SOR]: B, small crossover trial); the angiotensin II receptor blocker (ARB) candesartan may produce a similar reduction (SOR: C, conflicting crossover trials).
Considered as a group, ACE inhibitors and ARBs have a moderate to large effect on the frequency of migraine headaches (SOR: B, meta-analysis of small clinical trials), although only lisinopril and candesartan show fair to good evidence of efficacy.
Providers may consider lisinopril or candesartan for migraine prevention, taking into account their effect on other medical conditions (SOR: C, expert opinion).
