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Annual mammograms from age 40 linked with greatest reductions in mortality
Annual mammograms starting at age 40 and continuing until age 84 will achieve the greatest reductions in breast cancer deaths, according to a modeling study published in Cancer.
Researchers used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer models to compare three current mammography-based screening approaches for women at average risk of breast cancer. The first approach is for annual screening from ages 40-84 years, the second is a hybrid approach with annual screening from ages 45 to 54 then biennial screening from ages 55 to 79, and the third approach involves biennial mammograms from ages 50 to 74.
The modeling suggested that the largest mean reduction in mortality – 36.9% – was associated with annual screening starting at age 40. The second largest reduction of 30.8% occurred with the hybrid screening approach starting at age 45, while the smallest reduction in mortality – 23.2% – occurred with biennial screening starting at age 50 (Cancer 2017 Aug 21. doi: 10.1002/cncr.30842).
Annual screening also averted the most deaths from breast cancer – 11.9 per 1,000 women screened – and gained the most life-years (189 per 1,000 women screened, compared with 149 for the hybrid approach and 110 for biennial screening), reported Elizabeth K. Arleo, MD, of Weill Cornell Imaging at New York–Presbyterian, New York, and her coauthors.
However, the annual screening approach was also associated with the largest number of benign recalls and benign biopsies. The model suggested that a woman starting annual screening from age 40 could expect on average to be recalled for a benign diagnostic work-up every 13 years and undergo a benign biopsy every 187 years.
Overall, using a single-year cohort of women born in 1960 who were 100% compliant with screening, the model predicted that 44,671 would still die of breast cancer with annual screening, 51,211 would die under the hybrid screening model, and 56,887 would die under the biennial screening model.
“If the goal is to avert the most breast cancer deaths and gain the most life-years, CISNET modeling shows that the optimal age of initiation for screening mammography is 40 years, the optimal screening frequency is annual, and the optimal stopping age is when a woman’s life expectancy is less than 5-7 years,” the researchers wrote. “Individual women should continue to have the choice to reduce their risk of dying from breast cancer as much as possible, and as CISNET models show, annual mammography starting at age 40 years is the best way to do so.”
Two of the researchers reported consulting or institutional support from GE Healthcare. No other conflicts of interest were reported.
Annual mammograms starting at age 40 and continuing until age 84 will achieve the greatest reductions in breast cancer deaths, according to a modeling study published in Cancer.
Researchers used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer models to compare three current mammography-based screening approaches for women at average risk of breast cancer. The first approach is for annual screening from ages 40-84 years, the second is a hybrid approach with annual screening from ages 45 to 54 then biennial screening from ages 55 to 79, and the third approach involves biennial mammograms from ages 50 to 74.
The modeling suggested that the largest mean reduction in mortality – 36.9% – was associated with annual screening starting at age 40. The second largest reduction of 30.8% occurred with the hybrid screening approach starting at age 45, while the smallest reduction in mortality – 23.2% – occurred with biennial screening starting at age 50 (Cancer 2017 Aug 21. doi: 10.1002/cncr.30842).
Annual screening also averted the most deaths from breast cancer – 11.9 per 1,000 women screened – and gained the most life-years (189 per 1,000 women screened, compared with 149 for the hybrid approach and 110 for biennial screening), reported Elizabeth K. Arleo, MD, of Weill Cornell Imaging at New York–Presbyterian, New York, and her coauthors.
However, the annual screening approach was also associated with the largest number of benign recalls and benign biopsies. The model suggested that a woman starting annual screening from age 40 could expect on average to be recalled for a benign diagnostic work-up every 13 years and undergo a benign biopsy every 187 years.
Overall, using a single-year cohort of women born in 1960 who were 100% compliant with screening, the model predicted that 44,671 would still die of breast cancer with annual screening, 51,211 would die under the hybrid screening model, and 56,887 would die under the biennial screening model.
“If the goal is to avert the most breast cancer deaths and gain the most life-years, CISNET modeling shows that the optimal age of initiation for screening mammography is 40 years, the optimal screening frequency is annual, and the optimal stopping age is when a woman’s life expectancy is less than 5-7 years,” the researchers wrote. “Individual women should continue to have the choice to reduce their risk of dying from breast cancer as much as possible, and as CISNET models show, annual mammography starting at age 40 years is the best way to do so.”
Two of the researchers reported consulting or institutional support from GE Healthcare. No other conflicts of interest were reported.
Annual mammograms starting at age 40 and continuing until age 84 will achieve the greatest reductions in breast cancer deaths, according to a modeling study published in Cancer.
Researchers used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer models to compare three current mammography-based screening approaches for women at average risk of breast cancer. The first approach is for annual screening from ages 40-84 years, the second is a hybrid approach with annual screening from ages 45 to 54 then biennial screening from ages 55 to 79, and the third approach involves biennial mammograms from ages 50 to 74.
The modeling suggested that the largest mean reduction in mortality – 36.9% – was associated with annual screening starting at age 40. The second largest reduction of 30.8% occurred with the hybrid screening approach starting at age 45, while the smallest reduction in mortality – 23.2% – occurred with biennial screening starting at age 50 (Cancer 2017 Aug 21. doi: 10.1002/cncr.30842).
Annual screening also averted the most deaths from breast cancer – 11.9 per 1,000 women screened – and gained the most life-years (189 per 1,000 women screened, compared with 149 for the hybrid approach and 110 for biennial screening), reported Elizabeth K. Arleo, MD, of Weill Cornell Imaging at New York–Presbyterian, New York, and her coauthors.
However, the annual screening approach was also associated with the largest number of benign recalls and benign biopsies. The model suggested that a woman starting annual screening from age 40 could expect on average to be recalled for a benign diagnostic work-up every 13 years and undergo a benign biopsy every 187 years.
Overall, using a single-year cohort of women born in 1960 who were 100% compliant with screening, the model predicted that 44,671 would still die of breast cancer with annual screening, 51,211 would die under the hybrid screening model, and 56,887 would die under the biennial screening model.
“If the goal is to avert the most breast cancer deaths and gain the most life-years, CISNET modeling shows that the optimal age of initiation for screening mammography is 40 years, the optimal screening frequency is annual, and the optimal stopping age is when a woman’s life expectancy is less than 5-7 years,” the researchers wrote. “Individual women should continue to have the choice to reduce their risk of dying from breast cancer as much as possible, and as CISNET models show, annual mammography starting at age 40 years is the best way to do so.”
Two of the researchers reported consulting or institutional support from GE Healthcare. No other conflicts of interest were reported.
FROM CANCER
Key clinical point:
Major finding: Annual mammograms from age 40 are associated with a 36.9% mean reduction in mortality, compared with a 23.2% reduction with biennial screening from age 50.
Data source: A study using Cancer Intervention and Surveillance Modeling Network models.
Disclosures: Two of the researchers reported consulting or institutional support from GE Healthcare. No other conflicts of interest were reported.
The opioid crisis: Psychiatrists are well equipped to intervene
The U.S. opioid crisis and ongoing epidemic of chronic pain are inextricably intertwined, and psychiatrists are increasingly being called upon to intervene.
In a June 2016 blog post penned in the wake of new Centers for Disease Control and Prevention prescribing guidelines calling for a move away from opioids as the first-line treatment for many types of chronic noncancer pain, National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, decried the absence of psychiatrists on the front lines.
“Thus far, psychiatrists have not taken an active role in addressing the problem of chronic pain, but they have an important role to play here, for multiple reasons,” she wrote.
Chronic pain is closely linked to multiple psychiatric problems, she explained.
Furthermore, extensive evidence supports the use of some nonpharmacologic psychiatric therapies, she noted.
Indeed, there are numerous approaches, which have been shown to be effective or are showing promise in trials, that psychiatrists can take to intervene in the crisis and to help individual patients control pain and reduce the need for opioid medication. One that is underused and undervalued despite decades of research demonstrating its effectiveness, and which, according to David Spiegel, MD, has the potential to help at least two-thirds of affected adults, is hypnosis.
Power of hypnosis
“The brain has a whole lot to do with pain perception, and there’s a lot you can do to control it,” said Dr. Spiegel, the Jack, Samuel, and Lulu Willson Professor in Medicine in the department of psychiatry and behavioral sciences at Stanford (Calif.) University and a member of the Institute of Medicine.
And despite what many patients and physicians believe, it’s simply not true that if you’re not using a drug, you can’t actually control pain, he added.
For example, in a prospective randomized study of 241 patients undergoing percutaneous vascular and renal procedures, he and his colleagues found that self-hypnotic relaxation was superior to both intraoperative standard of care and structured attention (i.e., the “friendly nurse” group) for reducing pain and anxiety, and was better than standard of care for reducing drug use and reducing procedure time. It also improved hemodynamic stability compared with the other approaches (Lancet. 2000 Apr 29;355[9214]:1486-90).
“It works,” said Dr. Spiegel, also associate chair of the psychiatry department at Stanford.
Hypnotizability can be assessed using various validated scales; he said he can determine hypnotizability within 5 minutes, in part by giving a suggestion that the patient’s arm is getting lighter and is beginning to float. A component of involuntariness – if the patient’s arm feels like it is floating effortlessly and actually moves up in the air – indicates hypnotizability.
Most children, and about two of every three adults, can be hypnotized, he said.
Self-hypnosis, particularly in the chronic pain setting, can be life-changing, as patients can use it whenever needed once they learn how, he said, describing one young patient who had been suffering from intractable migraines and associated vomiting for years, and had failed to respond to numerous medications. Within minutes of being taught self-hypnosis, she said her pain had decreased from 7 to 3 on a 0-10 scale, and after coming out of the hypnotic state, she described feeling as rested as if she’d been sleeping for a decade.
Her mother broke down in tears of relief, Dr. Spiegel said.
Another patient who had suffered from immobilizing back pain had a similar experience: His back pain was immediately reduced by about 60% .
“Does it always work? No, but no treatment always works, and at worst it’s harmless,” Dr. Spiegel said, adding: “I don’t get people addicted to hypnosis. It just doesn’t happen.”
So why is hypnosis still considered outside the mainstream? In part that’s the case because of its “purple cape, dangling watch” image, but there also is a conception that hypnosis takes away control. In reality, it enhances control, he said.
“I think every psychiatrist – every physician – should know hypnosis,” he said.
Many, but not all medical schools teach hypnosis, and at least two U.S. societies – the American Society of Clinical Hypnosis and the Society for Clinical and Experimental Hypnosis – conduct workshops and annual scientific meetings where those interested can learn, he noted.
“It’s not that hard to learn ... and it’s a very useful skill for a professional,” he said.
Other approaches to pain management
For the one in three adults who are not hypnotizable, Dr. Spiegel teaches distraction techniques, and sometimes recommends acupuncture, which can be helpful for some patients. Exercise and physical therapy also can be of benefit for chronic pain.
“You can have very real pain that you can learn to deal with as people did throughout history. That doesn’t mean you should suffer unnecessarily; there is a time and place for opiates and other [pharmacologic] strategies, but they should be one among an array of choices,” he said, adding that for chronic pain, opioids can be more of a problem than a solution, and learning these techniques “can really help people safely deal with pain.”
Jeffrey Borckardt, PhD, professor and director of the division of biobehavioral medicine at the Medical University of South Carolina (MUSC), Charleston, agreed that hypnosis is a well-researched and effective treatment for pain, despite being better known for weight loss and smoking cessation. Another, lesser-known treatment that has been shown to have some effect for pain is acceptance and commitment therapy, or ACT, which incorporates the practice of mindfulness. 
A 2014 study (J Pain. 2014 Jan;15[1]:101-13) demonstrated a beneficial effect of ACT in nearly 50% of patients studied, and in a 2017 study (J Pain. 2017 Jun;18[6]:664-72), ACT was associated with improved function in chronic pain patients.
However, there is another well-researched – and well-known – nonpharmacologic approach to the treatment of pain: cognitive-behavioral therapy, or CBT. CBT isn’t as new and exciting as some experimental approaches that Dr. Borckardt is working with and studying, such as transcranial magnetic stimulation and transcranial direct current stimulation. But CBT is readily available and typically covered by insurance (unlike those experimental therapies), and has been shown in numerous studies to be highly effective, he said.
CBT and ‘360’ programs
CBT also was mentioned by Dr. Volkow in her June 2016 blog post. She called it “one of the most effective pain treatments,” and said that “assisting patients in learning to change their pain-related thoughts, emotions, and behaviors is going to help with their condition, regardless of other pharmacological interventions.”
Dr. Borckardt said it is particularly effective in the context of programs that provide what he called “a 360 approach.” These multifaceted treatment programs aim to help chronic pain patients taper off of opioid medications and to find other approaches to managing pain.
Only a handful of such comprehensive, intensive outpatient programs exist across the United States, but the concept is taking hold, driven in part by the opioid crisis, and more centers are opening. In fact, Dr. Borckardt is helping to develop such a program at MUSC. The program will likely be housed in the MUSC Wellness Center, and much like the Mayo Clinic’s Pain Rehabilitation Center, which opened in 1974 and was one of the first such programs in the world, the MUSC program will involve an integrated team of health care professionals that provide CBT for pain, physical therapy, occupational therapy, and other programs designed to help patients living with pain.
This is widely accepted as being the best approach for pain rehabilitation, Dr. Borckardt said.
TMS and TDCS
Dr. Borckardt also has worked with some more cutting-edge approaches to pain management. Transcranial magnetic stimulation (TMS), which is approved for the treatment of depression, also has shown promise for treating pain. TMS can target areas in the brain involved with specific functioning, such as emotional regulation. The high-frequency stimulation is believed to enhance that particular area and produce a clinical effect.
“Pain is a subjective, largely psychological experience, and it involves an emotional component,” he said, explaining that the rationale for the use of TMS for pain is that the emotional component of the pain experience can be targeted along with the sensory and cognitive aspects of the pain experience.
TMS is being used in various studies, and has been used off label for pain management, but the out-of-pocket cost is high because it is not currently approved for pain and is therefore not covered by insurance, he said.
For depression, TMS typically is used 5 days per week for 3 weeks – at a cost ranging anywhere from $100 to $500 per session. It remains unclear how many sessions would be required for pain treatment to produce a sustained effect, but it would likely be similar to the requirements for depression treatment, and may also require follow-up treatments, Dr. Borckardt said.
“We do know with reasonable confidence that it impacts pain perception and can impact sensory or emotional components of pain, depending on the part of the brain treated. But we don’t know how long we have to treat, how often, or how durable the effects are,” he said, noting that several groups are studying TMS for pain.
Notably, there is also some very preliminary evidence that TMS may be useful for treating addiction by affecting cravings for substances such as opiates, nicotine, and alcohol. If that effect is confirmed, TMS could help chronic pain patients reduce their need for higher opioid doses, thereby lowering the risk of overdose, which is an important factor in the opioid crisis; most patients who use opioids don’t become addicted, but they can be at risk for overdose because of the need for high doses to control their pain, he explained.
In one study, the use of TMS postoperatively reduced the amount of in-hospital drug use by 40%, he said, noting that the reduction could convert to a reduction in the use of pain medication after discharge as well.
A related treatment, transcranial direct current stimulation, or tDCS, involves placement of electrodes directly on the scalp to run weak electrical currents through the brain, again trying to alter areas associated with pain perception. Ongoing studies are looking at combining tDCS and CBT with the hope that the two will have synergistic effects, including one in veterans with low back pain and opioid misuse. Another small pilot study in patients with fibromyalgia recently concluded and had some promising results.
These and other nonpharmacologic approaches to pain management could play an important role in the effort to reduce opioid prescribing. Currently, about 90 Americans die each day after overdosing on opioids, according to NIDA, and the CDC estimates that prescription opioid misuse alone in the United States costs $78.5 billion per year in health care, lost productivity, addiction treatment, and criminal justice involvement.
In her plea to psychiatrists to take action to intervene, Dr. Volkow underscored the value that they bring to the table.
“It is crucial that we not lose sight of the reality and complexity of chronic pain as management of chronic noncancer pain moves toward greater caution around opioid medication. This should not be solely an issue for primary care medicine or neurology, but also for specialties such as psychiatry that have much to offer people who are suffering from complex disorders in which physical symptoms merge with psychological distress,” she wrote.
Dr. Volkow has written hundreds of peer-reviewed articles, including analyses of the opioid crisis (N Engl J Med. 2017 Jul 27;377[4]:391-4) and (Neuron. 2016 Oct 19[2]:294-7). Dr. Spiegel is coauthor of Trance and Treatment: Clinical Uses of Hypnosis (Washington: American Psychiatric Association Publishing, 2004), a textbook written to help psychiatrists and other physicians learn to use hypnosis. Dr. Borckardt receives research funding from the National Institutes of Health.
The U.S. opioid crisis and ongoing epidemic of chronic pain are inextricably intertwined, and psychiatrists are increasingly being called upon to intervene.
In a June 2016 blog post penned in the wake of new Centers for Disease Control and Prevention prescribing guidelines calling for a move away from opioids as the first-line treatment for many types of chronic noncancer pain, National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, decried the absence of psychiatrists on the front lines.
“Thus far, psychiatrists have not taken an active role in addressing the problem of chronic pain, but they have an important role to play here, for multiple reasons,” she wrote.
Chronic pain is closely linked to multiple psychiatric problems, she explained.
Furthermore, extensive evidence supports the use of some nonpharmacologic psychiatric therapies, she noted.
Indeed, there are numerous approaches, which have been shown to be effective or are showing promise in trials, that psychiatrists can take to intervene in the crisis and to help individual patients control pain and reduce the need for opioid medication. One that is underused and undervalued despite decades of research demonstrating its effectiveness, and which, according to David Spiegel, MD, has the potential to help at least two-thirds of affected adults, is hypnosis.
Power of hypnosis
“The brain has a whole lot to do with pain perception, and there’s a lot you can do to control it,” said Dr. Spiegel, the Jack, Samuel, and Lulu Willson Professor in Medicine in the department of psychiatry and behavioral sciences at Stanford (Calif.) University and a member of the Institute of Medicine.
And despite what many patients and physicians believe, it’s simply not true that if you’re not using a drug, you can’t actually control pain, he added.
For example, in a prospective randomized study of 241 patients undergoing percutaneous vascular and renal procedures, he and his colleagues found that self-hypnotic relaxation was superior to both intraoperative standard of care and structured attention (i.e., the “friendly nurse” group) for reducing pain and anxiety, and was better than standard of care for reducing drug use and reducing procedure time. It also improved hemodynamic stability compared with the other approaches (Lancet. 2000 Apr 29;355[9214]:1486-90).
“It works,” said Dr. Spiegel, also associate chair of the psychiatry department at Stanford.
Hypnotizability can be assessed using various validated scales; he said he can determine hypnotizability within 5 minutes, in part by giving a suggestion that the patient’s arm is getting lighter and is beginning to float. A component of involuntariness – if the patient’s arm feels like it is floating effortlessly and actually moves up in the air – indicates hypnotizability.
Most children, and about two of every three adults, can be hypnotized, he said.
Self-hypnosis, particularly in the chronic pain setting, can be life-changing, as patients can use it whenever needed once they learn how, he said, describing one young patient who had been suffering from intractable migraines and associated vomiting for years, and had failed to respond to numerous medications. Within minutes of being taught self-hypnosis, she said her pain had decreased from 7 to 3 on a 0-10 scale, and after coming out of the hypnotic state, she described feeling as rested as if she’d been sleeping for a decade.
Her mother broke down in tears of relief, Dr. Spiegel said.
Another patient who had suffered from immobilizing back pain had a similar experience: His back pain was immediately reduced by about 60% .
“Does it always work? No, but no treatment always works, and at worst it’s harmless,” Dr. Spiegel said, adding: “I don’t get people addicted to hypnosis. It just doesn’t happen.”
So why is hypnosis still considered outside the mainstream? In part that’s the case because of its “purple cape, dangling watch” image, but there also is a conception that hypnosis takes away control. In reality, it enhances control, he said.
“I think every psychiatrist – every physician – should know hypnosis,” he said.
Many, but not all medical schools teach hypnosis, and at least two U.S. societies – the American Society of Clinical Hypnosis and the Society for Clinical and Experimental Hypnosis – conduct workshops and annual scientific meetings where those interested can learn, he noted.
“It’s not that hard to learn ... and it’s a very useful skill for a professional,” he said.
Other approaches to pain management
For the one in three adults who are not hypnotizable, Dr. Spiegel teaches distraction techniques, and sometimes recommends acupuncture, which can be helpful for some patients. Exercise and physical therapy also can be of benefit for chronic pain.
“You can have very real pain that you can learn to deal with as people did throughout history. That doesn’t mean you should suffer unnecessarily; there is a time and place for opiates and other [pharmacologic] strategies, but they should be one among an array of choices,” he said, adding that for chronic pain, opioids can be more of a problem than a solution, and learning these techniques “can really help people safely deal with pain.”
Jeffrey Borckardt, PhD, professor and director of the division of biobehavioral medicine at the Medical University of South Carolina (MUSC), Charleston, agreed that hypnosis is a well-researched and effective treatment for pain, despite being better known for weight loss and smoking cessation. Another, lesser-known treatment that has been shown to have some effect for pain is acceptance and commitment therapy, or ACT, which incorporates the practice of mindfulness.
A 2014 study (J Pain. 2014 Jan;15[1]:101-13) demonstrated a beneficial effect of ACT in nearly 50% of patients studied, and in a 2017 study (J Pain. 2017 Jun;18[6]:664-72), ACT was associated with improved function in chronic pain patients.
However, there is another well-researched – and well-known – nonpharmacologic approach to the treatment of pain: cognitive-behavioral therapy, or CBT. CBT isn’t as new and exciting as some experimental approaches that Dr. Borckardt is working with and studying, such as transcranial magnetic stimulation and transcranial direct current stimulation. But CBT is readily available and typically covered by insurance (unlike those experimental therapies), and has been shown in numerous studies to be highly effective, he said.
CBT and ‘360’ programs
CBT also was mentioned by Dr. Volkow in her June 2016 blog post. She called it “one of the most effective pain treatments,” and said that “assisting patients in learning to change their pain-related thoughts, emotions, and behaviors is going to help with their condition, regardless of other pharmacological interventions.”
Dr. Borckardt said it is particularly effective in the context of programs that provide what he called “a 360 approach.” These multifaceted treatment programs aim to help chronic pain patients taper off of opioid medications and to find other approaches to managing pain.
Only a handful of such comprehensive, intensive outpatient programs exist across the United States, but the concept is taking hold, driven in part by the opioid crisis, and more centers are opening. In fact, Dr. Borckardt is helping to develop such a program at MUSC. The program will likely be housed in the MUSC Wellness Center, and much like the Mayo Clinic’s Pain Rehabilitation Center, which opened in 1974 and was one of the first such programs in the world, the MUSC program will involve an integrated team of health care professionals that provide CBT for pain, physical therapy, occupational therapy, and other programs designed to help patients living with pain.
This is widely accepted as being the best approach for pain rehabilitation, Dr. Borckardt said.
TMS and TDCS
Dr. Borckardt also has worked with some more cutting-edge approaches to pain management. Transcranial magnetic stimulation (TMS), which is approved for the treatment of depression, also has shown promise for treating pain. TMS can target areas in the brain involved with specific functioning, such as emotional regulation. The high-frequency stimulation is believed to enhance that particular area and produce a clinical effect.
“Pain is a subjective, largely psychological experience, and it involves an emotional component,” he said, explaining that the rationale for the use of TMS for pain is that the emotional component of the pain experience can be targeted along with the sensory and cognitive aspects of the pain experience.
TMS is being used in various studies, and has been used off label for pain management, but the out-of-pocket cost is high because it is not currently approved for pain and is therefore not covered by insurance, he said.
For depression, TMS typically is used 5 days per week for 3 weeks – at a cost ranging anywhere from $100 to $500 per session. It remains unclear how many sessions would be required for pain treatment to produce a sustained effect, but it would likely be similar to the requirements for depression treatment, and may also require follow-up treatments, Dr. Borckardt said.
“We do know with reasonable confidence that it impacts pain perception and can impact sensory or emotional components of pain, depending on the part of the brain treated. But we don’t know how long we have to treat, how often, or how durable the effects are,” he said, noting that several groups are studying TMS for pain.
Notably, there is also some very preliminary evidence that TMS may be useful for treating addiction by affecting cravings for substances such as opiates, nicotine, and alcohol. If that effect is confirmed, TMS could help chronic pain patients reduce their need for higher opioid doses, thereby lowering the risk of overdose, which is an important factor in the opioid crisis; most patients who use opioids don’t become addicted, but they can be at risk for overdose because of the need for high doses to control their pain, he explained.
In one study, the use of TMS postoperatively reduced the amount of in-hospital drug use by 40%, he said, noting that the reduction could convert to a reduction in the use of pain medication after discharge as well.
A related treatment, transcranial direct current stimulation, or tDCS, involves placement of electrodes directly on the scalp to run weak electrical currents through the brain, again trying to alter areas associated with pain perception. Ongoing studies are looking at combining tDCS and CBT with the hope that the two will have synergistic effects, including one in veterans with low back pain and opioid misuse. Another small pilot study in patients with fibromyalgia recently concluded and had some promising results.
These and other nonpharmacologic approaches to pain management could play an important role in the effort to reduce opioid prescribing. Currently, about 90 Americans die each day after overdosing on opioids, according to NIDA, and the CDC estimates that prescription opioid misuse alone in the United States costs $78.5 billion per year in health care, lost productivity, addiction treatment, and criminal justice involvement.
In her plea to psychiatrists to take action to intervene, Dr. Volkow underscored the value that they bring to the table.
“It is crucial that we not lose sight of the reality and complexity of chronic pain as management of chronic noncancer pain moves toward greater caution around opioid medication. This should not be solely an issue for primary care medicine or neurology, but also for specialties such as psychiatry that have much to offer people who are suffering from complex disorders in which physical symptoms merge with psychological distress,” she wrote.
Dr. Volkow has written hundreds of peer-reviewed articles, including analyses of the opioid crisis (N Engl J Med. 2017 Jul 27;377[4]:391-4) and (Neuron. 2016 Oct 19[2]:294-7). Dr. Spiegel is coauthor of Trance and Treatment: Clinical Uses of Hypnosis (Washington: American Psychiatric Association Publishing, 2004), a textbook written to help psychiatrists and other physicians learn to use hypnosis. Dr. Borckardt receives research funding from the National Institutes of Health.
The U.S. opioid crisis and ongoing epidemic of chronic pain are inextricably intertwined, and psychiatrists are increasingly being called upon to intervene.
In a June 2016 blog post penned in the wake of new Centers for Disease Control and Prevention prescribing guidelines calling for a move away from opioids as the first-line treatment for many types of chronic noncancer pain, National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, decried the absence of psychiatrists on the front lines.
“Thus far, psychiatrists have not taken an active role in addressing the problem of chronic pain, but they have an important role to play here, for multiple reasons,” she wrote.
Chronic pain is closely linked to multiple psychiatric problems, she explained.
Furthermore, extensive evidence supports the use of some nonpharmacologic psychiatric therapies, she noted.
Indeed, there are numerous approaches, which have been shown to be effective or are showing promise in trials, that psychiatrists can take to intervene in the crisis and to help individual patients control pain and reduce the need for opioid medication. One that is underused and undervalued despite decades of research demonstrating its effectiveness, and which, according to David Spiegel, MD, has the potential to help at least two-thirds of affected adults, is hypnosis.
Power of hypnosis
“The brain has a whole lot to do with pain perception, and there’s a lot you can do to control it,” said Dr. Spiegel, the Jack, Samuel, and Lulu Willson Professor in Medicine in the department of psychiatry and behavioral sciences at Stanford (Calif.) University and a member of the Institute of Medicine.
And despite what many patients and physicians believe, it’s simply not true that if you’re not using a drug, you can’t actually control pain, he added.
For example, in a prospective randomized study of 241 patients undergoing percutaneous vascular and renal procedures, he and his colleagues found that self-hypnotic relaxation was superior to both intraoperative standard of care and structured attention (i.e., the “friendly nurse” group) for reducing pain and anxiety, and was better than standard of care for reducing drug use and reducing procedure time. It also improved hemodynamic stability compared with the other approaches (Lancet. 2000 Apr 29;355[9214]:1486-90).
“It works,” said Dr. Spiegel, also associate chair of the psychiatry department at Stanford.
Hypnotizability can be assessed using various validated scales; he said he can determine hypnotizability within 5 minutes, in part by giving a suggestion that the patient’s arm is getting lighter and is beginning to float. A component of involuntariness – if the patient’s arm feels like it is floating effortlessly and actually moves up in the air – indicates hypnotizability.
Most children, and about two of every three adults, can be hypnotized, he said.
Self-hypnosis, particularly in the chronic pain setting, can be life-changing, as patients can use it whenever needed once they learn how, he said, describing one young patient who had been suffering from intractable migraines and associated vomiting for years, and had failed to respond to numerous medications. Within minutes of being taught self-hypnosis, she said her pain had decreased from 7 to 3 on a 0-10 scale, and after coming out of the hypnotic state, she described feeling as rested as if she’d been sleeping for a decade.
Her mother broke down in tears of relief, Dr. Spiegel said.
Another patient who had suffered from immobilizing back pain had a similar experience: His back pain was immediately reduced by about 60% .
“Does it always work? No, but no treatment always works, and at worst it’s harmless,” Dr. Spiegel said, adding: “I don’t get people addicted to hypnosis. It just doesn’t happen.”
So why is hypnosis still considered outside the mainstream? In part that’s the case because of its “purple cape, dangling watch” image, but there also is a conception that hypnosis takes away control. In reality, it enhances control, he said.
“I think every psychiatrist – every physician – should know hypnosis,” he said.
Many, but not all medical schools teach hypnosis, and at least two U.S. societies – the American Society of Clinical Hypnosis and the Society for Clinical and Experimental Hypnosis – conduct workshops and annual scientific meetings where those interested can learn, he noted.
“It’s not that hard to learn ... and it’s a very useful skill for a professional,” he said.
Other approaches to pain management
For the one in three adults who are not hypnotizable, Dr. Spiegel teaches distraction techniques, and sometimes recommends acupuncture, which can be helpful for some patients. Exercise and physical therapy also can be of benefit for chronic pain.
“You can have very real pain that you can learn to deal with as people did throughout history. That doesn’t mean you should suffer unnecessarily; there is a time and place for opiates and other [pharmacologic] strategies, but they should be one among an array of choices,” he said, adding that for chronic pain, opioids can be more of a problem than a solution, and learning these techniques “can really help people safely deal with pain.”
Jeffrey Borckardt, PhD, professor and director of the division of biobehavioral medicine at the Medical University of South Carolina (MUSC), Charleston, agreed that hypnosis is a well-researched and effective treatment for pain, despite being better known for weight loss and smoking cessation. Another, lesser-known treatment that has been shown to have some effect for pain is acceptance and commitment therapy, or ACT, which incorporates the practice of mindfulness.
A 2014 study (J Pain. 2014 Jan;15[1]:101-13) demonstrated a beneficial effect of ACT in nearly 50% of patients studied, and in a 2017 study (J Pain. 2017 Jun;18[6]:664-72), ACT was associated with improved function in chronic pain patients.
However, there is another well-researched – and well-known – nonpharmacologic approach to the treatment of pain: cognitive-behavioral therapy, or CBT. CBT isn’t as new and exciting as some experimental approaches that Dr. Borckardt is working with and studying, such as transcranial magnetic stimulation and transcranial direct current stimulation. But CBT is readily available and typically covered by insurance (unlike those experimental therapies), and has been shown in numerous studies to be highly effective, he said.
CBT and ‘360’ programs
CBT also was mentioned by Dr. Volkow in her June 2016 blog post. She called it “one of the most effective pain treatments,” and said that “assisting patients in learning to change their pain-related thoughts, emotions, and behaviors is going to help with their condition, regardless of other pharmacological interventions.”
Dr. Borckardt said it is particularly effective in the context of programs that provide what he called “a 360 approach.” These multifaceted treatment programs aim to help chronic pain patients taper off of opioid medications and to find other approaches to managing pain.
Only a handful of such comprehensive, intensive outpatient programs exist across the United States, but the concept is taking hold, driven in part by the opioid crisis, and more centers are opening. In fact, Dr. Borckardt is helping to develop such a program at MUSC. The program will likely be housed in the MUSC Wellness Center, and much like the Mayo Clinic’s Pain Rehabilitation Center, which opened in 1974 and was one of the first such programs in the world, the MUSC program will involve an integrated team of health care professionals that provide CBT for pain, physical therapy, occupational therapy, and other programs designed to help patients living with pain.
This is widely accepted as being the best approach for pain rehabilitation, Dr. Borckardt said.
TMS and TDCS
Dr. Borckardt also has worked with some more cutting-edge approaches to pain management. Transcranial magnetic stimulation (TMS), which is approved for the treatment of depression, also has shown promise for treating pain. TMS can target areas in the brain involved with specific functioning, such as emotional regulation. The high-frequency stimulation is believed to enhance that particular area and produce a clinical effect.
“Pain is a subjective, largely psychological experience, and it involves an emotional component,” he said, explaining that the rationale for the use of TMS for pain is that the emotional component of the pain experience can be targeted along with the sensory and cognitive aspects of the pain experience.
TMS is being used in various studies, and has been used off label for pain management, but the out-of-pocket cost is high because it is not currently approved for pain and is therefore not covered by insurance, he said.
For depression, TMS typically is used 5 days per week for 3 weeks – at a cost ranging anywhere from $100 to $500 per session. It remains unclear how many sessions would be required for pain treatment to produce a sustained effect, but it would likely be similar to the requirements for depression treatment, and may also require follow-up treatments, Dr. Borckardt said.
“We do know with reasonable confidence that it impacts pain perception and can impact sensory or emotional components of pain, depending on the part of the brain treated. But we don’t know how long we have to treat, how often, or how durable the effects are,” he said, noting that several groups are studying TMS for pain.
Notably, there is also some very preliminary evidence that TMS may be useful for treating addiction by affecting cravings for substances such as opiates, nicotine, and alcohol. If that effect is confirmed, TMS could help chronic pain patients reduce their need for higher opioid doses, thereby lowering the risk of overdose, which is an important factor in the opioid crisis; most patients who use opioids don’t become addicted, but they can be at risk for overdose because of the need for high doses to control their pain, he explained.
In one study, the use of TMS postoperatively reduced the amount of in-hospital drug use by 40%, he said, noting that the reduction could convert to a reduction in the use of pain medication after discharge as well.
A related treatment, transcranial direct current stimulation, or tDCS, involves placement of electrodes directly on the scalp to run weak electrical currents through the brain, again trying to alter areas associated with pain perception. Ongoing studies are looking at combining tDCS and CBT with the hope that the two will have synergistic effects, including one in veterans with low back pain and opioid misuse. Another small pilot study in patients with fibromyalgia recently concluded and had some promising results.
These and other nonpharmacologic approaches to pain management could play an important role in the effort to reduce opioid prescribing. Currently, about 90 Americans die each day after overdosing on opioids, according to NIDA, and the CDC estimates that prescription opioid misuse alone in the United States costs $78.5 billion per year in health care, lost productivity, addiction treatment, and criminal justice involvement.
In her plea to psychiatrists to take action to intervene, Dr. Volkow underscored the value that they bring to the table.
“It is crucial that we not lose sight of the reality and complexity of chronic pain as management of chronic noncancer pain moves toward greater caution around opioid medication. This should not be solely an issue for primary care medicine or neurology, but also for specialties such as psychiatry that have much to offer people who are suffering from complex disorders in which physical symptoms merge with psychological distress,” she wrote.
Dr. Volkow has written hundreds of peer-reviewed articles, including analyses of the opioid crisis (N Engl J Med. 2017 Jul 27;377[4]:391-4) and (Neuron. 2016 Oct 19[2]:294-7). Dr. Spiegel is coauthor of Trance and Treatment: Clinical Uses of Hypnosis (Washington: American Psychiatric Association Publishing, 2004), a textbook written to help psychiatrists and other physicians learn to use hypnosis. Dr. Borckardt receives research funding from the National Institutes of Health.
VIDEO: Rivaroxaban plus aspirin cut cardiovascular events in stable patients
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The dual regimen reduced the combined rate of cardiovascular disease events by 24%, compared with aspirin alone.
Data source: COMPASS is a multicenter, randomized controlled trial with 27,395 patients.
Disclosures: COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
Standard Assessments May Miss Psychotic Symptoms in Patients With Parkinson’s Disease
VANCOUVER—Standard clinical assessments of Parkinson’s disease psychosis may miss more than half of psychotic symptoms, according to research presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. Among 182 patients with Parkinson’s disease, a structured clinical interview w
“There is need for Parkinson’s disease psychosis scales such as our structured clinical interview that have greater sensitivity, particularly for delusions and olfactory, tactile, gustatory, and minor hallucinations,” said Catherine V. Kulick, a researcher at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at New York University School of Medicine, and colleagues. “Even isolated minor hallucinations were associated with reduced quality of life and higher prevalence of other nonmotor symptoms.”
As an alternative to standard rating scales for Parkinson’s disease psychosis, which focus on visual and auditory hallucinations and specific delusions, researchers developed a structured clinical interview based on the Parkinson’s disease–specific Scale for Assessment of Positive Symptoms with additional prompts for delusions and olfactory, tactile, gustatory, and minor hallucinations. To evaluate the new tool, the investigators conducted a cross-sectional analysis of 182 consecutive outpatients with Parkinson’s disease (mean age, 67). They evaluated patients with the structured clinical interview as well as a standardized battery of motor, psychiatric, and quality of life scales. Based on the results of the structured clinical interview, investigators classified patients has having major, minor, or no psychotic symptoms.
The structured clinical interview identified 52 patients (28.5%) with psychotic symptoms. Twenty-four patients had major symptoms, and 28 patients had minor symptoms.
A combination of clinical impression, the Unified Parkinson’s Disease Rating Scale (question 2), and the Nonmotor Symptoms Questionnaire (questions 14 and 30) identified 58% of the major psychotic symptoms and 17% of the isolated minor hallucinations that were detected during the structured clinical interview.
About 10% of patients reported major hallucinations, and more patients had major olfactory hallucinations (about 5% of patients) than had major visual, somatic, auditory, and gustatory hallucinations.
—Jake Remaly
Suggested Reading
Pagonabarraga J, Martinez-Horta S, Fernández de Bobadilla R, et al. Minor hallucinations occur in drug-naive Parkinson’s disease patients, even from the premotor phase. Mov Disord. 2016;31(1):45-52.
Voss T, Bahr D, Cummings J, et al. Performance of a shortened Scale for Assessment of Positive Symptoms for Parkinson’s disease psychosis. Parkinsonism Relat Disord. 2013;19(3):295-299.
VANCOUVER—Standard clinical assessments of Parkinson’s disease psychosis may miss more than half of psychotic symptoms, according to research presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. Among 182 patients with Parkinson’s disease, a structured clinical interview w
“There is need for Parkinson’s disease psychosis scales such as our structured clinical interview that have greater sensitivity, particularly for delusions and olfactory, tactile, gustatory, and minor hallucinations,” said Catherine V. Kulick, a researcher at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at New York University School of Medicine, and colleagues. “Even isolated minor hallucinations were associated with reduced quality of life and higher prevalence of other nonmotor symptoms.”
As an alternative to standard rating scales for Parkinson’s disease psychosis, which focus on visual and auditory hallucinations and specific delusions, researchers developed a structured clinical interview based on the Parkinson’s disease–specific Scale for Assessment of Positive Symptoms with additional prompts for delusions and olfactory, tactile, gustatory, and minor hallucinations. To evaluate the new tool, the investigators conducted a cross-sectional analysis of 182 consecutive outpatients with Parkinson’s disease (mean age, 67). They evaluated patients with the structured clinical interview as well as a standardized battery of motor, psychiatric, and quality of life scales. Based on the results of the structured clinical interview, investigators classified patients has having major, minor, or no psychotic symptoms.
The structured clinical interview identified 52 patients (28.5%) with psychotic symptoms. Twenty-four patients had major symptoms, and 28 patients had minor symptoms.
A combination of clinical impression, the Unified Parkinson’s Disease Rating Scale (question 2), and the Nonmotor Symptoms Questionnaire (questions 14 and 30) identified 58% of the major psychotic symptoms and 17% of the isolated minor hallucinations that were detected during the structured clinical interview.
About 10% of patients reported major hallucinations, and more patients had major olfactory hallucinations (about 5% of patients) than had major visual, somatic, auditory, and gustatory hallucinations.
—Jake Remaly
Suggested Reading
Pagonabarraga J, Martinez-Horta S, Fernández de Bobadilla R, et al. Minor hallucinations occur in drug-naive Parkinson’s disease patients, even from the premotor phase. Mov Disord. 2016;31(1):45-52.
Voss T, Bahr D, Cummings J, et al. Performance of a shortened Scale for Assessment of Positive Symptoms for Parkinson’s disease psychosis. Parkinsonism Relat Disord. 2013;19(3):295-299.
VANCOUVER—Standard clinical assessments of Parkinson’s disease psychosis may miss more than half of psychotic symptoms, according to research presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. Among 182 patients with Parkinson’s disease, a structured clinical interview w
“There is need for Parkinson’s disease psychosis scales such as our structured clinical interview that have greater sensitivity, particularly for delusions and olfactory, tactile, gustatory, and minor hallucinations,” said Catherine V. Kulick, a researcher at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at New York University School of Medicine, and colleagues. “Even isolated minor hallucinations were associated with reduced quality of life and higher prevalence of other nonmotor symptoms.”
As an alternative to standard rating scales for Parkinson’s disease psychosis, which focus on visual and auditory hallucinations and specific delusions, researchers developed a structured clinical interview based on the Parkinson’s disease–specific Scale for Assessment of Positive Symptoms with additional prompts for delusions and olfactory, tactile, gustatory, and minor hallucinations. To evaluate the new tool, the investigators conducted a cross-sectional analysis of 182 consecutive outpatients with Parkinson’s disease (mean age, 67). They evaluated patients with the structured clinical interview as well as a standardized battery of motor, psychiatric, and quality of life scales. Based on the results of the structured clinical interview, investigators classified patients has having major, minor, or no psychotic symptoms.
The structured clinical interview identified 52 patients (28.5%) with psychotic symptoms. Twenty-four patients had major symptoms, and 28 patients had minor symptoms.
A combination of clinical impression, the Unified Parkinson’s Disease Rating Scale (question 2), and the Nonmotor Symptoms Questionnaire (questions 14 and 30) identified 58% of the major psychotic symptoms and 17% of the isolated minor hallucinations that were detected during the structured clinical interview.
About 10% of patients reported major hallucinations, and more patients had major olfactory hallucinations (about 5% of patients) than had major visual, somatic, auditory, and gustatory hallucinations.
—Jake Remaly
Suggested Reading
Pagonabarraga J, Martinez-Horta S, Fernández de Bobadilla R, et al. Minor hallucinations occur in drug-naive Parkinson’s disease patients, even from the premotor phase. Mov Disord. 2016;31(1):45-52.
Voss T, Bahr D, Cummings J, et al. Performance of a shortened Scale for Assessment of Positive Symptoms for Parkinson’s disease psychosis. Parkinsonism Relat Disord. 2013;19(3):295-299.
CANTOS sings of novel strategy for cardiovascular, cancer prevention
BARCELONA – Inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer in the groundbreaking phase III CANTOS trial, Paul M. Ridker, MD, reported at the annual congress of the European Society of Cardiology.
“These data provide the first proof that inflammation inhibition in the absence of lipid lowering can improve atherogenic outcomes and potentially alter progression of some fatal cancers,” declared Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
“Just like we’ve learned that lower LDL is better, I think we’re now learning that lower inflammation is better,” he said.
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was a randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all of whom had a previous MI and a chronically high level of systemic inflammation as reflected in a median baseline high-sensitivity C-reactive protein (CRP) level of 4.1 mg/L. Ninety-one percent of participants were on statin therapy, with a median LDL cholesterol of 82 mg/dL when randomized to subcutaneous canakinumab at 50, 150, or 300 mg or to placebo once every 3 months.
Canakinumab is a fully human monoclonal antibody targeting IL-1B, a key player in systemic inflammation. The cytokine is activated by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, a part of the innate immune system. Canakinumab is approved as Ilaris for treatment of several uncommon rheumatologic diseases, including cryopryin-associated periodic syndrome and systemic juvenile idiopathic arthritis.
At a median follow-up of 3.7 years, the incidence of the primary composite efficacy endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was 4.5 events per 100 person-years in the control group, significantly higher than the 3.86 and 3.9 events per 100 person-years in patients on canakinumab at 150 and 300 mg, respectively.
Since event rates were virtually identical in the 150- and 300-mg study arms, Dr. Ridker combined those two patient groups in his analysis. They showed a 15% reduction in the risk of the primary efficacy endpoint, compared with placebo-treated controls, along with a 39% reduction from baseline in CRP. They also were 30% less likely to undergo percutaneous coronary intervention or coronary artery bypass graft during follow-up.
“That’s quite important, because that’s a progression-of-atherosclerosis endpoint and also obviously a cost and financial endpoint,” he observed.
A key finding in CANTOS was that patients with a reduction in CRP at or exceeding the median decrease just 3 months into the study – that is, after a single injection – had a 27% reduction in major vascular events during follow-up. Patients with a lesser reduction in CRP at that point did not experience a significant reduction in the primary endpoint, compared with placebo.
“The clinician in me would say we probably ought to give a single dose of the drug, see what happens, and if you get a large inflammation reduction we could perhaps consider treating that patient, but if you did not get a large reduction perhaps this is not a therapy for that patient. Why not avoid the toxicity in people who aren’t going to respond?” Dr. Ridker said.
Side effects related to canakinumab consisted of mild leukopenia and a small but statistically significant increase in fatal infections, which he called “not surprising.”
“It’s in the same range as one gets in treating rheumatoid arthritis with a biologic drug, which rheumatologists are very comfortable doing. You would imagine that if this does become a treatment, physicians will get much better at bringing patients in early when they have signs and symptoms of infection,” the cardiologist continued.
Patients on canakinumab showed significant reductions in incident rheumatoid arthritis, gout, and osteoarthritis. The drug had no kidney or liver adverse events.
Cancer was a prespecified secondary outcome in CANTOS. The investigators saw the trial as an opportunity to test a longstanding hypothesis that inhibiting IL-1B would have a positive impact on lung cancer in particular.
“Smoking, exposure to diesel fuel, inhalation of asbestos or other silicates – these cause inflammation which activates the NLRP3 inflammasome, but in the pulmonary system rather than the arteries,” Dr. Ridker explained.
An entry requirement in CANTOS was that patients needed to be free of known cancer. During study follow-up, 129 patients were diagnosed with lung cancer. The risk was reduced in dose-dependent fashion with canakinumab: by 39% relative to placebo in the 150-mg group and by 67% in the 300-mg group. Lung cancer mortality was reduced by 77% in the canakinumab 300-mg group.
“I don’t think this is about oncogenesis per se. I think the tumors are already there, but they don’t progress because we’ve altered the tumor’s inflammatory microenvironment,” he continued.
Since CANTOS was first and foremost a study of atherosclerotic disease prevention, the cancer results need to be replicated on a high-priority basis. Dr. Ridker predicted that Novartis, which sponsored CANTOS, will quickly mount a clinical trial examining canakinumab’s potential as an adjunctive treatment to either chemotherapy or radiation following resection of lung cancer.
He stressed that CANTOS is only the beginning stanza in what will be an entirely new approach to preventive cardiology. Numerous other inflammatory pathways also might serve as targets.
“I think this is going to open up all kinds of approaches using a variety of agents that have really been in the rheumatology and immunology world,” the cardiologist predicted.
For example, he is principal investigator in the ongoing National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), a randomized, double-blind, placebo-controlled study of low-dose methotrexate for prevention of cardiovascular events in a planned 7,000 patients with type 2 diabetes or metabolic syndrome who’ve had an MI or have multivessel CAD. Results are probably 4-6 years off.
“Right now, we know canakinumab works. If methotrexate were to work, then we’d have a generic, inexpensive approach as well,” Dr. Ridker noted.
Novartis officials indicated that, on the basis of the positive CANTOS results, the company plans to file for an expanded indication for canakinumab for cardiovascular prevention. The company also is gearing up for studies of the drug in oncology.
Simultaneous with Dr. Ridker’s presentation in Barcelona, both the atherosclerotic disease findings (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914) and the cancer findings (Lancet. 2017 Aug 27. doi: 10.1016/S0140-6736(17)32247-X) were published.
He reported serving as a consultant to Novartis.
BARCELONA – Inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer in the groundbreaking phase III CANTOS trial, Paul M. Ridker, MD, reported at the annual congress of the European Society of Cardiology.
“These data provide the first proof that inflammation inhibition in the absence of lipid lowering can improve atherogenic outcomes and potentially alter progression of some fatal cancers,” declared Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
“Just like we’ve learned that lower LDL is better, I think we’re now learning that lower inflammation is better,” he said.
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was a randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all of whom had a previous MI and a chronically high level of systemic inflammation as reflected in a median baseline high-sensitivity C-reactive protein (CRP) level of 4.1 mg/L. Ninety-one percent of participants were on statin therapy, with a median LDL cholesterol of 82 mg/dL when randomized to subcutaneous canakinumab at 50, 150, or 300 mg or to placebo once every 3 months.
Canakinumab is a fully human monoclonal antibody targeting IL-1B, a key player in systemic inflammation. The cytokine is activated by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, a part of the innate immune system. Canakinumab is approved as Ilaris for treatment of several uncommon rheumatologic diseases, including cryopryin-associated periodic syndrome and systemic juvenile idiopathic arthritis.
At a median follow-up of 3.7 years, the incidence of the primary composite efficacy endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was 4.5 events per 100 person-years in the control group, significantly higher than the 3.86 and 3.9 events per 100 person-years in patients on canakinumab at 150 and 300 mg, respectively.
Since event rates were virtually identical in the 150- and 300-mg study arms, Dr. Ridker combined those two patient groups in his analysis. They showed a 15% reduction in the risk of the primary efficacy endpoint, compared with placebo-treated controls, along with a 39% reduction from baseline in CRP. They also were 30% less likely to undergo percutaneous coronary intervention or coronary artery bypass graft during follow-up.
“That’s quite important, because that’s a progression-of-atherosclerosis endpoint and also obviously a cost and financial endpoint,” he observed.
A key finding in CANTOS was that patients with a reduction in CRP at or exceeding the median decrease just 3 months into the study – that is, after a single injection – had a 27% reduction in major vascular events during follow-up. Patients with a lesser reduction in CRP at that point did not experience a significant reduction in the primary endpoint, compared with placebo.
“The clinician in me would say we probably ought to give a single dose of the drug, see what happens, and if you get a large inflammation reduction we could perhaps consider treating that patient, but if you did not get a large reduction perhaps this is not a therapy for that patient. Why not avoid the toxicity in people who aren’t going to respond?” Dr. Ridker said.
Side effects related to canakinumab consisted of mild leukopenia and a small but statistically significant increase in fatal infections, which he called “not surprising.”
“It’s in the same range as one gets in treating rheumatoid arthritis with a biologic drug, which rheumatologists are very comfortable doing. You would imagine that if this does become a treatment, physicians will get much better at bringing patients in early when they have signs and symptoms of infection,” the cardiologist continued.
Patients on canakinumab showed significant reductions in incident rheumatoid arthritis, gout, and osteoarthritis. The drug had no kidney or liver adverse events.
Cancer was a prespecified secondary outcome in CANTOS. The investigators saw the trial as an opportunity to test a longstanding hypothesis that inhibiting IL-1B would have a positive impact on lung cancer in particular.
“Smoking, exposure to diesel fuel, inhalation of asbestos or other silicates – these cause inflammation which activates the NLRP3 inflammasome, but in the pulmonary system rather than the arteries,” Dr. Ridker explained.
An entry requirement in CANTOS was that patients needed to be free of known cancer. During study follow-up, 129 patients were diagnosed with lung cancer. The risk was reduced in dose-dependent fashion with canakinumab: by 39% relative to placebo in the 150-mg group and by 67% in the 300-mg group. Lung cancer mortality was reduced by 77% in the canakinumab 300-mg group.
“I don’t think this is about oncogenesis per se. I think the tumors are already there, but they don’t progress because we’ve altered the tumor’s inflammatory microenvironment,” he continued.
Since CANTOS was first and foremost a study of atherosclerotic disease prevention, the cancer results need to be replicated on a high-priority basis. Dr. Ridker predicted that Novartis, which sponsored CANTOS, will quickly mount a clinical trial examining canakinumab’s potential as an adjunctive treatment to either chemotherapy or radiation following resection of lung cancer.
He stressed that CANTOS is only the beginning stanza in what will be an entirely new approach to preventive cardiology. Numerous other inflammatory pathways also might serve as targets.
“I think this is going to open up all kinds of approaches using a variety of agents that have really been in the rheumatology and immunology world,” the cardiologist predicted.
For example, he is principal investigator in the ongoing National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), a randomized, double-blind, placebo-controlled study of low-dose methotrexate for prevention of cardiovascular events in a planned 7,000 patients with type 2 diabetes or metabolic syndrome who’ve had an MI or have multivessel CAD. Results are probably 4-6 years off.
“Right now, we know canakinumab works. If methotrexate were to work, then we’d have a generic, inexpensive approach as well,” Dr. Ridker noted.
Novartis officials indicated that, on the basis of the positive CANTOS results, the company plans to file for an expanded indication for canakinumab for cardiovascular prevention. The company also is gearing up for studies of the drug in oncology.
Simultaneous with Dr. Ridker’s presentation in Barcelona, both the atherosclerotic disease findings (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914) and the cancer findings (Lancet. 2017 Aug 27. doi: 10.1016/S0140-6736(17)32247-X) were published.
He reported serving as a consultant to Novartis.
BARCELONA – Inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer in the groundbreaking phase III CANTOS trial, Paul M. Ridker, MD, reported at the annual congress of the European Society of Cardiology.
“These data provide the first proof that inflammation inhibition in the absence of lipid lowering can improve atherogenic outcomes and potentially alter progression of some fatal cancers,” declared Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
“Just like we’ve learned that lower LDL is better, I think we’re now learning that lower inflammation is better,” he said.
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was a randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all of whom had a previous MI and a chronically high level of systemic inflammation as reflected in a median baseline high-sensitivity C-reactive protein (CRP) level of 4.1 mg/L. Ninety-one percent of participants were on statin therapy, with a median LDL cholesterol of 82 mg/dL when randomized to subcutaneous canakinumab at 50, 150, or 300 mg or to placebo once every 3 months.
Canakinumab is a fully human monoclonal antibody targeting IL-1B, a key player in systemic inflammation. The cytokine is activated by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, a part of the innate immune system. Canakinumab is approved as Ilaris for treatment of several uncommon rheumatologic diseases, including cryopryin-associated periodic syndrome and systemic juvenile idiopathic arthritis.
At a median follow-up of 3.7 years, the incidence of the primary composite efficacy endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was 4.5 events per 100 person-years in the control group, significantly higher than the 3.86 and 3.9 events per 100 person-years in patients on canakinumab at 150 and 300 mg, respectively.
Since event rates were virtually identical in the 150- and 300-mg study arms, Dr. Ridker combined those two patient groups in his analysis. They showed a 15% reduction in the risk of the primary efficacy endpoint, compared with placebo-treated controls, along with a 39% reduction from baseline in CRP. They also were 30% less likely to undergo percutaneous coronary intervention or coronary artery bypass graft during follow-up.
“That’s quite important, because that’s a progression-of-atherosclerosis endpoint and also obviously a cost and financial endpoint,” he observed.
A key finding in CANTOS was that patients with a reduction in CRP at or exceeding the median decrease just 3 months into the study – that is, after a single injection – had a 27% reduction in major vascular events during follow-up. Patients with a lesser reduction in CRP at that point did not experience a significant reduction in the primary endpoint, compared with placebo.
“The clinician in me would say we probably ought to give a single dose of the drug, see what happens, and if you get a large inflammation reduction we could perhaps consider treating that patient, but if you did not get a large reduction perhaps this is not a therapy for that patient. Why not avoid the toxicity in people who aren’t going to respond?” Dr. Ridker said.
Side effects related to canakinumab consisted of mild leukopenia and a small but statistically significant increase in fatal infections, which he called “not surprising.”
“It’s in the same range as one gets in treating rheumatoid arthritis with a biologic drug, which rheumatologists are very comfortable doing. You would imagine that if this does become a treatment, physicians will get much better at bringing patients in early when they have signs and symptoms of infection,” the cardiologist continued.
Patients on canakinumab showed significant reductions in incident rheumatoid arthritis, gout, and osteoarthritis. The drug had no kidney or liver adverse events.
Cancer was a prespecified secondary outcome in CANTOS. The investigators saw the trial as an opportunity to test a longstanding hypothesis that inhibiting IL-1B would have a positive impact on lung cancer in particular.
“Smoking, exposure to diesel fuel, inhalation of asbestos or other silicates – these cause inflammation which activates the NLRP3 inflammasome, but in the pulmonary system rather than the arteries,” Dr. Ridker explained.
An entry requirement in CANTOS was that patients needed to be free of known cancer. During study follow-up, 129 patients were diagnosed with lung cancer. The risk was reduced in dose-dependent fashion with canakinumab: by 39% relative to placebo in the 150-mg group and by 67% in the 300-mg group. Lung cancer mortality was reduced by 77% in the canakinumab 300-mg group.
“I don’t think this is about oncogenesis per se. I think the tumors are already there, but they don’t progress because we’ve altered the tumor’s inflammatory microenvironment,” he continued.
Since CANTOS was first and foremost a study of atherosclerotic disease prevention, the cancer results need to be replicated on a high-priority basis. Dr. Ridker predicted that Novartis, which sponsored CANTOS, will quickly mount a clinical trial examining canakinumab’s potential as an adjunctive treatment to either chemotherapy or radiation following resection of lung cancer.
He stressed that CANTOS is only the beginning stanza in what will be an entirely new approach to preventive cardiology. Numerous other inflammatory pathways also might serve as targets.
“I think this is going to open up all kinds of approaches using a variety of agents that have really been in the rheumatology and immunology world,” the cardiologist predicted.
For example, he is principal investigator in the ongoing National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), a randomized, double-blind, placebo-controlled study of low-dose methotrexate for prevention of cardiovascular events in a planned 7,000 patients with type 2 diabetes or metabolic syndrome who’ve had an MI or have multivessel CAD. Results are probably 4-6 years off.
“Right now, we know canakinumab works. If methotrexate were to work, then we’d have a generic, inexpensive approach as well,” Dr. Ridker noted.
Novartis officials indicated that, on the basis of the positive CANTOS results, the company plans to file for an expanded indication for canakinumab for cardiovascular prevention. The company also is gearing up for studies of the drug in oncology.
Simultaneous with Dr. Ridker’s presentation in Barcelona, both the atherosclerotic disease findings (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914) and the cancer findings (Lancet. 2017 Aug 27. doi: 10.1016/S0140-6736(17)32247-X) were published.
He reported serving as a consultant to Novartis.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: Canakinumab reduced the risk of recurrent cardiovascular events in a very-high-risk population by 15%, compared with placebo, while cutting incident lung cancer by 67% in a major clinical trial.
Data source: CANTOS was a phase III, randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all with a previous MI and chronically high systemic inflammation.
Disclosures: The study was sponsored by Novartis. The presenter reported serving as a consultant to the company.
Sneak Peek: The Hospital Leader blog - Aug. 2017 “A Conversation with Dr. Eric Howell”
Quality improvement became a foundational theme for SHM early in the growth of hospitalists. It’s not a coincidence that many of our leaders, such as Bob Wachter, Win Whitcomb, Greg Maynard, and Mark Williams are QI leaders as well. As hospitalists, we were and are best positioned to impact quality in the hospital.
Eric Howell, MD, of Johns Hopkins Bayview Medical Center in Baltimore serves as the senior physician advisor for SHM’s Center for Quality Improvement, while Jenna Goldstein runs the day-to-day aspects at SHM headquarters. A few months ago, Dr. Howell and I discussed how he started in QI, the role of SHM’s Center, and how hospitalists can receive effective QI training. The following Q&A is edited for conciseness and clarity.
You’ve been a leader in QI for many years; how did you get started in QI?
I trained as an electrical engineer before I went to medical school, which helped me when I went to residency.
When I was a chief at Hopkins Bayview in 1999, there were a number of systems-related issues, including throughput from the emergency department. I became involved with QI because I looked at these systems, thinking they could be better if I used the lens of an engineer. The hospital was very interested in reducing costs, and the physicians, including myself, were interested in making things safer. I was successful because I didn’t just focus on QI but on both sides of the value equation. In the early 2000s, I started to do more and more re-engineering and system improvement projects, and I found them very rewarding. As I showed some success, I was asked to do more.
What you are describing is hands-on training, learning by doing. It seems a lot of your QI training was hands on, as opposed to structured coursework. Was there formal training or is getting your hands dirty in a project the best way to start learning QI?
There is no replacement for actually doing it.
My training was in leadership, which is an integral part of QI. It’s pretty hard to get people to change for quality if you can’t lead them through that change. Initially, I did a lot of work to improve my leadership potential. As faculty, we taught teaching skills, which is a part of leadership. I spent time teaching residents best practices. That’s why I became involved early on with SHM’s Leadership Academy from its start in 2005. I also read a lot of books and still read often to improve my weaknesses. I have my own physicians go through Lean Six Sigma training and get their green belt or black belt.
That said, there is no substitute for doing it and, as they say, “bruising your knuckles” in QI.
Read the full post at hospitalleader.org.
Also on The Hospital Leader…
- From SXSW to SHM: Our Tour to Promote Value Conversations Between Doctors & Patients by Chris Moriates, MD
- It’s Time for a Buzz Cut by Tracy Cardin, ACNP-NC, SFHM
- The Essentials of QI Leadership: A Conversation with Dr. Eric Howell, Part 2 by Jordan Messler, MD, SFHM
Quality improvement became a foundational theme for SHM early in the growth of hospitalists. It’s not a coincidence that many of our leaders, such as Bob Wachter, Win Whitcomb, Greg Maynard, and Mark Williams are QI leaders as well. As hospitalists, we were and are best positioned to impact quality in the hospital.
Eric Howell, MD, of Johns Hopkins Bayview Medical Center in Baltimore serves as the senior physician advisor for SHM’s Center for Quality Improvement, while Jenna Goldstein runs the day-to-day aspects at SHM headquarters. A few months ago, Dr. Howell and I discussed how he started in QI, the role of SHM’s Center, and how hospitalists can receive effective QI training. The following Q&A is edited for conciseness and clarity.
You’ve been a leader in QI for many years; how did you get started in QI?
I trained as an electrical engineer before I went to medical school, which helped me when I went to residency.
When I was a chief at Hopkins Bayview in 1999, there were a number of systems-related issues, including throughput from the emergency department. I became involved with QI because I looked at these systems, thinking they could be better if I used the lens of an engineer. The hospital was very interested in reducing costs, and the physicians, including myself, were interested in making things safer. I was successful because I didn’t just focus on QI but on both sides of the value equation. In the early 2000s, I started to do more and more re-engineering and system improvement projects, and I found them very rewarding. As I showed some success, I was asked to do more.
What you are describing is hands-on training, learning by doing. It seems a lot of your QI training was hands on, as opposed to structured coursework. Was there formal training or is getting your hands dirty in a project the best way to start learning QI?
There is no replacement for actually doing it.
My training was in leadership, which is an integral part of QI. It’s pretty hard to get people to change for quality if you can’t lead them through that change. Initially, I did a lot of work to improve my leadership potential. As faculty, we taught teaching skills, which is a part of leadership. I spent time teaching residents best practices. That’s why I became involved early on with SHM’s Leadership Academy from its start in 2005. I also read a lot of books and still read often to improve my weaknesses. I have my own physicians go through Lean Six Sigma training and get their green belt or black belt.
That said, there is no substitute for doing it and, as they say, “bruising your knuckles” in QI.
Read the full post at hospitalleader.org.
Also on The Hospital Leader…
- From SXSW to SHM: Our Tour to Promote Value Conversations Between Doctors & Patients by Chris Moriates, MD
- It’s Time for a Buzz Cut by Tracy Cardin, ACNP-NC, SFHM
- The Essentials of QI Leadership: A Conversation with Dr. Eric Howell, Part 2 by Jordan Messler, MD, SFHM
Quality improvement became a foundational theme for SHM early in the growth of hospitalists. It’s not a coincidence that many of our leaders, such as Bob Wachter, Win Whitcomb, Greg Maynard, and Mark Williams are QI leaders as well. As hospitalists, we were and are best positioned to impact quality in the hospital.
Eric Howell, MD, of Johns Hopkins Bayview Medical Center in Baltimore serves as the senior physician advisor for SHM’s Center for Quality Improvement, while Jenna Goldstein runs the day-to-day aspects at SHM headquarters. A few months ago, Dr. Howell and I discussed how he started in QI, the role of SHM’s Center, and how hospitalists can receive effective QI training. The following Q&A is edited for conciseness and clarity.
You’ve been a leader in QI for many years; how did you get started in QI?
I trained as an electrical engineer before I went to medical school, which helped me when I went to residency.
When I was a chief at Hopkins Bayview in 1999, there were a number of systems-related issues, including throughput from the emergency department. I became involved with QI because I looked at these systems, thinking they could be better if I used the lens of an engineer. The hospital was very interested in reducing costs, and the physicians, including myself, were interested in making things safer. I was successful because I didn’t just focus on QI but on both sides of the value equation. In the early 2000s, I started to do more and more re-engineering and system improvement projects, and I found them very rewarding. As I showed some success, I was asked to do more.
What you are describing is hands-on training, learning by doing. It seems a lot of your QI training was hands on, as opposed to structured coursework. Was there formal training or is getting your hands dirty in a project the best way to start learning QI?
There is no replacement for actually doing it.
My training was in leadership, which is an integral part of QI. It’s pretty hard to get people to change for quality if you can’t lead them through that change. Initially, I did a lot of work to improve my leadership potential. As faculty, we taught teaching skills, which is a part of leadership. I spent time teaching residents best practices. That’s why I became involved early on with SHM’s Leadership Academy from its start in 2005. I also read a lot of books and still read often to improve my weaknesses. I have my own physicians go through Lean Six Sigma training and get their green belt or black belt.
That said, there is no substitute for doing it and, as they say, “bruising your knuckles” in QI.
Read the full post at hospitalleader.org.
Also on The Hospital Leader…
- From SXSW to SHM: Our Tour to Promote Value Conversations Between Doctors & Patients by Chris Moriates, MD
- It’s Time for a Buzz Cut by Tracy Cardin, ACNP-NC, SFHM
- The Essentials of QI Leadership: A Conversation with Dr. Eric Howell, Part 2 by Jordan Messler, MD, SFHM
Forgo supplemental oxygen in adequately perfused patients with acute MI, study suggests
Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.
Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.
Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.
The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).
Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.
A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).
“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.
The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
The study by Hofmann and coworkers provides definitive evidence for a lack of benefit of supplemental oxygen therapy in patients with acute myocardial infarction who have normal oxygen saturation. Although the mechanisms underlying physiological and biochemical adaptation to myocardial ischemia are complex, the answer to the question is straightforward, and its implications for coronary care are indisputable: Supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia. It is clearly time for clinical practice to change to reflect this definitive evidence.
Joseph Loscalzo, MD, PhD, is in the department of medicine, Brigham and Women’s Hospital, Boston. He is an editor-at-large for the New England Journal of Medicine. He had no other disclosures. These comments are from his accompanying editorial (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMe1709250).
The study by Hofmann and coworkers provides definitive evidence for a lack of benefit of supplemental oxygen therapy in patients with acute myocardial infarction who have normal oxygen saturation. Although the mechanisms underlying physiological and biochemical adaptation to myocardial ischemia are complex, the answer to the question is straightforward, and its implications for coronary care are indisputable: Supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia. It is clearly time for clinical practice to change to reflect this definitive evidence.
Joseph Loscalzo, MD, PhD, is in the department of medicine, Brigham and Women’s Hospital, Boston. He is an editor-at-large for the New England Journal of Medicine. He had no other disclosures. These comments are from his accompanying editorial (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMe1709250).
The study by Hofmann and coworkers provides definitive evidence for a lack of benefit of supplemental oxygen therapy in patients with acute myocardial infarction who have normal oxygen saturation. Although the mechanisms underlying physiological and biochemical adaptation to myocardial ischemia are complex, the answer to the question is straightforward, and its implications for coronary care are indisputable: Supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia. It is clearly time for clinical practice to change to reflect this definitive evidence.
Joseph Loscalzo, MD, PhD, is in the department of medicine, Brigham and Women’s Hospital, Boston. He is an editor-at-large for the New England Journal of Medicine. He had no other disclosures. These comments are from his accompanying editorial (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMe1709250).
Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.
Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.
Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.
The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).
Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.
A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).
“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.
The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.
Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.
Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.
The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).
Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.
A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).
“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.
The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
FROM THE ESC CONGRESS 2017
Key clinical point: Supplemental oxygen did not benefit patients with suspected myocardial infarction who did not have hypoxemia.
Major finding: At 1 year, rates of all-cause mortality were 5% among patients who received supplemental oxygen and 5.1% among those who received no oxygen.
Data source: A registry-based, randomized clinical trial of 6,629 patients with suspected myocardial infarction without hypoxemia.
Disclosures: The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
Therapy shows promise for PUPs with severe hemophilia A
A fourth-generation recombinant factor VIII (FVIII) therapy has demonstrated “convincing” efficacy and tolerability as well as low immunogenicity in previously untreated patients (PUPs) with severe hemophilia A, according to researchers.
The therapy, simoctocog alfa, is a B-domain-deleted recombinant FVIII product derived from a human cell line.
In the NuProtect study (also known as GENA-05), researchers are evaluating simoctocog alfa in PUPs with severe hemophilia A.
Interim results from this study were recently published in Haemophilia. The research is sponsored by Octapharma, makers of simoctocog alfa.
Thus far, NuProtect has enrolled 110 PUPs who will receive simoctocog alfa for up to 100 exposure days (EDs).
The Haemophilia article describes interim results for 66 PUPs treated for at least 20 EDs, the time by which most inhibitors arise. The patients’ median age at first treatment was 13 months (range, 3 months to 135 months).
The patients received simoctocog alfa for standard prophylaxis, surgical prophylaxis, or on-demand treatment.
Forty-five (68.2%) patients received standard prophylaxis, 13 (19.7%) received only on-demand treatment, 8 (12.1%) were initially treated on-demand but later received prophylaxis, and 13 (19.7%) patients received surgical prophylaxis (for 14 procedures).
The median number of EDs was 43.0 (range, 4-120).
Results
The primary objective of this study is to assess the immunogenicity of simoctocog alfa by determining inhibitor activity using the Nijmegen-modified Bethesda assay at a central laboratory.
After a median of 11.5 EDs (range, 6-24), 8 patients had developed high-titer anti-FVIII inhibitors, and 5 patients had developed low-titer inhibitors, 4 of them transient.
The cumulative incidence of all inhibitors was 20.8%—12.8% for high-titer and 8.4% for low-titer inhibitors.
For patients who received prophylaxis, the median annual bleeding rate, during inhibitor-free periods, was 2.40 for all bleeds and 0 for spontaneous bleeds.
When simoctocog alfa was used on-demand, 92.4% of bleeds were controlled with 1 or 2 infusions. In addition, simoctocog alfa was said to demonstrate “excellent” or “good” efficacy in 89% of surgical procedures.
Three patients experienced adverse events (other than inhibitor development) that were considered related to simoctocog alfa.
One patient developed a mild fever. Another had a mild allergic reaction after 3 consecutive infusions of simoctocog alfa (but not after subsequent infusions).
The third patient developed a rash that was described as mild but considered serious due to hospitalization. This patient continued treatment and completed the study. 
A fourth-generation recombinant factor VIII (FVIII) therapy has demonstrated “convincing” efficacy and tolerability as well as low immunogenicity in previously untreated patients (PUPs) with severe hemophilia A, according to researchers.
The therapy, simoctocog alfa, is a B-domain-deleted recombinant FVIII product derived from a human cell line.
In the NuProtect study (also known as GENA-05), researchers are evaluating simoctocog alfa in PUPs with severe hemophilia A.
Interim results from this study were recently published in Haemophilia. The research is sponsored by Octapharma, makers of simoctocog alfa.
Thus far, NuProtect has enrolled 110 PUPs who will receive simoctocog alfa for up to 100 exposure days (EDs).
The Haemophilia article describes interim results for 66 PUPs treated for at least 20 EDs, the time by which most inhibitors arise. The patients’ median age at first treatment was 13 months (range, 3 months to 135 months).
The patients received simoctocog alfa for standard prophylaxis, surgical prophylaxis, or on-demand treatment.
Forty-five (68.2%) patients received standard prophylaxis, 13 (19.7%) received only on-demand treatment, 8 (12.1%) were initially treated on-demand but later received prophylaxis, and 13 (19.7%) patients received surgical prophylaxis (for 14 procedures).
The median number of EDs was 43.0 (range, 4-120).
Results
The primary objective of this study is to assess the immunogenicity of simoctocog alfa by determining inhibitor activity using the Nijmegen-modified Bethesda assay at a central laboratory.
After a median of 11.5 EDs (range, 6-24), 8 patients had developed high-titer anti-FVIII inhibitors, and 5 patients had developed low-titer inhibitors, 4 of them transient.
The cumulative incidence of all inhibitors was 20.8%—12.8% for high-titer and 8.4% for low-titer inhibitors.
For patients who received prophylaxis, the median annual bleeding rate, during inhibitor-free periods, was 2.40 for all bleeds and 0 for spontaneous bleeds.
When simoctocog alfa was used on-demand, 92.4% of bleeds were controlled with 1 or 2 infusions. In addition, simoctocog alfa was said to demonstrate “excellent” or “good” efficacy in 89% of surgical procedures.
Three patients experienced adverse events (other than inhibitor development) that were considered related to simoctocog alfa.
One patient developed a mild fever. Another had a mild allergic reaction after 3 consecutive infusions of simoctocog alfa (but not after subsequent infusions).
The third patient developed a rash that was described as mild but considered serious due to hospitalization. This patient continued treatment and completed the study.
A fourth-generation recombinant factor VIII (FVIII) therapy has demonstrated “convincing” efficacy and tolerability as well as low immunogenicity in previously untreated patients (PUPs) with severe hemophilia A, according to researchers.
The therapy, simoctocog alfa, is a B-domain-deleted recombinant FVIII product derived from a human cell line.
In the NuProtect study (also known as GENA-05), researchers are evaluating simoctocog alfa in PUPs with severe hemophilia A.
Interim results from this study were recently published in Haemophilia. The research is sponsored by Octapharma, makers of simoctocog alfa.
Thus far, NuProtect has enrolled 110 PUPs who will receive simoctocog alfa for up to 100 exposure days (EDs).
The Haemophilia article describes interim results for 66 PUPs treated for at least 20 EDs, the time by which most inhibitors arise. The patients’ median age at first treatment was 13 months (range, 3 months to 135 months).
The patients received simoctocog alfa for standard prophylaxis, surgical prophylaxis, or on-demand treatment.
Forty-five (68.2%) patients received standard prophylaxis, 13 (19.7%) received only on-demand treatment, 8 (12.1%) were initially treated on-demand but later received prophylaxis, and 13 (19.7%) patients received surgical prophylaxis (for 14 procedures).
The median number of EDs was 43.0 (range, 4-120).
Results
The primary objective of this study is to assess the immunogenicity of simoctocog alfa by determining inhibitor activity using the Nijmegen-modified Bethesda assay at a central laboratory.
After a median of 11.5 EDs (range, 6-24), 8 patients had developed high-titer anti-FVIII inhibitors, and 5 patients had developed low-titer inhibitors, 4 of them transient.
The cumulative incidence of all inhibitors was 20.8%—12.8% for high-titer and 8.4% for low-titer inhibitors.
For patients who received prophylaxis, the median annual bleeding rate, during inhibitor-free periods, was 2.40 for all bleeds and 0 for spontaneous bleeds.
When simoctocog alfa was used on-demand, 92.4% of bleeds were controlled with 1 or 2 infusions. In addition, simoctocog alfa was said to demonstrate “excellent” or “good” efficacy in 89% of surgical procedures.
Three patients experienced adverse events (other than inhibitor development) that were considered related to simoctocog alfa.
One patient developed a mild fever. Another had a mild allergic reaction after 3 consecutive infusions of simoctocog alfa (but not after subsequent infusions).
The third patient developed a rash that was described as mild but considered serious due to hospitalization. This patient continued treatment and completed the study.
Reimmunization appears safe in children with history of adverse events
(AEFI), but there are not enough data to make firm conclusions about severe AEFIs, according to a systematic review of studies that were published in English and French between 1982 and 2016 and were made available to Medline via PubMed, Embase, and the Cochrane library.
Apnea was found to be of concern only in children under the age of 1 year and usually found only in lower birth weight babies and those with ongoing hospitalization for complications related to prematurity, the investigators said. A 10-g increase in birth weight was associated with a 6% reduction in risk of apnea recurrence (odds ratio, 0.94; 95% CI, 0.89-1.00), and odds of recurrence were 23 times higher in infants hospitalized for complications related to prematurity (OR, 23; 95% CI, 2-272).
Some of the studies also evaluated for injection site reactions, Henoch-Schönlein purpura, or other AEFI, Dr. Zafack and her coauthors continued. Injection site reactions varied depending on vaccine and number of doses, but all children recovered within 19 days of immunization. Only one child in one study had a recurrence of Henoch-Schönlein purpura. Vomiting, persistent crying, decreased appetite, and drowsiness recurred in 15%, 24%, 25%, and 35% of the reimmunized patients, respectively, across all the studies.
“In a context of vaccine hesitancy and growing concerns regarding vaccine safety, evaluating the risk of recurrence of all AEFIs should become part of the standard evaluation of vaccine safety,” the researchers wrote. “Reimmunization appears to be safe for patients with mild to moderate AEFIs. However, the data are insufficient to draw firm conclusions regarding the safety of reimmunization after a severe AEFI.”
In this study, “it appears that the risk of recurrence of serious AEFIs (anaphylaxis, seizures, or apnea in term infants) was low (less than 1%). For minor to moderate AEFIs (fever, extensive limb swelling, oculorespiratory syndrome, allergic-like events, sleepiness, thrombocytopenia, decreased appetite, vomiting, or persistent crying), the risk of recurrence ranged from 4% to 48%,” the investigators concluded.
The study was funded by the Canadian Immunization Research Network, which is sponsored by the Public Health Agency of Canada and the Canadian Institutes of Health Research. Dr. Zafack reported no financial disclosures. Some of her coauthors reported financial support from GlaxoSmithKline and Pfizer.
There are few experiences more challenging for a pediatrician than trying to convince a parent to continue vaccinating his or her child after witnessing a seemingly related adverse event following immunization (AEFI). The question they want answered is, Will it happen again?
Zafack et al. have sought to answer that question by providing previously lacking estimates of the risk of recurrence. By consolidating the data available in a range of literature, they showed that the risk of a serious AEFI is less than 1%. More accurate risk assessments also are available for mild to moderate AEFI for many vaccines.
The Zafack et al. article also reinforces what vaccinologists and pediatricians have known for many years: Vaccines are incredibly safe. Vaccines are administered to millions of children every year, and the list of known adverse events still is very short. The researchers reaffirm the overwhelming value and safety of vaccines that protect infants and children from complications and death resulting from infectious diseases.
Even though this article does not address AEFI risk for all vaccines, it is impressively comprehensive and will be a useful reference for practicing pediatricians everywhere for years to come.
Sean T. O’Leary, MD, MPH , is an associate professor in the division of infectious diseases in the department of pediatrics at the University of Colorado at Denver, Aurora. Yvonne A. Maldonado, MD , is chief of the division of pediatric infectious diseases and a professor of pediatrics at Stanford (Calif.) University. She serves on a Data Safety Monitoring Board for a Pfizer vaccine trial. Both authors are members of the American Academy of Pediatrics committee on infectious disease and subcommittee on vaccine policy and vaccine hesitancy. These comments were published in an editorial accompanying the Zafack et al. article in Pediatrics (2017. doi: 10.1542/peds.2017-1760 ).
There are few experiences more challenging for a pediatrician than trying to convince a parent to continue vaccinating his or her child after witnessing a seemingly related adverse event following immunization (AEFI). The question they want answered is, Will it happen again?
Zafack et al. have sought to answer that question by providing previously lacking estimates of the risk of recurrence. By consolidating the data available in a range of literature, they showed that the risk of a serious AEFI is less than 1%. More accurate risk assessments also are available for mild to moderate AEFI for many vaccines.
The Zafack et al. article also reinforces what vaccinologists and pediatricians have known for many years: Vaccines are incredibly safe. Vaccines are administered to millions of children every year, and the list of known adverse events still is very short. The researchers reaffirm the overwhelming value and safety of vaccines that protect infants and children from complications and death resulting from infectious diseases.
Even though this article does not address AEFI risk for all vaccines, it is impressively comprehensive and will be a useful reference for practicing pediatricians everywhere for years to come.
Sean T. O’Leary, MD, MPH , is an associate professor in the division of infectious diseases in the department of pediatrics at the University of Colorado at Denver, Aurora. Yvonne A. Maldonado, MD , is chief of the division of pediatric infectious diseases and a professor of pediatrics at Stanford (Calif.) University. She serves on a Data Safety Monitoring Board for a Pfizer vaccine trial. Both authors are members of the American Academy of Pediatrics committee on infectious disease and subcommittee on vaccine policy and vaccine hesitancy. These comments were published in an editorial accompanying the Zafack et al. article in Pediatrics (2017. doi: 10.1542/peds.2017-1760 ).
There are few experiences more challenging for a pediatrician than trying to convince a parent to continue vaccinating his or her child after witnessing a seemingly related adverse event following immunization (AEFI). The question they want answered is, Will it happen again?
Zafack et al. have sought to answer that question by providing previously lacking estimates of the risk of recurrence. By consolidating the data available in a range of literature, they showed that the risk of a serious AEFI is less than 1%. More accurate risk assessments also are available for mild to moderate AEFI for many vaccines.
The Zafack et al. article also reinforces what vaccinologists and pediatricians have known for many years: Vaccines are incredibly safe. Vaccines are administered to millions of children every year, and the list of known adverse events still is very short. The researchers reaffirm the overwhelming value and safety of vaccines that protect infants and children from complications and death resulting from infectious diseases.
Even though this article does not address AEFI risk for all vaccines, it is impressively comprehensive and will be a useful reference for practicing pediatricians everywhere for years to come.
Sean T. O’Leary, MD, MPH , is an associate professor in the division of infectious diseases in the department of pediatrics at the University of Colorado at Denver, Aurora. Yvonne A. Maldonado, MD , is chief of the division of pediatric infectious diseases and a professor of pediatrics at Stanford (Calif.) University. She serves on a Data Safety Monitoring Board for a Pfizer vaccine trial. Both authors are members of the American Academy of Pediatrics committee on infectious disease and subcommittee on vaccine policy and vaccine hesitancy. These comments were published in an editorial accompanying the Zafack et al. article in Pediatrics (2017. doi: 10.1542/peds.2017-1760 ).
(AEFI), but there are not enough data to make firm conclusions about severe AEFIs, according to a systematic review of studies that were published in English and French between 1982 and 2016 and were made available to Medline via PubMed, Embase, and the Cochrane library.
Apnea was found to be of concern only in children under the age of 1 year and usually found only in lower birth weight babies and those with ongoing hospitalization for complications related to prematurity, the investigators said. A 10-g increase in birth weight was associated with a 6% reduction in risk of apnea recurrence (odds ratio, 0.94; 95% CI, 0.89-1.00), and odds of recurrence were 23 times higher in infants hospitalized for complications related to prematurity (OR, 23; 95% CI, 2-272).
Some of the studies also evaluated for injection site reactions, Henoch-Schönlein purpura, or other AEFI, Dr. Zafack and her coauthors continued. Injection site reactions varied depending on vaccine and number of doses, but all children recovered within 19 days of immunization. Only one child in one study had a recurrence of Henoch-Schönlein purpura. Vomiting, persistent crying, decreased appetite, and drowsiness recurred in 15%, 24%, 25%, and 35% of the reimmunized patients, respectively, across all the studies.
“In a context of vaccine hesitancy and growing concerns regarding vaccine safety, evaluating the risk of recurrence of all AEFIs should become part of the standard evaluation of vaccine safety,” the researchers wrote. “Reimmunization appears to be safe for patients with mild to moderate AEFIs. However, the data are insufficient to draw firm conclusions regarding the safety of reimmunization after a severe AEFI.”
In this study, “it appears that the risk of recurrence of serious AEFIs (anaphylaxis, seizures, or apnea in term infants) was low (less than 1%). For minor to moderate AEFIs (fever, extensive limb swelling, oculorespiratory syndrome, allergic-like events, sleepiness, thrombocytopenia, decreased appetite, vomiting, or persistent crying), the risk of recurrence ranged from 4% to 48%,” the investigators concluded.
The study was funded by the Canadian Immunization Research Network, which is sponsored by the Public Health Agency of Canada and the Canadian Institutes of Health Research. Dr. Zafack reported no financial disclosures. Some of her coauthors reported financial support from GlaxoSmithKline and Pfizer.
(AEFI), but there are not enough data to make firm conclusions about severe AEFIs, according to a systematic review of studies that were published in English and French between 1982 and 2016 and were made available to Medline via PubMed, Embase, and the Cochrane library.
Apnea was found to be of concern only in children under the age of 1 year and usually found only in lower birth weight babies and those with ongoing hospitalization for complications related to prematurity, the investigators said. A 10-g increase in birth weight was associated with a 6% reduction in risk of apnea recurrence (odds ratio, 0.94; 95% CI, 0.89-1.00), and odds of recurrence were 23 times higher in infants hospitalized for complications related to prematurity (OR, 23; 95% CI, 2-272).
Some of the studies also evaluated for injection site reactions, Henoch-Schönlein purpura, or other AEFI, Dr. Zafack and her coauthors continued. Injection site reactions varied depending on vaccine and number of doses, but all children recovered within 19 days of immunization. Only one child in one study had a recurrence of Henoch-Schönlein purpura. Vomiting, persistent crying, decreased appetite, and drowsiness recurred in 15%, 24%, 25%, and 35% of the reimmunized patients, respectively, across all the studies.
“In a context of vaccine hesitancy and growing concerns regarding vaccine safety, evaluating the risk of recurrence of all AEFIs should become part of the standard evaluation of vaccine safety,” the researchers wrote. “Reimmunization appears to be safe for patients with mild to moderate AEFIs. However, the data are insufficient to draw firm conclusions regarding the safety of reimmunization after a severe AEFI.”
In this study, “it appears that the risk of recurrence of serious AEFIs (anaphylaxis, seizures, or apnea in term infants) was low (less than 1%). For minor to moderate AEFIs (fever, extensive limb swelling, oculorespiratory syndrome, allergic-like events, sleepiness, thrombocytopenia, decreased appetite, vomiting, or persistent crying), the risk of recurrence ranged from 4% to 48%,” the investigators concluded.
The study was funded by the Canadian Immunization Research Network, which is sponsored by the Public Health Agency of Canada and the Canadian Institutes of Health Research. Dr. Zafack reported no financial disclosures. Some of her coauthors reported financial support from GlaxoSmithKline and Pfizer.
FROM PEDIATRICS
Key clinical point: Reimmunization appears to be safe for patients with mild to moderate adverse events following immunization.
Major finding: The risk of a serious AEFI is less than 1%. More accurate risk assessments also are available for mild to moderate AEFI.
Data source: A systematic review of 29 studies assessing the risks of AEFI.
Disclosures: The study was funded by the Canadian Immunization Research Network, which is sponsored by the Public Health Agency of Canada and the Canadian Institutes of Health Research. Dr. Zafack reported no financial disclosures. Some of her coauthors reported financial support from GlaxoSmithKline and Pfizer.
Rapid AMI rule out
Clinical Question: Can a single high-sensitivity cardiac troponin-T (hs-cTnT) reliably rule-out acute myocardial infarction (AMI) to safely enable earlier discharge?
Background: Current practice includes serial measures of hs-cTnT to rule out AMI.
Study Design: A meta-analysis of 11 prospective cohorts at various international locations
Setting: Patients presenting to emergency departments with chest pain.
Synopsis: Of 9,241, a total of 2,825 patients were classified as low risk with a single negative hs-cTnT and nonischemic EKG. The primary outcome was AMI during initial hospitalization. Of low-risk patients, 14 (0.5%) had AMI. Pooled estimated sensitivity was 98.7% and pooled negative predictive value was 99.3%. For the secondary outcome of 30-day major adverse cardiac events, pooled sensitivity was 98%. Limitations include a small number of studies, high statistical heterogeneity, variation in troponin assays, and variable prevalence of AMI across studies.
Bottom Line: A single negative hs-cTnT and nonischemic EKG after three hours of chest pain can reliably rule out AMI. Further research is, however, required to validate the unequivocal use of this early rule out strategy.
Citation: Pickering J, Than M, Cullen L, et al. Rapid rule-out of acute myocardial infarction with a single high-sensitivity cardiac troponin t measurement below the limit of detection: A collaborative meta-analysis. Ann Intern Med. 2017 May 16;166(10):715-24.
Dr. Dogra is clinical instructor of medicine in the University of Kentucky division of hospital medicine.
Clinical Question: Can a single high-sensitivity cardiac troponin-T (hs-cTnT) reliably rule-out acute myocardial infarction (AMI) to safely enable earlier discharge?
Background: Current practice includes serial measures of hs-cTnT to rule out AMI.
Study Design: A meta-analysis of 11 prospective cohorts at various international locations
Setting: Patients presenting to emergency departments with chest pain.
Synopsis: Of 9,241, a total of 2,825 patients were classified as low risk with a single negative hs-cTnT and nonischemic EKG. The primary outcome was AMI during initial hospitalization. Of low-risk patients, 14 (0.5%) had AMI. Pooled estimated sensitivity was 98.7% and pooled negative predictive value was 99.3%. For the secondary outcome of 30-day major adverse cardiac events, pooled sensitivity was 98%. Limitations include a small number of studies, high statistical heterogeneity, variation in troponin assays, and variable prevalence of AMI across studies.
Bottom Line: A single negative hs-cTnT and nonischemic EKG after three hours of chest pain can reliably rule out AMI. Further research is, however, required to validate the unequivocal use of this early rule out strategy.
Citation: Pickering J, Than M, Cullen L, et al. Rapid rule-out of acute myocardial infarction with a single high-sensitivity cardiac troponin t measurement below the limit of detection: A collaborative meta-analysis. Ann Intern Med. 2017 May 16;166(10):715-24.
Dr. Dogra is clinical instructor of medicine in the University of Kentucky division of hospital medicine.
Clinical Question: Can a single high-sensitivity cardiac troponin-T (hs-cTnT) reliably rule-out acute myocardial infarction (AMI) to safely enable earlier discharge?
Background: Current practice includes serial measures of hs-cTnT to rule out AMI.
Study Design: A meta-analysis of 11 prospective cohorts at various international locations
Setting: Patients presenting to emergency departments with chest pain.
Synopsis: Of 9,241, a total of 2,825 patients were classified as low risk with a single negative hs-cTnT and nonischemic EKG. The primary outcome was AMI during initial hospitalization. Of low-risk patients, 14 (0.5%) had AMI. Pooled estimated sensitivity was 98.7% and pooled negative predictive value was 99.3%. For the secondary outcome of 30-day major adverse cardiac events, pooled sensitivity was 98%. Limitations include a small number of studies, high statistical heterogeneity, variation in troponin assays, and variable prevalence of AMI across studies.
Bottom Line: A single negative hs-cTnT and nonischemic EKG after three hours of chest pain can reliably rule out AMI. Further research is, however, required to validate the unequivocal use of this early rule out strategy.
Citation: Pickering J, Than M, Cullen L, et al. Rapid rule-out of acute myocardial infarction with a single high-sensitivity cardiac troponin t measurement below the limit of detection: A collaborative meta-analysis. Ann Intern Med. 2017 May 16;166(10):715-24.
Dr. Dogra is clinical instructor of medicine in the University of Kentucky division of hospital medicine.
