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Revised ACA premium calculator could up uninsured rate
– changes that critics caution could leave more people uninsured.
But the Centers for Medicare & Medicaid Services says the changes would lower premiums and give enrollees the option to choose a plan that doesn’t offer abortion services.
The CMS released the proposed rule online Jan. 17, and it’s expected to be published in the Federal Register Jan. 24. (A fact sheet highlighting the changes can be found here.)
Under one of the proposals, the CMS would alter the risk-adjustment model used to determine premium growth beginning in 2020.
But the proposed rule’s regulatory impact statement notes that the risk-adjustment change could reduce enrollment in health insurance products through the federal exchanges by 100,000 people in each of the years from 2020 through 2023. And the revised risk-adjustment model could reduce federal spending on premium tax credits by $900 million in both 2020 and 2021, and by $1 billion in 2022 and 2023.
“Some of the 100,000 individuals estimated to enroll in exchange coverage as a result of the proposed change ... may purchase short-term, limited-duration insurance, though a majority is likely to become uninsured,” the CMS stated in its proposed rule. “Either transition may result in greater exposure to health care costs, which previous research suggests reduces utilization of health care services.”
Matt Fiedler, fellow at the Brookings Institution’s Center for Health Policy, highlighted the potential effect a drop in premium tax credits could have on potential enrollees.
According to Mr. Fiedler, a single person at 300% of the federal poverty level (FPL) would lose $92 per year in premium tax credits. And a family of four at 300% of FPL would lose $189 per year in premium tax credits, he calculated. He predicted “smaller effects at lower income levels and larger effects at higher income levels.”
The proposed rule would also require issuers of qualified health plans that offer abortion services to provide at least one “mirror” plan that omits abortion coverage. That could lead insurers to drop abortion coverage in their qualified health plans, the CMS noted, but it didn’t estimate how many issuers are expected to drop abortion coverage.
The agency said the proposed requirement “would increase consumer choice by offering additional plan options to potential enrollees who may refuse to enroll in, or may be discouraged from enrolling in, qualified health plans because the plans in their service area cover non-Hyde abortion services.” The CMS conceded that the existence of two such plans could confuse consumers, and “research has shown that offering consumers additional health plan options may result in consumers opting to not purchase a plan at all.”
The CMS also is seeking comment on changes to the automatic re-enrollment policy.
“Most current enrollees receive significant government subsidies, making them potentially less sensitive to premiums and premium changes,” the agency stated in the proposed rule. “Some consumers who are automatically re-enrolled in their current plan may be shielded from changes to their coverage, which may result in consumers being less aware of their options from year to year.”
Comments on the proposed rule are due by Feb. 19.
– changes that critics caution could leave more people uninsured.
But the Centers for Medicare & Medicaid Services says the changes would lower premiums and give enrollees the option to choose a plan that doesn’t offer abortion services.
The CMS released the proposed rule online Jan. 17, and it’s expected to be published in the Federal Register Jan. 24. (A fact sheet highlighting the changes can be found here.)
Under one of the proposals, the CMS would alter the risk-adjustment model used to determine premium growth beginning in 2020.
But the proposed rule’s regulatory impact statement notes that the risk-adjustment change could reduce enrollment in health insurance products through the federal exchanges by 100,000 people in each of the years from 2020 through 2023. And the revised risk-adjustment model could reduce federal spending on premium tax credits by $900 million in both 2020 and 2021, and by $1 billion in 2022 and 2023.
“Some of the 100,000 individuals estimated to enroll in exchange coverage as a result of the proposed change ... may purchase short-term, limited-duration insurance, though a majority is likely to become uninsured,” the CMS stated in its proposed rule. “Either transition may result in greater exposure to health care costs, which previous research suggests reduces utilization of health care services.”
Matt Fiedler, fellow at the Brookings Institution’s Center for Health Policy, highlighted the potential effect a drop in premium tax credits could have on potential enrollees.
According to Mr. Fiedler, a single person at 300% of the federal poverty level (FPL) would lose $92 per year in premium tax credits. And a family of four at 300% of FPL would lose $189 per year in premium tax credits, he calculated. He predicted “smaller effects at lower income levels and larger effects at higher income levels.”
The proposed rule would also require issuers of qualified health plans that offer abortion services to provide at least one “mirror” plan that omits abortion coverage. That could lead insurers to drop abortion coverage in their qualified health plans, the CMS noted, but it didn’t estimate how many issuers are expected to drop abortion coverage.
The agency said the proposed requirement “would increase consumer choice by offering additional plan options to potential enrollees who may refuse to enroll in, or may be discouraged from enrolling in, qualified health plans because the plans in their service area cover non-Hyde abortion services.” The CMS conceded that the existence of two such plans could confuse consumers, and “research has shown that offering consumers additional health plan options may result in consumers opting to not purchase a plan at all.”
The CMS also is seeking comment on changes to the automatic re-enrollment policy.
“Most current enrollees receive significant government subsidies, making them potentially less sensitive to premiums and premium changes,” the agency stated in the proposed rule. “Some consumers who are automatically re-enrolled in their current plan may be shielded from changes to their coverage, which may result in consumers being less aware of their options from year to year.”
Comments on the proposed rule are due by Feb. 19.
– changes that critics caution could leave more people uninsured.
But the Centers for Medicare & Medicaid Services says the changes would lower premiums and give enrollees the option to choose a plan that doesn’t offer abortion services.
The CMS released the proposed rule online Jan. 17, and it’s expected to be published in the Federal Register Jan. 24. (A fact sheet highlighting the changes can be found here.)
Under one of the proposals, the CMS would alter the risk-adjustment model used to determine premium growth beginning in 2020.
But the proposed rule’s regulatory impact statement notes that the risk-adjustment change could reduce enrollment in health insurance products through the federal exchanges by 100,000 people in each of the years from 2020 through 2023. And the revised risk-adjustment model could reduce federal spending on premium tax credits by $900 million in both 2020 and 2021, and by $1 billion in 2022 and 2023.
“Some of the 100,000 individuals estimated to enroll in exchange coverage as a result of the proposed change ... may purchase short-term, limited-duration insurance, though a majority is likely to become uninsured,” the CMS stated in its proposed rule. “Either transition may result in greater exposure to health care costs, which previous research suggests reduces utilization of health care services.”
Matt Fiedler, fellow at the Brookings Institution’s Center for Health Policy, highlighted the potential effect a drop in premium tax credits could have on potential enrollees.
According to Mr. Fiedler, a single person at 300% of the federal poverty level (FPL) would lose $92 per year in premium tax credits. And a family of four at 300% of FPL would lose $189 per year in premium tax credits, he calculated. He predicted “smaller effects at lower income levels and larger effects at higher income levels.”
The proposed rule would also require issuers of qualified health plans that offer abortion services to provide at least one “mirror” plan that omits abortion coverage. That could lead insurers to drop abortion coverage in their qualified health plans, the CMS noted, but it didn’t estimate how many issuers are expected to drop abortion coverage.
The agency said the proposed requirement “would increase consumer choice by offering additional plan options to potential enrollees who may refuse to enroll in, or may be discouraged from enrolling in, qualified health plans because the plans in their service area cover non-Hyde abortion services.” The CMS conceded that the existence of two such plans could confuse consumers, and “research has shown that offering consumers additional health plan options may result in consumers opting to not purchase a plan at all.”
The CMS also is seeking comment on changes to the automatic re-enrollment policy.
“Most current enrollees receive significant government subsidies, making them potentially less sensitive to premiums and premium changes,” the agency stated in the proposed rule. “Some consumers who are automatically re-enrolled in their current plan may be shielded from changes to their coverage, which may result in consumers being less aware of their options from year to year.”
Comments on the proposed rule are due by Feb. 19.
How seizure prediction may benefit patients with epilepsy
NEW ORLEANS – For people with epilepsy, “the sudden and apparently unpredictable nature of seizures is one of the most disabling aspects of having the disorder,” said Michael Privitera, MD.
If a patient knew that “tomorrow will be a dangerous day” with a 50% chance of having a seizure, the patient could avoid hazardous activities, try to reduce stress, or increase supervision to reduce the risk of sudden, unexpected death in epilepsy, said Dr. Privitera, professor of neurology and director of the epilepsy center at the University of Cincinnati Gardner Neuroscience Institute. Physicians might be able to intervene during high-risk periods by altering antiepileptic drug regimens.
Evidence suggests that seizure prediction is possible today and that advances in wearable devices and analysis of chronic EEG recordings likely will improve the ability to predict seizures, Dr. Privitera said at the annual meeting of the American Epilepsy Society. Studies have found that some patients can predict the likelihood of seizures in the next 24 hours better than chance. In the future, algorithms that incorporate variables such as pulse, stress, mood, electrodermal activity, circadian rhythms, and EEG may further refine seizure prediction.
A complex picture
One problem with predicting seizures is that “you can have substantial changes in the seizure tendency, but not have a seizure,” Dr. Privitera said. Stress, alcohol, and missed medications, for example, may affect the seizure threshold. “They may be additive, and it may be when those things all hit at once that a seizure happens.”
Many patients report prodromal or premonitory symptoms before a seizure. “Most of us as clinicians will say, ‘Well, maybe you have some inkling, but I don’t think you’re really able to predict it,’ ” Dr. Privitera said.
Sheryl R. Haut, MD, professor of neurology at the Albert Einstein College of Medicine, New York, and her colleagues prospectively looked at patient self-prediction in 2007 (Neurology. 2007 Jan 23;68[4]:262-6). The investigators followed 74 people with epilepsy who completed a daily diary in which they predicted the likelihood of a seizure occurring in the next 24 hours. Their analysis included approximately 15,000 diary days and 1,400 seizure days.
A subset of participants, about 20%, was significantly better than chance at predicting when a seizure would happen. If a patient in this subgroup said that a seizure was extremely likely, then a seizure occurred approximately 37% of the time. If a patient predicted that a seizure was extremely unlikely, there was about a 10% chance of having a seizure.
“This was a pretty substantial difference,” Dr. Privitera said. Combining patients’ predictions with their self-reported stress levels seemed to yield the most accurate predictions.
Stress and the SMILE study
About 90% of people with epilepsy identify at least one seizure precipitant, and the most commonly cited trigger is stress. When Dr. Privitera and his colleagues surveyed patients in their clinic, 82% identified stress as a trigger (Epilepsy Behav. 2014 Dec;41:74-7). More than half of these patients had used some form of stress reduction, such as exercise, yoga, or meditation; 88% of those patients thought that stress reduction helped their seizures.
Underlying anxiety was the only difference between patients who thought that their seizures were triggered by stress and those who did not. Patients who did not think that stress triggered their seizures had significantly lower scores on the Generalized Anxiety Disorders–7.
Subsequently, Dr. Haut, Dr. Privitera, and colleagues conducted the Stress Management Intervention for Living with Epilepsy (SMILE) study, a prospective, controlled trial assessing the efficacy of a stress reduction intervention for reducing seizures, as well as measuring seizure self-prediction (Neurology. 2018 Mar 13;90[11]:e963-70). The researchers randomized patients to a progressive muscle relaxation intervention or to a control group; patients in the control group wrote down their activities for the day.
Patients posted diary entries twice daily into a smartphone, reporting stress levels and mood-related variables. As in Dr. Haut’s earlier study, patients predicted whether having a seizure was extremely unlikely, unlikely, neutral, likely, or extremely likely. Mood and stress variables (such as feeling unpleasant or pleasant, relaxed or stressed, and not worried or extremely worried) were ranked on a visual analog scale from 0 to 100.
The trial included participants who had at least two seizures per month and any seizure trigger. Medications were kept stable throughout the study. During a 2-month baseline, patients tracked their seizures and stress levels. During the 3-month treatment period, patients received the active or control intervention.
In all, 64 subjects completed the study, completing all diary entries on 94% of the days. In the active-treatment group, median seizure frequency decreased by 29%, compared with a 25% decrease in the control group. However, the difference between the groups was not statistically significant. Although the 25% reduction in the control group probably is partly attributable to the placebo effect, part of the decrease may be related to a mindfulness effect from completing the diary, Dr. Privitera said.
The active-treatment group had a statistically significant reduction in self-reported stress, compared with the control group, but this decrease did not correlate with seizure reduction. Changes in anxiety levels also did not correlate with seizures.
“It does not disprove the [stress] hypothesis, but it does tell us that there is more going on with stress and seizure triggers than just patients’ self-reported stress,” Dr. Privitera said.
Patients’ predictions
The seizure prediction findings in SMILE were similar to those of Dr. Haut’s earlier study. Among the 10 highest predictors out of the 64 participants, “when they said that a seizure was extremely likely, they were 8.36 times more likely to have a seizure than when they said a seizure was extremely unlikely,” Dr. Privitera said.
Many patients seemed to increase their predicted seizure probabilities in the days after having a seizure. In addition, feeling sad, nervous, worried, tense, or stressed significantly increased the likelihood that a patient would predict that a seizure was coming. However, these feelings were “not very accurate [for predicting] actual seizures,” he said. “Some people are better predictors, but really the basis of that prediction remains to be seen. One of my hypotheses is that some of these people may actually be responding to subclinical EEG changes.”
Together, these self-prediction studies include data from 4,500 seizures and 26,000 diary entries and show that “there is some information in patient self-report that can help us in understanding how to predict and when to predict seizures,” Dr. Privitera said.
Incorporating cardiac, EEG, and other variables
Various other factors may warrant inclusion in a seizure forecasting system. A new vagus nerve stimulation system responds to heart rate changes that occur at seizure onset. And for decades, researchers have studied the potential for EEG readings to predict seizures. A 2008 analysis of 47 reports concluded that limited progress had been made in predicting a seizure from interictal EEG (Epilepsy Behav. 2008 Jan;12[1]:128-35). Now, however, long-term intracranial recordings are providing new and important information about EEG patterns.
Whereas early studies examined EEG recordings from epilepsy monitoring units – when patients may have been sleep deprived, had medications removed, or recently undergone surgery – chronic intracranial recordings from devices such as the RNS (responsive neurostimulation) System have allowed researchers to look long term at EEG changes that are more representative of patients’ typical EEG patterns.
The RNS System detects interictal spikes and seizure discharges and then provides an electrical stimulation to stop seizures. “When you look at these recordings, there are a lot more electrographic seizures than clinical seizures that trigger these stimulations,” said Dr. Privitera. “If you look at somebody with a typical RNS, they may have 100 stimulations in a day and no clinical seizures. There are lots and lots of subclinical electrographic bursts – and not just spikes, but things that look like short electrographic seizures – that occur throughout the day.”
A handheld device
Researchers in Melbourne designed a system that uses implanted electrodes to provide chronic recordings (Lancet Neurol. 2013 Jun;12[6]:563-71). An algorithm then learned to predict the likelihood of a seizure from the patient’s data as the system recorded over time. The system could indicate when a seizure was likely by displaying a light on a handheld device. Patients were recorded for between 6 months and 3 years.
“There was a statistically significant ability to predict when seizures were happening,” Dr. Privitera said. “There is information in long-term intracranial recordings in many of these people that will help allow us to do a better prediction than what we are able to do right now, which is essentially not much.”
This research suggests that pooling data across patients may not be an effective seizure prediction strategy because different epilepsy types have different patterns. In addition, an individual’s patterns may differ from a group’s patterns. Complicating matters, individual patients may have multiple seizure types with different onset mechanisms.
“Another important lesson is that false positives in a deterministic sense may not represent false positives in a probabilistic sense,” Dr. Privitera said. “That is, when the seizure prediction program – whether it is the diary or the intracranial EEG or anything else – says the threshold changed, but you did not have a seizure, it does not mean that your prediction system was wrong. If the seizure tendency is going up … and your system says the seizure tendency went up, but all you are measuring is actual seizures, it looks like it is a false positive prediction of seizures. But in fact it is a true positive prediction of the seizure tendency changing but not necessarily reaching seizure threshold.”
Multiday patterns
Recent research shows that “we are just at the start,” Dr. Privitera said. “There are patterns underlying seizure frequency that … we are only beginning to be able to look at because of these chronic recordings.”
Baud et al. analyzed interictal epileptiform activity and seizures in patients who have had responsive neurostimulators for as long as 10 years (Nat Commun. 2018 Jan 8;9[1]:88). “What they found was that interictal spikes and rhythmic discharges oscillate with circadian and multiday periods that differ from person to person,” Dr. Privitera said. “There were multiday periodicities, most commonly in the 20- to 30-day duration, that were relatively stable over periods of time that lasted up to years.”
Researchers knew that seizures in women of childbearing age can cluster in association with the menstrual cycle, but similar cycles also were seen in men. In addition, the researchers found that seizures “occur preferentially during the rising phase of these multiday interictal rhythms,” which has implications for seizure forecasts, Dr. Privitera noted.
Stress biomarkers and wearables
Future seizure prediction methods may incorporate other biomarkers, such as stress hormones. A researcher at the University of Cincinnati, Jason Heikenfeld, PhD, is conducting research with a sensor that sticks to the wrist and measures sweat content, Dr. Privitera said. The technology originally was developed to measure sodium and potassium in sweat, but Dr. Privitera’s group has been working with him to measure cortisol, which may be a biomarker for stress and be useful for seizure prediction.
“Multivariate models are needed. We have lots of different ways that we can look at seizure prediction, and most likely the most accurate seizure prediction programs will incorporate multiple different areas,” Dr. Privitera said. “Seizure forecasting is possible. We can do it now. We can probably do it better than chance in many patients. ... It is important because changes in seizure likelihood could lead to pharmacologic or device or behavioral interventions that may help prevent seizures.”
Dr. Privitera reported conducting contracted research for Greenwich and SK Life Science and receiving consulting fees from Upsher-Smith and Astellas.
SOURCE: Privitera M. AES 2018, Judith Hoyer Lecture in Epilepsy.
NEW ORLEANS – For people with epilepsy, “the sudden and apparently unpredictable nature of seizures is one of the most disabling aspects of having the disorder,” said Michael Privitera, MD.
If a patient knew that “tomorrow will be a dangerous day” with a 50% chance of having a seizure, the patient could avoid hazardous activities, try to reduce stress, or increase supervision to reduce the risk of sudden, unexpected death in epilepsy, said Dr. Privitera, professor of neurology and director of the epilepsy center at the University of Cincinnati Gardner Neuroscience Institute. Physicians might be able to intervene during high-risk periods by altering antiepileptic drug regimens.
Evidence suggests that seizure prediction is possible today and that advances in wearable devices and analysis of chronic EEG recordings likely will improve the ability to predict seizures, Dr. Privitera said at the annual meeting of the American Epilepsy Society. Studies have found that some patients can predict the likelihood of seizures in the next 24 hours better than chance. In the future, algorithms that incorporate variables such as pulse, stress, mood, electrodermal activity, circadian rhythms, and EEG may further refine seizure prediction.
A complex picture
One problem with predicting seizures is that “you can have substantial changes in the seizure tendency, but not have a seizure,” Dr. Privitera said. Stress, alcohol, and missed medications, for example, may affect the seizure threshold. “They may be additive, and it may be when those things all hit at once that a seizure happens.”
Many patients report prodromal or premonitory symptoms before a seizure. “Most of us as clinicians will say, ‘Well, maybe you have some inkling, but I don’t think you’re really able to predict it,’ ” Dr. Privitera said.
Sheryl R. Haut, MD, professor of neurology at the Albert Einstein College of Medicine, New York, and her colleagues prospectively looked at patient self-prediction in 2007 (Neurology. 2007 Jan 23;68[4]:262-6). The investigators followed 74 people with epilepsy who completed a daily diary in which they predicted the likelihood of a seizure occurring in the next 24 hours. Their analysis included approximately 15,000 diary days and 1,400 seizure days.
A subset of participants, about 20%, was significantly better than chance at predicting when a seizure would happen. If a patient in this subgroup said that a seizure was extremely likely, then a seizure occurred approximately 37% of the time. If a patient predicted that a seizure was extremely unlikely, there was about a 10% chance of having a seizure.
“This was a pretty substantial difference,” Dr. Privitera said. Combining patients’ predictions with their self-reported stress levels seemed to yield the most accurate predictions.
Stress and the SMILE study
About 90% of people with epilepsy identify at least one seizure precipitant, and the most commonly cited trigger is stress. When Dr. Privitera and his colleagues surveyed patients in their clinic, 82% identified stress as a trigger (Epilepsy Behav. 2014 Dec;41:74-7). More than half of these patients had used some form of stress reduction, such as exercise, yoga, or meditation; 88% of those patients thought that stress reduction helped their seizures.
Underlying anxiety was the only difference between patients who thought that their seizures were triggered by stress and those who did not. Patients who did not think that stress triggered their seizures had significantly lower scores on the Generalized Anxiety Disorders–7.
Subsequently, Dr. Haut, Dr. Privitera, and colleagues conducted the Stress Management Intervention for Living with Epilepsy (SMILE) study, a prospective, controlled trial assessing the efficacy of a stress reduction intervention for reducing seizures, as well as measuring seizure self-prediction (Neurology. 2018 Mar 13;90[11]:e963-70). The researchers randomized patients to a progressive muscle relaxation intervention or to a control group; patients in the control group wrote down their activities for the day.
Patients posted diary entries twice daily into a smartphone, reporting stress levels and mood-related variables. As in Dr. Haut’s earlier study, patients predicted whether having a seizure was extremely unlikely, unlikely, neutral, likely, or extremely likely. Mood and stress variables (such as feeling unpleasant or pleasant, relaxed or stressed, and not worried or extremely worried) were ranked on a visual analog scale from 0 to 100.
The trial included participants who had at least two seizures per month and any seizure trigger. Medications were kept stable throughout the study. During a 2-month baseline, patients tracked their seizures and stress levels. During the 3-month treatment period, patients received the active or control intervention.
In all, 64 subjects completed the study, completing all diary entries on 94% of the days. In the active-treatment group, median seizure frequency decreased by 29%, compared with a 25% decrease in the control group. However, the difference between the groups was not statistically significant. Although the 25% reduction in the control group probably is partly attributable to the placebo effect, part of the decrease may be related to a mindfulness effect from completing the diary, Dr. Privitera said.
The active-treatment group had a statistically significant reduction in self-reported stress, compared with the control group, but this decrease did not correlate with seizure reduction. Changes in anxiety levels also did not correlate with seizures.
“It does not disprove the [stress] hypothesis, but it does tell us that there is more going on with stress and seizure triggers than just patients’ self-reported stress,” Dr. Privitera said.
Patients’ predictions
The seizure prediction findings in SMILE were similar to those of Dr. Haut’s earlier study. Among the 10 highest predictors out of the 64 participants, “when they said that a seizure was extremely likely, they were 8.36 times more likely to have a seizure than when they said a seizure was extremely unlikely,” Dr. Privitera said.
Many patients seemed to increase their predicted seizure probabilities in the days after having a seizure. In addition, feeling sad, nervous, worried, tense, or stressed significantly increased the likelihood that a patient would predict that a seizure was coming. However, these feelings were “not very accurate [for predicting] actual seizures,” he said. “Some people are better predictors, but really the basis of that prediction remains to be seen. One of my hypotheses is that some of these people may actually be responding to subclinical EEG changes.”
Together, these self-prediction studies include data from 4,500 seizures and 26,000 diary entries and show that “there is some information in patient self-report that can help us in understanding how to predict and when to predict seizures,” Dr. Privitera said.
Incorporating cardiac, EEG, and other variables
Various other factors may warrant inclusion in a seizure forecasting system. A new vagus nerve stimulation system responds to heart rate changes that occur at seizure onset. And for decades, researchers have studied the potential for EEG readings to predict seizures. A 2008 analysis of 47 reports concluded that limited progress had been made in predicting a seizure from interictal EEG (Epilepsy Behav. 2008 Jan;12[1]:128-35). Now, however, long-term intracranial recordings are providing new and important information about EEG patterns.
Whereas early studies examined EEG recordings from epilepsy monitoring units – when patients may have been sleep deprived, had medications removed, or recently undergone surgery – chronic intracranial recordings from devices such as the RNS (responsive neurostimulation) System have allowed researchers to look long term at EEG changes that are more representative of patients’ typical EEG patterns.
The RNS System detects interictal spikes and seizure discharges and then provides an electrical stimulation to stop seizures. “When you look at these recordings, there are a lot more electrographic seizures than clinical seizures that trigger these stimulations,” said Dr. Privitera. “If you look at somebody with a typical RNS, they may have 100 stimulations in a day and no clinical seizures. There are lots and lots of subclinical electrographic bursts – and not just spikes, but things that look like short electrographic seizures – that occur throughout the day.”
A handheld device
Researchers in Melbourne designed a system that uses implanted electrodes to provide chronic recordings (Lancet Neurol. 2013 Jun;12[6]:563-71). An algorithm then learned to predict the likelihood of a seizure from the patient’s data as the system recorded over time. The system could indicate when a seizure was likely by displaying a light on a handheld device. Patients were recorded for between 6 months and 3 years.
“There was a statistically significant ability to predict when seizures were happening,” Dr. Privitera said. “There is information in long-term intracranial recordings in many of these people that will help allow us to do a better prediction than what we are able to do right now, which is essentially not much.”
This research suggests that pooling data across patients may not be an effective seizure prediction strategy because different epilepsy types have different patterns. In addition, an individual’s patterns may differ from a group’s patterns. Complicating matters, individual patients may have multiple seizure types with different onset mechanisms.
“Another important lesson is that false positives in a deterministic sense may not represent false positives in a probabilistic sense,” Dr. Privitera said. “That is, when the seizure prediction program – whether it is the diary or the intracranial EEG or anything else – says the threshold changed, but you did not have a seizure, it does not mean that your prediction system was wrong. If the seizure tendency is going up … and your system says the seizure tendency went up, but all you are measuring is actual seizures, it looks like it is a false positive prediction of seizures. But in fact it is a true positive prediction of the seizure tendency changing but not necessarily reaching seizure threshold.”
Multiday patterns
Recent research shows that “we are just at the start,” Dr. Privitera said. “There are patterns underlying seizure frequency that … we are only beginning to be able to look at because of these chronic recordings.”
Baud et al. analyzed interictal epileptiform activity and seizures in patients who have had responsive neurostimulators for as long as 10 years (Nat Commun. 2018 Jan 8;9[1]:88). “What they found was that interictal spikes and rhythmic discharges oscillate with circadian and multiday periods that differ from person to person,” Dr. Privitera said. “There were multiday periodicities, most commonly in the 20- to 30-day duration, that were relatively stable over periods of time that lasted up to years.”
Researchers knew that seizures in women of childbearing age can cluster in association with the menstrual cycle, but similar cycles also were seen in men. In addition, the researchers found that seizures “occur preferentially during the rising phase of these multiday interictal rhythms,” which has implications for seizure forecasts, Dr. Privitera noted.
Stress biomarkers and wearables
Future seizure prediction methods may incorporate other biomarkers, such as stress hormones. A researcher at the University of Cincinnati, Jason Heikenfeld, PhD, is conducting research with a sensor that sticks to the wrist and measures sweat content, Dr. Privitera said. The technology originally was developed to measure sodium and potassium in sweat, but Dr. Privitera’s group has been working with him to measure cortisol, which may be a biomarker for stress and be useful for seizure prediction.
“Multivariate models are needed. We have lots of different ways that we can look at seizure prediction, and most likely the most accurate seizure prediction programs will incorporate multiple different areas,” Dr. Privitera said. “Seizure forecasting is possible. We can do it now. We can probably do it better than chance in many patients. ... It is important because changes in seizure likelihood could lead to pharmacologic or device or behavioral interventions that may help prevent seizures.”
Dr. Privitera reported conducting contracted research for Greenwich and SK Life Science and receiving consulting fees from Upsher-Smith and Astellas.
SOURCE: Privitera M. AES 2018, Judith Hoyer Lecture in Epilepsy.
NEW ORLEANS – For people with epilepsy, “the sudden and apparently unpredictable nature of seizures is one of the most disabling aspects of having the disorder,” said Michael Privitera, MD.
If a patient knew that “tomorrow will be a dangerous day” with a 50% chance of having a seizure, the patient could avoid hazardous activities, try to reduce stress, or increase supervision to reduce the risk of sudden, unexpected death in epilepsy, said Dr. Privitera, professor of neurology and director of the epilepsy center at the University of Cincinnati Gardner Neuroscience Institute. Physicians might be able to intervene during high-risk periods by altering antiepileptic drug regimens.
Evidence suggests that seizure prediction is possible today and that advances in wearable devices and analysis of chronic EEG recordings likely will improve the ability to predict seizures, Dr. Privitera said at the annual meeting of the American Epilepsy Society. Studies have found that some patients can predict the likelihood of seizures in the next 24 hours better than chance. In the future, algorithms that incorporate variables such as pulse, stress, mood, electrodermal activity, circadian rhythms, and EEG may further refine seizure prediction.
A complex picture
One problem with predicting seizures is that “you can have substantial changes in the seizure tendency, but not have a seizure,” Dr. Privitera said. Stress, alcohol, and missed medications, for example, may affect the seizure threshold. “They may be additive, and it may be when those things all hit at once that a seizure happens.”
Many patients report prodromal or premonitory symptoms before a seizure. “Most of us as clinicians will say, ‘Well, maybe you have some inkling, but I don’t think you’re really able to predict it,’ ” Dr. Privitera said.
Sheryl R. Haut, MD, professor of neurology at the Albert Einstein College of Medicine, New York, and her colleagues prospectively looked at patient self-prediction in 2007 (Neurology. 2007 Jan 23;68[4]:262-6). The investigators followed 74 people with epilepsy who completed a daily diary in which they predicted the likelihood of a seizure occurring in the next 24 hours. Their analysis included approximately 15,000 diary days and 1,400 seizure days.
A subset of participants, about 20%, was significantly better than chance at predicting when a seizure would happen. If a patient in this subgroup said that a seizure was extremely likely, then a seizure occurred approximately 37% of the time. If a patient predicted that a seizure was extremely unlikely, there was about a 10% chance of having a seizure.
“This was a pretty substantial difference,” Dr. Privitera said. Combining patients’ predictions with their self-reported stress levels seemed to yield the most accurate predictions.
Stress and the SMILE study
About 90% of people with epilepsy identify at least one seizure precipitant, and the most commonly cited trigger is stress. When Dr. Privitera and his colleagues surveyed patients in their clinic, 82% identified stress as a trigger (Epilepsy Behav. 2014 Dec;41:74-7). More than half of these patients had used some form of stress reduction, such as exercise, yoga, or meditation; 88% of those patients thought that stress reduction helped their seizures.
Underlying anxiety was the only difference between patients who thought that their seizures were triggered by stress and those who did not. Patients who did not think that stress triggered their seizures had significantly lower scores on the Generalized Anxiety Disorders–7.
Subsequently, Dr. Haut, Dr. Privitera, and colleagues conducted the Stress Management Intervention for Living with Epilepsy (SMILE) study, a prospective, controlled trial assessing the efficacy of a stress reduction intervention for reducing seizures, as well as measuring seizure self-prediction (Neurology. 2018 Mar 13;90[11]:e963-70). The researchers randomized patients to a progressive muscle relaxation intervention or to a control group; patients in the control group wrote down their activities for the day.
Patients posted diary entries twice daily into a smartphone, reporting stress levels and mood-related variables. As in Dr. Haut’s earlier study, patients predicted whether having a seizure was extremely unlikely, unlikely, neutral, likely, or extremely likely. Mood and stress variables (such as feeling unpleasant or pleasant, relaxed or stressed, and not worried or extremely worried) were ranked on a visual analog scale from 0 to 100.
The trial included participants who had at least two seizures per month and any seizure trigger. Medications were kept stable throughout the study. During a 2-month baseline, patients tracked their seizures and stress levels. During the 3-month treatment period, patients received the active or control intervention.
In all, 64 subjects completed the study, completing all diary entries on 94% of the days. In the active-treatment group, median seizure frequency decreased by 29%, compared with a 25% decrease in the control group. However, the difference between the groups was not statistically significant. Although the 25% reduction in the control group probably is partly attributable to the placebo effect, part of the decrease may be related to a mindfulness effect from completing the diary, Dr. Privitera said.
The active-treatment group had a statistically significant reduction in self-reported stress, compared with the control group, but this decrease did not correlate with seizure reduction. Changes in anxiety levels also did not correlate with seizures.
“It does not disprove the [stress] hypothesis, but it does tell us that there is more going on with stress and seizure triggers than just patients’ self-reported stress,” Dr. Privitera said.
Patients’ predictions
The seizure prediction findings in SMILE were similar to those of Dr. Haut’s earlier study. Among the 10 highest predictors out of the 64 participants, “when they said that a seizure was extremely likely, they were 8.36 times more likely to have a seizure than when they said a seizure was extremely unlikely,” Dr. Privitera said.
Many patients seemed to increase their predicted seizure probabilities in the days after having a seizure. In addition, feeling sad, nervous, worried, tense, or stressed significantly increased the likelihood that a patient would predict that a seizure was coming. However, these feelings were “not very accurate [for predicting] actual seizures,” he said. “Some people are better predictors, but really the basis of that prediction remains to be seen. One of my hypotheses is that some of these people may actually be responding to subclinical EEG changes.”
Together, these self-prediction studies include data from 4,500 seizures and 26,000 diary entries and show that “there is some information in patient self-report that can help us in understanding how to predict and when to predict seizures,” Dr. Privitera said.
Incorporating cardiac, EEG, and other variables
Various other factors may warrant inclusion in a seizure forecasting system. A new vagus nerve stimulation system responds to heart rate changes that occur at seizure onset. And for decades, researchers have studied the potential for EEG readings to predict seizures. A 2008 analysis of 47 reports concluded that limited progress had been made in predicting a seizure from interictal EEG (Epilepsy Behav. 2008 Jan;12[1]:128-35). Now, however, long-term intracranial recordings are providing new and important information about EEG patterns.
Whereas early studies examined EEG recordings from epilepsy monitoring units – when patients may have been sleep deprived, had medications removed, or recently undergone surgery – chronic intracranial recordings from devices such as the RNS (responsive neurostimulation) System have allowed researchers to look long term at EEG changes that are more representative of patients’ typical EEG patterns.
The RNS System detects interictal spikes and seizure discharges and then provides an electrical stimulation to stop seizures. “When you look at these recordings, there are a lot more electrographic seizures than clinical seizures that trigger these stimulations,” said Dr. Privitera. “If you look at somebody with a typical RNS, they may have 100 stimulations in a day and no clinical seizures. There are lots and lots of subclinical electrographic bursts – and not just spikes, but things that look like short electrographic seizures – that occur throughout the day.”
A handheld device
Researchers in Melbourne designed a system that uses implanted electrodes to provide chronic recordings (Lancet Neurol. 2013 Jun;12[6]:563-71). An algorithm then learned to predict the likelihood of a seizure from the patient’s data as the system recorded over time. The system could indicate when a seizure was likely by displaying a light on a handheld device. Patients were recorded for between 6 months and 3 years.
“There was a statistically significant ability to predict when seizures were happening,” Dr. Privitera said. “There is information in long-term intracranial recordings in many of these people that will help allow us to do a better prediction than what we are able to do right now, which is essentially not much.”
This research suggests that pooling data across patients may not be an effective seizure prediction strategy because different epilepsy types have different patterns. In addition, an individual’s patterns may differ from a group’s patterns. Complicating matters, individual patients may have multiple seizure types with different onset mechanisms.
“Another important lesson is that false positives in a deterministic sense may not represent false positives in a probabilistic sense,” Dr. Privitera said. “That is, when the seizure prediction program – whether it is the diary or the intracranial EEG or anything else – says the threshold changed, but you did not have a seizure, it does not mean that your prediction system was wrong. If the seizure tendency is going up … and your system says the seizure tendency went up, but all you are measuring is actual seizures, it looks like it is a false positive prediction of seizures. But in fact it is a true positive prediction of the seizure tendency changing but not necessarily reaching seizure threshold.”
Multiday patterns
Recent research shows that “we are just at the start,” Dr. Privitera said. “There are patterns underlying seizure frequency that … we are only beginning to be able to look at because of these chronic recordings.”
Baud et al. analyzed interictal epileptiform activity and seizures in patients who have had responsive neurostimulators for as long as 10 years (Nat Commun. 2018 Jan 8;9[1]:88). “What they found was that interictal spikes and rhythmic discharges oscillate with circadian and multiday periods that differ from person to person,” Dr. Privitera said. “There were multiday periodicities, most commonly in the 20- to 30-day duration, that were relatively stable over periods of time that lasted up to years.”
Researchers knew that seizures in women of childbearing age can cluster in association with the menstrual cycle, but similar cycles also were seen in men. In addition, the researchers found that seizures “occur preferentially during the rising phase of these multiday interictal rhythms,” which has implications for seizure forecasts, Dr. Privitera noted.
Stress biomarkers and wearables
Future seizure prediction methods may incorporate other biomarkers, such as stress hormones. A researcher at the University of Cincinnati, Jason Heikenfeld, PhD, is conducting research with a sensor that sticks to the wrist and measures sweat content, Dr. Privitera said. The technology originally was developed to measure sodium and potassium in sweat, but Dr. Privitera’s group has been working with him to measure cortisol, which may be a biomarker for stress and be useful for seizure prediction.
“Multivariate models are needed. We have lots of different ways that we can look at seizure prediction, and most likely the most accurate seizure prediction programs will incorporate multiple different areas,” Dr. Privitera said. “Seizure forecasting is possible. We can do it now. We can probably do it better than chance in many patients. ... It is important because changes in seizure likelihood could lead to pharmacologic or device or behavioral interventions that may help prevent seizures.”
Dr. Privitera reported conducting contracted research for Greenwich and SK Life Science and receiving consulting fees from Upsher-Smith and Astellas.
SOURCE: Privitera M. AES 2018, Judith Hoyer Lecture in Epilepsy.
REPORTING FROM AES 2018
Ezetimibe effective as primary prevention
Also today, the FDA says that the benefits of paclitaxel-coated devices outweigh risks for peripheral arterial disease, flu activity is down for the second consecutive week, and a look at homelessness among LGBT youth in the United States.
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Also today, the FDA says that the benefits of paclitaxel-coated devices outweigh risks for peripheral arterial disease, flu activity is down for the second consecutive week, and a look at homelessness among LGBT youth in the United States.
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Also today, the FDA says that the benefits of paclitaxel-coated devices outweigh risks for peripheral arterial disease, flu activity is down for the second consecutive week, and a look at homelessness among LGBT youth in the United States.
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With RRMM and renal impairment, carfilzomib improves survival
Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.
In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.
Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.
The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.
In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.
For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).
Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).
The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.
Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).
“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.
Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.
Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.
However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.
The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”
These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.
The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.
SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.
Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.
In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.
Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.
The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.
In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.
For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).
Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).
The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.
Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).
“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.
Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.
Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.
However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.
The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”
These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.
The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.
SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.
Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.
In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.
Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.
The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.
In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.
For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).
Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).
The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.
Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).
“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.
Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.
Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.
However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.
The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”
These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.
The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.
SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.
FROM BLOOD
Key clinical point:
Major finding: Median progression-free survival was better with carfilzomib for patients with relapsed/refractory multiple myeloma (hazard ratios, 0.48-0.60).
Study details: Post hoc subgroup analysis of open-label randomized controlled trial of 929 patients receiving either carfilzomib or bortezomib with dexamethasone for relapsed/refractory multiple myeloma.
Disclosures: The authors reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and sponsored the study.
Source: Dimopoulos M et al. Blood. 2019;133(2):147-55.
Emphasize disease prevention in communications about HPV vaccine
Parents were much more confident about vaccinating their children against the human papillomavirus (HPV) when they were told about the diseases that the vaccine prevents rather than about safety, new research found.
In Pediatrics, researchers reported the outcomes of an online video-messaging study that attempted to address the most common parental questions and concerns about the HPV vaccine. They surveyed a national sample of 1,196 parents of children (aged 9-17 years) who watched four brief videos of a pediatrician talking about one of seven common concerns regarding HPV vaccination. The parents then were asked how each video affected them.
Parents who were exposed to messages about the diseases that the HPV vaccine prevented had the highest confidence in the HPV vaccine (46%). These messages included “HPV is a common virus that millions of people get every year. The HPV vaccine will protect your child from some cancers and genital warts” and “HPV infection can cause cancer in both men and women. The HPV vaccine will protect your child from many of these cancers.”
Similarly, parents exposed to messages about the need for HPV vaccination for both boys and girls also had the highest levels of confidence about HPV vaccination (44%).
Confidence was lower in parents exposed to messages about safety and side effects (30%)
“As such, reiterating vaccination benefits (including cancer prevention) when addressing concerns may also improve the impact of messages,” wrote Parth D. Shah, PhD, from the Fred Hutchinson Cancer Research Center, Seattle, and his coauthors.
Parents who received messages that expressed urgency about vaccination had lower confidence in the HPV vaccine.
“One reason may be that parents who are hesitant feel inappropriately rushed or that their concerns are not being treated with appropriate care,” the authors wrote.
However, messages that required a higher reading grade level and messages that were longer also seemed to inspire more confidence among parents. Parents who were exposed to messages about cancer prevention additionally were even more confident in HPV vaccine, Dr. Shah and his associates reported.
The study also found that 84% of parents wanted to talk to their children’s doctor about the diseases that the HPV vaccine prevented, while 68% wanted to talk about safety and side effects.
The study was funded by the Centers for Disease Control and Prevention and the National Cancer Institute. Dr. Shah was partially supported by an Agency for Healthcare Research and Quality grant. Another author declared being on paid advisory boards of research grants from Merck, Pfizer, and GlaxoSmithKline. No other conflicts of interest were declared.
SOURCE: Shah PD et al. Pediatrics. 2019 Feb. doi: 10.1542/peds.2018-1872.
Parents were much more confident about vaccinating their children against the human papillomavirus (HPV) when they were told about the diseases that the vaccine prevents rather than about safety, new research found.
In Pediatrics, researchers reported the outcomes of an online video-messaging study that attempted to address the most common parental questions and concerns about the HPV vaccine. They surveyed a national sample of 1,196 parents of children (aged 9-17 years) who watched four brief videos of a pediatrician talking about one of seven common concerns regarding HPV vaccination. The parents then were asked how each video affected them.
Parents who were exposed to messages about the diseases that the HPV vaccine prevented had the highest confidence in the HPV vaccine (46%). These messages included “HPV is a common virus that millions of people get every year. The HPV vaccine will protect your child from some cancers and genital warts” and “HPV infection can cause cancer in both men and women. The HPV vaccine will protect your child from many of these cancers.”
Similarly, parents exposed to messages about the need for HPV vaccination for both boys and girls also had the highest levels of confidence about HPV vaccination (44%).
Confidence was lower in parents exposed to messages about safety and side effects (30%)
“As such, reiterating vaccination benefits (including cancer prevention) when addressing concerns may also improve the impact of messages,” wrote Parth D. Shah, PhD, from the Fred Hutchinson Cancer Research Center, Seattle, and his coauthors.
Parents who received messages that expressed urgency about vaccination had lower confidence in the HPV vaccine.
“One reason may be that parents who are hesitant feel inappropriately rushed or that their concerns are not being treated with appropriate care,” the authors wrote.
However, messages that required a higher reading grade level and messages that were longer also seemed to inspire more confidence among parents. Parents who were exposed to messages about cancer prevention additionally were even more confident in HPV vaccine, Dr. Shah and his associates reported.
The study also found that 84% of parents wanted to talk to their children’s doctor about the diseases that the HPV vaccine prevented, while 68% wanted to talk about safety and side effects.
The study was funded by the Centers for Disease Control and Prevention and the National Cancer Institute. Dr. Shah was partially supported by an Agency for Healthcare Research and Quality grant. Another author declared being on paid advisory boards of research grants from Merck, Pfizer, and GlaxoSmithKline. No other conflicts of interest were declared.
SOURCE: Shah PD et al. Pediatrics. 2019 Feb. doi: 10.1542/peds.2018-1872.
Parents were much more confident about vaccinating their children against the human papillomavirus (HPV) when they were told about the diseases that the vaccine prevents rather than about safety, new research found.
In Pediatrics, researchers reported the outcomes of an online video-messaging study that attempted to address the most common parental questions and concerns about the HPV vaccine. They surveyed a national sample of 1,196 parents of children (aged 9-17 years) who watched four brief videos of a pediatrician talking about one of seven common concerns regarding HPV vaccination. The parents then were asked how each video affected them.
Parents who were exposed to messages about the diseases that the HPV vaccine prevented had the highest confidence in the HPV vaccine (46%). These messages included “HPV is a common virus that millions of people get every year. The HPV vaccine will protect your child from some cancers and genital warts” and “HPV infection can cause cancer in both men and women. The HPV vaccine will protect your child from many of these cancers.”
Similarly, parents exposed to messages about the need for HPV vaccination for both boys and girls also had the highest levels of confidence about HPV vaccination (44%).
Confidence was lower in parents exposed to messages about safety and side effects (30%)
“As such, reiterating vaccination benefits (including cancer prevention) when addressing concerns may also improve the impact of messages,” wrote Parth D. Shah, PhD, from the Fred Hutchinson Cancer Research Center, Seattle, and his coauthors.
Parents who received messages that expressed urgency about vaccination had lower confidence in the HPV vaccine.
“One reason may be that parents who are hesitant feel inappropriately rushed or that their concerns are not being treated with appropriate care,” the authors wrote.
However, messages that required a higher reading grade level and messages that were longer also seemed to inspire more confidence among parents. Parents who were exposed to messages about cancer prevention additionally were even more confident in HPV vaccine, Dr. Shah and his associates reported.
The study also found that 84% of parents wanted to talk to their children’s doctor about the diseases that the HPV vaccine prevented, while 68% wanted to talk about safety and side effects.
The study was funded by the Centers for Disease Control and Prevention and the National Cancer Institute. Dr. Shah was partially supported by an Agency for Healthcare Research and Quality grant. Another author declared being on paid advisory boards of research grants from Merck, Pfizer, and GlaxoSmithKline. No other conflicts of interest were declared.
SOURCE: Shah PD et al. Pediatrics. 2019 Feb. doi: 10.1542/peds.2018-1872.
FROM PEDIATRICS
Key clinical point: Information on the benefits of HPV vaccination can improve parent confidence.
Major finding: Messages about the disease and cancer prevention benefits of HPV vaccination inspired greater parent confidence.
Study details: Study in 1,196 parents of children aged 9-17 years.
Disclosures: The study was funded by the Centers for Disease Control and Prevention and the National Cancer Institute. Dr. Shah was partially supported by an Agency for Healthcare Research and Quality grant. Another author declared being on paid advisory boards of research grants from Merck, Pfizer, and GlaxoSmithKline. No other conflicts of interest were declared.
Source: Shah P et al. Pediatrics. 2019 Feb. doi. 10.1542/peds.2018-1872.
Renal transplant improves survival in lupus nephritis patients
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: Renal transplant is associated with a substantial survival benefit in patients with end-stage renal disease (ESRD) due to lupus nephritis,
Major finding: Transplant conferred a 70% reduction in overall death risk in these lupus nephritis ESRD patients, largely due to reduced deaths caused by infection and cardiovascular disease,
Study details: Analysis of 9,659 patients with lupus nephritis ESRD in the United States Renal Data System.
Disclosures: Support for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One co-author provided disclosures related to Teva Pharmaceuticals and Gilead Sciences.
Source: Jorge A, et al. Ann Intern Med. 2019 Jan 21. doi: 10.7326/M18-1570.
Doctors: Shutdown affects patient health
Also today, a mental disorder diagnosis increases the risk for all mental disorders, frailty may affect the expression of dementia, and nearly one-quarter of antibiotic fills are deemed unnecessary.
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Also today, a mental disorder diagnosis increases the risk for all mental disorders, frailty may affect the expression of dementia, and nearly one-quarter of antibiotic fills are deemed unnecessary.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, a mental disorder diagnosis increases the risk for all mental disorders, frailty may affect the expression of dementia, and nearly one-quarter of antibiotic fills are deemed unnecessary.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
CTPA may not rule out VTE in high-risk patients
Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?
Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.
Study design: Meta-analysis.
Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.
Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).
Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).
Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.
Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.
Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?
Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.
Study design: Meta-analysis.
Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.
Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).
Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).
Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.
Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.
Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?
Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.
Study design: Meta-analysis.
Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.
Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).
Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).
Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.
Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.
Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Platelet-rich plasma: Is your practice ready?
ORLANDO – Platelet-rich plasma offers much for patients and dermatologists: It’s low-risk, has a low cost of entry, and usefully augments other medications and procedures for androgenetic alopecia and facial rejuvenation.
But there’s work to be done in standardizing its use and really understanding where, when, and for whom platelet-rich plasma (PRP) will be best used, said Dierdre Hooper, MD, a dermatologist in private practice in New Orleans.
As far back as the 1970s, PRP was used as a transfusion product, with use expanding during the following decade. “It’s really the ‘everywhere’ product,’” said Dr. Hooper, speaking at the Aesthetic, Surgical, and Clinical Dermatology Conference (ODAC).
Over the course of the past four decades, PRP has been explored for musculoskeletal healing, in gynecology, urology, cardiac surgery, ophthalmology, and for plastic surgery. “Initial skepticism has given way as some evidence is building,” said Dr. Hooper.
PRP, considered a biologic product, is produced by centrifuging a donor venipuncture. Among the pros of using PRP in a clinical practice, said Dr. Hooper, is the fact that numerous clinical studies do show benefit. The risk is low, as is the cost, and downtime is brief. All of these contribute to attractiveness to patients, who also like the idea of an all-natural product with an autologous source.
But consensus is lacking about some key aspects of utilization, including the best mode of preparation and optimal treatment schedule. Outcomes can be unpredictable, making it tough to say how cost-effective the regimen will be for a particular patient. “The ‘cons’ just come down to no consensus,” said Dr. Hooper.
Some of the basic science makes a compelling case for PRP: Activated platelets have secretory granules. These modify the pericellular milieu through release of a variety of growth factors by secretory granules. “We all were taught back in the day that platelets adhere to promote clotting, but they do a lot more than that – when the platelet is activated, it releases growth factors,” said Dr. Hooper. “Big picture? Think: This is how we heal.”
After blood collection, the sample is centrifuged. The goal of centrifuging is to achieve a platelet concentration of 1 to 1.5 million platelets per mL, or four to six times the platelet concentration seen in whole blood. In practice, there are variations in the mode of preparation, and in an individual’s platelet level at the time of venipuncture, said Dr. Hooper, so it’s hard to know what the platelet “dose” is from PRP.
After centrifuging, the sample will be stratified into a bottom portion, consisting primarily of red blood cells, a middle portion that’s the PRP, and a top portion that is platelet-poor plasma. Dr. Hooper draws up and saves the platelet- poor plasma as well, since it probably also contains some growth factors. She’ll save that for application or injection after a PRP treatment for some patients.
Dermatology presents a host of uses for PRP. In addition to application after microneedling or resurfacing and injectable aesthetic uses, PRP can also be used to treat melasma, acne scarring, and androgenetic alopecia.
The strongest data for PRP currently are for androgenetic alopecia, said Dr. Hooper, because that’s where most of the work has been done to date. Growth factors in PRP can target the dermal papillae, shortening the anagen phase. “You will improve the anagen:telogen ratio and increase hair density and thickness,” she said.
“When you talk to your hair loss patients, there are drawbacks” with home therapy such as minoxidil and finasteride, said Dr. Hooper. “Compliance is an issue. I’m a firm believer in combination treatment for hair loss.” Studies have shown increased hair thickness and moderately decreased hair loss with PRP. Anecdotally, said Dr. Hooper, hair becomes coarser, feeling fuller and thicker; one study found that about a quarter of patients reported this effect.
Through experience, Dr. Hooper’s learned some pearls for using PRP for androgenetic alopecia. Her male patients appreciate the use of a chilling device to help with pain, especially since Dr. Hooper uses a triple-needle syringe to stamp the scalp as she injects the PRP. Depending on how her patients are tolerating the procedure, she’ll follow up by injecting some platelet-poor plasma as well.
An additional pearl? “Have your patients bring a baseball cap.” Between procedure preparation, some oozing of PRP, and bleeding from injection sites, men don’t leave as well-coiffed as when they entered, she said.
Dr. Hooper has patients return four times over the course of 6 months for androgenetic alopecia, with repeat treatments about every 6 months thereafter.
Several studies have looked at using intradermal PRP for facial rejuvenation, with largely positive results. “Once again, we see consistent efficacy with no side effects,” said Dr. Hooper. She will use PRP either intradermally or topically after microneedling or fractional ablative laser resurfacing.
If it’s being used topically, Dr. Hooper will simply wipe the PRP on after the resurfacing treatment. For microneedling, “As we finish one zone, we topically apply the PRP and move on,” she said, adding that she instructs the patient not to wash her face until bedtime.
“I like injectable delivery for PRP as well,” said Dr. Hooper. She will often use it for crepey skin under the eyes as an add-on to other treatments, she said.
Her patients report that one major upside of post-resurfacing PRP is that they feel they recover more quickly. “Less erythema and less recovery time – that’s something that’s always helpful,” said Dr. Hooper. She uses the same treatment schedule for rejuvenation as for alopecia.
Some studies have shown promise for injected PRP for striae, said Dr. Hooper. She has just begun using injected PRP for striae in her practice and is encouraged by early results she’s seeing. It’s easier for patients than using multiple at-home treatments: “I think it’s just an option, they can pop in 3 times over the next few months” for some added benefit, she said.
Scanning the audience, Dr. Hooper said, “I see a lot of younger faces out there. I would challenge you to do the studies” to build evidence-based protocols for PRP in dermatology, since lack of consensus still hinders both adoption and high-quality research.
Dr. Hooper reported multiple financial relationships with pharmaceutical and cosmetic companies.
SOURCE: Hooper, D. ODAC 2018.
ORLANDO – Platelet-rich plasma offers much for patients and dermatologists: It’s low-risk, has a low cost of entry, and usefully augments other medications and procedures for androgenetic alopecia and facial rejuvenation.
But there’s work to be done in standardizing its use and really understanding where, when, and for whom platelet-rich plasma (PRP) will be best used, said Dierdre Hooper, MD, a dermatologist in private practice in New Orleans.
As far back as the 1970s, PRP was used as a transfusion product, with use expanding during the following decade. “It’s really the ‘everywhere’ product,’” said Dr. Hooper, speaking at the Aesthetic, Surgical, and Clinical Dermatology Conference (ODAC).
Over the course of the past four decades, PRP has been explored for musculoskeletal healing, in gynecology, urology, cardiac surgery, ophthalmology, and for plastic surgery. “Initial skepticism has given way as some evidence is building,” said Dr. Hooper.
PRP, considered a biologic product, is produced by centrifuging a donor venipuncture. Among the pros of using PRP in a clinical practice, said Dr. Hooper, is the fact that numerous clinical studies do show benefit. The risk is low, as is the cost, and downtime is brief. All of these contribute to attractiveness to patients, who also like the idea of an all-natural product with an autologous source.
But consensus is lacking about some key aspects of utilization, including the best mode of preparation and optimal treatment schedule. Outcomes can be unpredictable, making it tough to say how cost-effective the regimen will be for a particular patient. “The ‘cons’ just come down to no consensus,” said Dr. Hooper.
Some of the basic science makes a compelling case for PRP: Activated platelets have secretory granules. These modify the pericellular milieu through release of a variety of growth factors by secretory granules. “We all were taught back in the day that platelets adhere to promote clotting, but they do a lot more than that – when the platelet is activated, it releases growth factors,” said Dr. Hooper. “Big picture? Think: This is how we heal.”
After blood collection, the sample is centrifuged. The goal of centrifuging is to achieve a platelet concentration of 1 to 1.5 million platelets per mL, or four to six times the platelet concentration seen in whole blood. In practice, there are variations in the mode of preparation, and in an individual’s platelet level at the time of venipuncture, said Dr. Hooper, so it’s hard to know what the platelet “dose” is from PRP.
After centrifuging, the sample will be stratified into a bottom portion, consisting primarily of red blood cells, a middle portion that’s the PRP, and a top portion that is platelet-poor plasma. Dr. Hooper draws up and saves the platelet- poor plasma as well, since it probably also contains some growth factors. She’ll save that for application or injection after a PRP treatment for some patients.
Dermatology presents a host of uses for PRP. In addition to application after microneedling or resurfacing and injectable aesthetic uses, PRP can also be used to treat melasma, acne scarring, and androgenetic alopecia.
The strongest data for PRP currently are for androgenetic alopecia, said Dr. Hooper, because that’s where most of the work has been done to date. Growth factors in PRP can target the dermal papillae, shortening the anagen phase. “You will improve the anagen:telogen ratio and increase hair density and thickness,” she said.
“When you talk to your hair loss patients, there are drawbacks” with home therapy such as minoxidil and finasteride, said Dr. Hooper. “Compliance is an issue. I’m a firm believer in combination treatment for hair loss.” Studies have shown increased hair thickness and moderately decreased hair loss with PRP. Anecdotally, said Dr. Hooper, hair becomes coarser, feeling fuller and thicker; one study found that about a quarter of patients reported this effect.
Through experience, Dr. Hooper’s learned some pearls for using PRP for androgenetic alopecia. Her male patients appreciate the use of a chilling device to help with pain, especially since Dr. Hooper uses a triple-needle syringe to stamp the scalp as she injects the PRP. Depending on how her patients are tolerating the procedure, she’ll follow up by injecting some platelet-poor plasma as well.
An additional pearl? “Have your patients bring a baseball cap.” Between procedure preparation, some oozing of PRP, and bleeding from injection sites, men don’t leave as well-coiffed as when they entered, she said.
Dr. Hooper has patients return four times over the course of 6 months for androgenetic alopecia, with repeat treatments about every 6 months thereafter.
Several studies have looked at using intradermal PRP for facial rejuvenation, with largely positive results. “Once again, we see consistent efficacy with no side effects,” said Dr. Hooper. She will use PRP either intradermally or topically after microneedling or fractional ablative laser resurfacing.
If it’s being used topically, Dr. Hooper will simply wipe the PRP on after the resurfacing treatment. For microneedling, “As we finish one zone, we topically apply the PRP and move on,” she said, adding that she instructs the patient not to wash her face until bedtime.
“I like injectable delivery for PRP as well,” said Dr. Hooper. She will often use it for crepey skin under the eyes as an add-on to other treatments, she said.
Her patients report that one major upside of post-resurfacing PRP is that they feel they recover more quickly. “Less erythema and less recovery time – that’s something that’s always helpful,” said Dr. Hooper. She uses the same treatment schedule for rejuvenation as for alopecia.
Some studies have shown promise for injected PRP for striae, said Dr. Hooper. She has just begun using injected PRP for striae in her practice and is encouraged by early results she’s seeing. It’s easier for patients than using multiple at-home treatments: “I think it’s just an option, they can pop in 3 times over the next few months” for some added benefit, she said.
Scanning the audience, Dr. Hooper said, “I see a lot of younger faces out there. I would challenge you to do the studies” to build evidence-based protocols for PRP in dermatology, since lack of consensus still hinders both adoption and high-quality research.
Dr. Hooper reported multiple financial relationships with pharmaceutical and cosmetic companies.
SOURCE: Hooper, D. ODAC 2018.
ORLANDO – Platelet-rich plasma offers much for patients and dermatologists: It’s low-risk, has a low cost of entry, and usefully augments other medications and procedures for androgenetic alopecia and facial rejuvenation.
But there’s work to be done in standardizing its use and really understanding where, when, and for whom platelet-rich plasma (PRP) will be best used, said Dierdre Hooper, MD, a dermatologist in private practice in New Orleans.
As far back as the 1970s, PRP was used as a transfusion product, with use expanding during the following decade. “It’s really the ‘everywhere’ product,’” said Dr. Hooper, speaking at the Aesthetic, Surgical, and Clinical Dermatology Conference (ODAC).
Over the course of the past four decades, PRP has been explored for musculoskeletal healing, in gynecology, urology, cardiac surgery, ophthalmology, and for plastic surgery. “Initial skepticism has given way as some evidence is building,” said Dr. Hooper.
PRP, considered a biologic product, is produced by centrifuging a donor venipuncture. Among the pros of using PRP in a clinical practice, said Dr. Hooper, is the fact that numerous clinical studies do show benefit. The risk is low, as is the cost, and downtime is brief. All of these contribute to attractiveness to patients, who also like the idea of an all-natural product with an autologous source.
But consensus is lacking about some key aspects of utilization, including the best mode of preparation and optimal treatment schedule. Outcomes can be unpredictable, making it tough to say how cost-effective the regimen will be for a particular patient. “The ‘cons’ just come down to no consensus,” said Dr. Hooper.
Some of the basic science makes a compelling case for PRP: Activated platelets have secretory granules. These modify the pericellular milieu through release of a variety of growth factors by secretory granules. “We all were taught back in the day that platelets adhere to promote clotting, but they do a lot more than that – when the platelet is activated, it releases growth factors,” said Dr. Hooper. “Big picture? Think: This is how we heal.”
After blood collection, the sample is centrifuged. The goal of centrifuging is to achieve a platelet concentration of 1 to 1.5 million platelets per mL, or four to six times the platelet concentration seen in whole blood. In practice, there are variations in the mode of preparation, and in an individual’s platelet level at the time of venipuncture, said Dr. Hooper, so it’s hard to know what the platelet “dose” is from PRP.
After centrifuging, the sample will be stratified into a bottom portion, consisting primarily of red blood cells, a middle portion that’s the PRP, and a top portion that is platelet-poor plasma. Dr. Hooper draws up and saves the platelet- poor plasma as well, since it probably also contains some growth factors. She’ll save that for application or injection after a PRP treatment for some patients.
Dermatology presents a host of uses for PRP. In addition to application after microneedling or resurfacing and injectable aesthetic uses, PRP can also be used to treat melasma, acne scarring, and androgenetic alopecia.
The strongest data for PRP currently are for androgenetic alopecia, said Dr. Hooper, because that’s where most of the work has been done to date. Growth factors in PRP can target the dermal papillae, shortening the anagen phase. “You will improve the anagen:telogen ratio and increase hair density and thickness,” she said.
“When you talk to your hair loss patients, there are drawbacks” with home therapy such as minoxidil and finasteride, said Dr. Hooper. “Compliance is an issue. I’m a firm believer in combination treatment for hair loss.” Studies have shown increased hair thickness and moderately decreased hair loss with PRP. Anecdotally, said Dr. Hooper, hair becomes coarser, feeling fuller and thicker; one study found that about a quarter of patients reported this effect.
Through experience, Dr. Hooper’s learned some pearls for using PRP for androgenetic alopecia. Her male patients appreciate the use of a chilling device to help with pain, especially since Dr. Hooper uses a triple-needle syringe to stamp the scalp as she injects the PRP. Depending on how her patients are tolerating the procedure, she’ll follow up by injecting some platelet-poor plasma as well.
An additional pearl? “Have your patients bring a baseball cap.” Between procedure preparation, some oozing of PRP, and bleeding from injection sites, men don’t leave as well-coiffed as when they entered, she said.
Dr. Hooper has patients return four times over the course of 6 months for androgenetic alopecia, with repeat treatments about every 6 months thereafter.
Several studies have looked at using intradermal PRP for facial rejuvenation, with largely positive results. “Once again, we see consistent efficacy with no side effects,” said Dr. Hooper. She will use PRP either intradermally or topically after microneedling or fractional ablative laser resurfacing.
If it’s being used topically, Dr. Hooper will simply wipe the PRP on after the resurfacing treatment. For microneedling, “As we finish one zone, we topically apply the PRP and move on,” she said, adding that she instructs the patient not to wash her face until bedtime.
“I like injectable delivery for PRP as well,” said Dr. Hooper. She will often use it for crepey skin under the eyes as an add-on to other treatments, she said.
Her patients report that one major upside of post-resurfacing PRP is that they feel they recover more quickly. “Less erythema and less recovery time – that’s something that’s always helpful,” said Dr. Hooper. She uses the same treatment schedule for rejuvenation as for alopecia.
Some studies have shown promise for injected PRP for striae, said Dr. Hooper. She has just begun using injected PRP for striae in her practice and is encouraged by early results she’s seeing. It’s easier for patients than using multiple at-home treatments: “I think it’s just an option, they can pop in 3 times over the next few months” for some added benefit, she said.
Scanning the audience, Dr. Hooper said, “I see a lot of younger faces out there. I would challenge you to do the studies” to build evidence-based protocols for PRP in dermatology, since lack of consensus still hinders both adoption and high-quality research.
Dr. Hooper reported multiple financial relationships with pharmaceutical and cosmetic companies.
SOURCE: Hooper, D. ODAC 2018.
EXPERT ANALYSIS FROM ODAC 2019
Ezetimibe found effective for primary prevention in elderly
CHICAGO – has been provided by the Japanese EWTOPIA 75 trial.
Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.
There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.
The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.
“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.
Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.
The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.
The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.
Ezetimibe was the lipid-lowering agent selected for EWTOPIA because it has an excellent safety record in older patients. There were no important differences between the two study arms in terms of adverse events, according to Dr. Ouchi.
Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.
She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.
“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.
“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.
Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.
“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.
As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.
Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
SOURCE: Ouchi Y. AHA Late Breaker 02.
CHICAGO – has been provided by the Japanese EWTOPIA 75 trial.
Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.
There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.
The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.
“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.
Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.
The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.
The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.
Ezetimibe was the lipid-lowering agent selected for EWTOPIA because it has an excellent safety record in older patients. There were no important differences between the two study arms in terms of adverse events, according to Dr. Ouchi.
Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.
She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.
“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.
“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.
Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.
“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.
As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.
Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
SOURCE: Ouchi Y. AHA Late Breaker 02.
CHICAGO – has been provided by the Japanese EWTOPIA 75 trial.
Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.
There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.
The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.
“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.
Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.
The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.
The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.
Ezetimibe was the lipid-lowering agent selected for EWTOPIA because it has an excellent safety record in older patients. There were no important differences between the two study arms in terms of adverse events, according to Dr. Ouchi.
Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.
She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.
“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.
“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.
Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.
“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.
As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.
Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
SOURCE: Ouchi Y. AHA Late Breaker 02.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: LDL-lowering for primary cardiovascular prevention in elderly patients has been shown for the first time to impart significant net benefit.
Major finding: The incidence of atherosclerotic cardiovascular events was reduced by 34% in elderly patients on ezetimibe at 10 mg/day, compared with usual care.
Study details: The 5-year prospective randomized EWTOPIA 75 trial included 3,796 Japanese patients age 75 and older with elevated LDL and no history of CAD.
Disclosures: The presenter reported having no financial conflicts regarding the study, sponsored by the Japanese government.
Source: Ouchi Y. AHA Late Breaker 02.