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Colchicine: A New Tool for Ischemic Stroke, CVD Event Recurrence?
BASEL, SWITZERLAND — However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.
“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.
The results were presented at the European Stroke Organization Conference (ESOC) 2024.
Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.
Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.
The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.
Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.
Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.
The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.
Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.
Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.
In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
A Novel Target for Stroke Treatment
In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.
In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).
“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.
He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.
“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.
Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.
“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.
“I think we have a new tool, but of course we need further trials to confirm that,” she added.
The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.
“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.
The results were presented at the European Stroke Organization Conference (ESOC) 2024.
Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.
Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.
The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.
Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.
Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.
The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.
Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.
Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.
In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
A Novel Target for Stroke Treatment
In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.
In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).
“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.
He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.
“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.
Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.
“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.
“I think we have a new tool, but of course we need further trials to confirm that,” she added.
The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.
“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.
The results were presented at the European Stroke Organization Conference (ESOC) 2024.
Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.
Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.
The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.
Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.
Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.
The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.
Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.
Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.
In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
A Novel Target for Stroke Treatment
In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.
In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).
“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.
He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.
“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.
Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.
“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.
“I think we have a new tool, but of course we need further trials to confirm that,” she added.
The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ESOC 2024
Counting Steps or Watching the Clock for a Longer Life?
Exercise recommendations typically focus on the duration of physical activity. For example, the World Health Organization advises at least 150 minutes of moderate physical activity per week. A new analysis of data from the Women’s Health Study, published in JAMA Internal Medicine, suggested that step count could also be a useful metric. For some, such a recommendation might be easier to follow.
“It’s not so easy to keep track of how long you’ve been moderately active in a given week,” Cary P. Gross, MD, from the Department of Medicine at Yale University in New Haven, Connecticut, wrote in an editorial. “Counting steps might be easier for some people, especially since most carry a phone that can serve as a pedometer.”
The 10,000-Step Recommendation
However, there are no well-founded recommendations for step counts, partly due to a lack of scientific evidence linking steps with mortality and cardiovascular diseases. The often-cited 10,000 steps per day originated from a marketing campaign in Japan in the 1960s.
The research team led by Rikuta Hamaya, MD, from the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, analyzed data from participants in the Women’s Health Study. This clinical trial in the United States from 1992 to 2004 investigated the use of aspirin and vitamin E for cancer and cardiovascular disease prevention.
The current analysis included 14,399 women who were aged ≥ 62 years and had not developed cardiovascular disease or cancer. Between 2011 and 2015, they measured their physical activity and step count over 7 days using an accelerometer. They were followed-up for an average of 9 years.
Risk Reduction With Both Parameters
Moderate physical activity among the participants amounted to a median of 62 minutes per week, with a median daily step count of 5183. Hamaya and his colleagues found that both physical activity parameters were associated with lower mortality and reduced risk for cardiovascular diseases.
Participants who engaged in more than the recommended 150 minutes of moderate-intensity activity per week had a 32% lower mortality risk than those who were the least physically active. Women with > 7000 steps per day had a 42% lower mortality risk than those with the lowest daily step count.
Women in the top three quartiles of physical activity outlived those in the lowest quartile by an average of 2.22 months (time) or 2.36 months (steps), according to Hamaya and his team. The survival advantage was independent of body mass index.
For the endpoint of cardiovascular diseases (heart attack, stroke, and cardiovascular mortality), the researchers observed similar results as for mortality.
More Ways to Reach the Goal
Dr. Hamaya emphasized the importance of offering multiple ways to meet exercise recommendations: “For some, especially younger people, physical activity includes sports like tennis, soccer, walking, or jogging. All these can be tracked well with step counting. But for others, activity means cycling or swimming, which is easier to measure by duration.”
For Dr. Gross, the new findings provide a basis for using step counts to set physical activity goals — both in individual patient counseling and in formal guidelines. However, he stressed that further studies are necessary.
“The results need to be replicated in various populations, not just among men and younger people but also among ethnic minorities and lower-income populations, who often have less time and space for structured physical activity.”
This story was translated from Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Exercise recommendations typically focus on the duration of physical activity. For example, the World Health Organization advises at least 150 minutes of moderate physical activity per week. A new analysis of data from the Women’s Health Study, published in JAMA Internal Medicine, suggested that step count could also be a useful metric. For some, such a recommendation might be easier to follow.
“It’s not so easy to keep track of how long you’ve been moderately active in a given week,” Cary P. Gross, MD, from the Department of Medicine at Yale University in New Haven, Connecticut, wrote in an editorial. “Counting steps might be easier for some people, especially since most carry a phone that can serve as a pedometer.”
The 10,000-Step Recommendation
However, there are no well-founded recommendations for step counts, partly due to a lack of scientific evidence linking steps with mortality and cardiovascular diseases. The often-cited 10,000 steps per day originated from a marketing campaign in Japan in the 1960s.
The research team led by Rikuta Hamaya, MD, from the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, analyzed data from participants in the Women’s Health Study. This clinical trial in the United States from 1992 to 2004 investigated the use of aspirin and vitamin E for cancer and cardiovascular disease prevention.
The current analysis included 14,399 women who were aged ≥ 62 years and had not developed cardiovascular disease or cancer. Between 2011 and 2015, they measured their physical activity and step count over 7 days using an accelerometer. They were followed-up for an average of 9 years.
Risk Reduction With Both Parameters
Moderate physical activity among the participants amounted to a median of 62 minutes per week, with a median daily step count of 5183. Hamaya and his colleagues found that both physical activity parameters were associated with lower mortality and reduced risk for cardiovascular diseases.
Participants who engaged in more than the recommended 150 minutes of moderate-intensity activity per week had a 32% lower mortality risk than those who were the least physically active. Women with > 7000 steps per day had a 42% lower mortality risk than those with the lowest daily step count.
Women in the top three quartiles of physical activity outlived those in the lowest quartile by an average of 2.22 months (time) or 2.36 months (steps), according to Hamaya and his team. The survival advantage was independent of body mass index.
For the endpoint of cardiovascular diseases (heart attack, stroke, and cardiovascular mortality), the researchers observed similar results as for mortality.
More Ways to Reach the Goal
Dr. Hamaya emphasized the importance of offering multiple ways to meet exercise recommendations: “For some, especially younger people, physical activity includes sports like tennis, soccer, walking, or jogging. All these can be tracked well with step counting. But for others, activity means cycling or swimming, which is easier to measure by duration.”
For Dr. Gross, the new findings provide a basis for using step counts to set physical activity goals — both in individual patient counseling and in formal guidelines. However, he stressed that further studies are necessary.
“The results need to be replicated in various populations, not just among men and younger people but also among ethnic minorities and lower-income populations, who often have less time and space for structured physical activity.”
This story was translated from Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Exercise recommendations typically focus on the duration of physical activity. For example, the World Health Organization advises at least 150 minutes of moderate physical activity per week. A new analysis of data from the Women’s Health Study, published in JAMA Internal Medicine, suggested that step count could also be a useful metric. For some, such a recommendation might be easier to follow.
“It’s not so easy to keep track of how long you’ve been moderately active in a given week,” Cary P. Gross, MD, from the Department of Medicine at Yale University in New Haven, Connecticut, wrote in an editorial. “Counting steps might be easier for some people, especially since most carry a phone that can serve as a pedometer.”
The 10,000-Step Recommendation
However, there are no well-founded recommendations for step counts, partly due to a lack of scientific evidence linking steps with mortality and cardiovascular diseases. The often-cited 10,000 steps per day originated from a marketing campaign in Japan in the 1960s.
The research team led by Rikuta Hamaya, MD, from the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, analyzed data from participants in the Women’s Health Study. This clinical trial in the United States from 1992 to 2004 investigated the use of aspirin and vitamin E for cancer and cardiovascular disease prevention.
The current analysis included 14,399 women who were aged ≥ 62 years and had not developed cardiovascular disease or cancer. Between 2011 and 2015, they measured their physical activity and step count over 7 days using an accelerometer. They were followed-up for an average of 9 years.
Risk Reduction With Both Parameters
Moderate physical activity among the participants amounted to a median of 62 minutes per week, with a median daily step count of 5183. Hamaya and his colleagues found that both physical activity parameters were associated with lower mortality and reduced risk for cardiovascular diseases.
Participants who engaged in more than the recommended 150 minutes of moderate-intensity activity per week had a 32% lower mortality risk than those who were the least physically active. Women with > 7000 steps per day had a 42% lower mortality risk than those with the lowest daily step count.
Women in the top three quartiles of physical activity outlived those in the lowest quartile by an average of 2.22 months (time) or 2.36 months (steps), according to Hamaya and his team. The survival advantage was independent of body mass index.
For the endpoint of cardiovascular diseases (heart attack, stroke, and cardiovascular mortality), the researchers observed similar results as for mortality.
More Ways to Reach the Goal
Dr. Hamaya emphasized the importance of offering multiple ways to meet exercise recommendations: “For some, especially younger people, physical activity includes sports like tennis, soccer, walking, or jogging. All these can be tracked well with step counting. But for others, activity means cycling or swimming, which is easier to measure by duration.”
For Dr. Gross, the new findings provide a basis for using step counts to set physical activity goals — both in individual patient counseling and in formal guidelines. However, he stressed that further studies are necessary.
“The results need to be replicated in various populations, not just among men and younger people but also among ethnic minorities and lower-income populations, who often have less time and space for structured physical activity.”
This story was translated from Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Gene Tests Could Predict if a Drug Will Work for a Patient
What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?
That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.
“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.
Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.
Dr. Cicali said.
Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.
Why PGx Tests Can Have a Big Impact
These tests work by looking for genes that control drug metabolism.
“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”
While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.
Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)
“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”
What the Research Shows
When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.
The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.
When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.
The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.
“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”
Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.
By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:
- In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
- In a 2023 from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
- In a University of Pennsylvania of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.
PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.
The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.
Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.
“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”
When, Why, and How to Test
“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.
You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.
Here’s how four PGx experts suggest consumers and physicians approach this option.
Find a Test
More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)
Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.
The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.
For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.
Consider Cost
The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.
In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.
Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.
Understand the Results
As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.
In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.
Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.
Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).
Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.
Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.
Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.
A version of this article appeared on Medscape.com.
What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?
That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.
“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.
Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.
Dr. Cicali said.
Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.
Why PGx Tests Can Have a Big Impact
These tests work by looking for genes that control drug metabolism.
“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”
While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.
Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)
“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”
What the Research Shows
When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.
The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.
When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.
The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.
“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”
Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.
By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:
- In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
- In a 2023 from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
- In a University of Pennsylvania of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.
PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.
The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.
Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.
“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”
When, Why, and How to Test
“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.
You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.
Here’s how four PGx experts suggest consumers and physicians approach this option.
Find a Test
More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)
Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.
The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.
For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.
Consider Cost
The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.
In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.
Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.
Understand the Results
As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.
In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.
Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.
Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).
Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.
Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.
Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.
A version of this article appeared on Medscape.com.
What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?
That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.
“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.
Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.
Dr. Cicali said.
Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.
Why PGx Tests Can Have a Big Impact
These tests work by looking for genes that control drug metabolism.
“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”
While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.
Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)
“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”
What the Research Shows
When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.
The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.
When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.
The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.
“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”
Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.
By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:
- In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
- In a 2023 from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
- In a University of Pennsylvania of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.
PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.
The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.
Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.
“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”
When, Why, and How to Test
“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.
You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.
Here’s how four PGx experts suggest consumers and physicians approach this option.
Find a Test
More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)
Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.
The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.
For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.
Consider Cost
The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.
In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.
Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.
Understand the Results
As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.
In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.
Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.
Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).
Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.
Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.
Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.
A version of this article appeared on Medscape.com.
Roche Blood Test for Lp(a) Designated Breakthrough Device
The Tina-quant Lp(a) RxDx assay, developed by Roche in partnership with Amgen, is designed to identify adults with elevated Lp(a) levels who may benefit from lipid-lowering therapies currently in development.
Lp(a) is a type of lipoprotein that is genetically inherited. Elevated levels have been associated with an increased risk for heart disease, stroke, and other blood vessel diseases.
Worldwide, about 1 in 5 people have high Lp(a) levels that are not significantly affected by lifestyle changes, such as diet and exercise. Elevated Lp(a) is particularly prevalent among women and people of African descent.
Lp(a) testing is “an important tool for clinicians, enabling them to make a more accurate assessment of [cardiovascular] risk, and it is expected to become a part of regular diagnostic testing in the coming years,” Roche said in a news release announcing the breakthrough designation for the Lp(a) blood test.
If approved, the Tina-quant Lp(a) RxDx assay will be available on select Roche cobas platforms, the company reported.
Although low-density-lipoprotein (LDL) cholesterol particles are much more abundant than Lp(a) particles and carry the greatest overall risk for heart disease, on a per-particle basis, atherogenic risk associated with Lp(a) is about six times higher than that associated with LDL cholesterol, a recent study showed.
There currently are no approved pharmacologic therapies to lower Lp(a) levels in the United States, but several hopefuls are in development.
One is zerlasiran (Silence Therapeutics), a short interfering RNA (siRNA) agent, or “gene silencing” therapy, which binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein A, a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.
Treatment with zerlasiran produced significant and sustained reductions in Lp(a) concentrations in adults with elevated Lp(a) in the phase 1 APOLLO trial and the phase 2 ALPACAR-360 trial.
Other siRNA agents in development to lower Lp(a) levels include pelacarsen, lepodisiran, olpasiran, and muvalaplin.
A version of this article appeared on Medscape.com.
The Tina-quant Lp(a) RxDx assay, developed by Roche in partnership with Amgen, is designed to identify adults with elevated Lp(a) levels who may benefit from lipid-lowering therapies currently in development.
Lp(a) is a type of lipoprotein that is genetically inherited. Elevated levels have been associated with an increased risk for heart disease, stroke, and other blood vessel diseases.
Worldwide, about 1 in 5 people have high Lp(a) levels that are not significantly affected by lifestyle changes, such as diet and exercise. Elevated Lp(a) is particularly prevalent among women and people of African descent.
Lp(a) testing is “an important tool for clinicians, enabling them to make a more accurate assessment of [cardiovascular] risk, and it is expected to become a part of regular diagnostic testing in the coming years,” Roche said in a news release announcing the breakthrough designation for the Lp(a) blood test.
If approved, the Tina-quant Lp(a) RxDx assay will be available on select Roche cobas platforms, the company reported.
Although low-density-lipoprotein (LDL) cholesterol particles are much more abundant than Lp(a) particles and carry the greatest overall risk for heart disease, on a per-particle basis, atherogenic risk associated with Lp(a) is about six times higher than that associated with LDL cholesterol, a recent study showed.
There currently are no approved pharmacologic therapies to lower Lp(a) levels in the United States, but several hopefuls are in development.
One is zerlasiran (Silence Therapeutics), a short interfering RNA (siRNA) agent, or “gene silencing” therapy, which binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein A, a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.
Treatment with zerlasiran produced significant and sustained reductions in Lp(a) concentrations in adults with elevated Lp(a) in the phase 1 APOLLO trial and the phase 2 ALPACAR-360 trial.
Other siRNA agents in development to lower Lp(a) levels include pelacarsen, lepodisiran, olpasiran, and muvalaplin.
A version of this article appeared on Medscape.com.
The Tina-quant Lp(a) RxDx assay, developed by Roche in partnership with Amgen, is designed to identify adults with elevated Lp(a) levels who may benefit from lipid-lowering therapies currently in development.
Lp(a) is a type of lipoprotein that is genetically inherited. Elevated levels have been associated with an increased risk for heart disease, stroke, and other blood vessel diseases.
Worldwide, about 1 in 5 people have high Lp(a) levels that are not significantly affected by lifestyle changes, such as diet and exercise. Elevated Lp(a) is particularly prevalent among women and people of African descent.
Lp(a) testing is “an important tool for clinicians, enabling them to make a more accurate assessment of [cardiovascular] risk, and it is expected to become a part of regular diagnostic testing in the coming years,” Roche said in a news release announcing the breakthrough designation for the Lp(a) blood test.
If approved, the Tina-quant Lp(a) RxDx assay will be available on select Roche cobas platforms, the company reported.
Although low-density-lipoprotein (LDL) cholesterol particles are much more abundant than Lp(a) particles and carry the greatest overall risk for heart disease, on a per-particle basis, atherogenic risk associated with Lp(a) is about six times higher than that associated with LDL cholesterol, a recent study showed.
There currently are no approved pharmacologic therapies to lower Lp(a) levels in the United States, but several hopefuls are in development.
One is zerlasiran (Silence Therapeutics), a short interfering RNA (siRNA) agent, or “gene silencing” therapy, which binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein A, a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.
Treatment with zerlasiran produced significant and sustained reductions in Lp(a) concentrations in adults with elevated Lp(a) in the phase 1 APOLLO trial and the phase 2 ALPACAR-360 trial.
Other siRNA agents in development to lower Lp(a) levels include pelacarsen, lepodisiran, olpasiran, and muvalaplin.
A version of this article appeared on Medscape.com.
Greater Awareness Urged for Important, Overlooked Neuropsychiatric Symptoms of Lupus
Neuropsychiatric symptoms, including nightmares and hallucinatory “daymares,” may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science’s eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare.
“For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought,” lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in England, told this news organization.
“If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage,” Dr. Sloan said. “Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms.”
Alfred Kim, MD, PhD, associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition.
“There is some controversy about whether the neuropsychiatric manifestations that we have long attributed to lupus actually are due to lupus,” Dr. Kim told this news organization. Dr. Kim was part of a group that published a review on potential mechanisms underlying neuropsychiatric symptoms described by a committee of the American College of Rheumatology.
Since that committee’s findings, “we have long assumed that if we saw these symptoms, the best explanation was lupus,” Dr. Kim said. “The problem is that, in the real world, we can see many of these manifestations in patients with lupus that do not get better with lupus meds. This opens up the very real possibility that another etiology is at play.”
Dr. Kim noted that mood disorders such as depression and anxiety may be part of the neuropsychiatric SLE criteria, but they failed to correlate with overall lupus disease activity in a cohort he evaluated. That makes it hard to distinguish whether those neuropsychiatric symptoms can actually be attributed to lupus. “Probably the more accurate interpretation is that there may be certain symptoms, such as nightmares, that indicated a prodrome of lupus,” he said. “Whether these are actually lupus symptoms is debatable to me.”
There remains value in initiating discussions about these symptoms with patients, however, because the stigma associated with neuropsychiatric symptoms may prevent patients from bringing them up themselves.
“It is important to remember that many of these patients, in common with other chronic diseases, will often have had long and traumatic journeys to diagnosis,” including having been misdiagnosed with a psychiatric condition, Dr. Sloan said. “Many of the patients then lose trust in doctors and are reluctant to report symptoms that may lead to another misdiagnosis.”
Clinicians may also be reluctant to bring up these symptoms, but for different reasons. Their reluctance may stem from insufficient time to discuss the symptoms or not having the support available to help the patients with these particular problems, Dr. Sloan said. The invisible nature of these symptoms, which lack biomarkers, makes them harder to identify and makes listening to patients more important, she added.
Study Details
In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). “The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution,” the authors reported.
During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%).
The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%).
The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. “Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these,” the authors wrote.
The researchers also conducted video conference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term “daymare” was used to discuss possible hallucinations.
Linking Neuropsychiatric Symptoms and Disease
Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an “established theory” that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms.
Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked.
A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. “For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more ‘reactive’ low mood that could be more attributable to a consequence of psychological distress,” the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue.
Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an “early warning system.” Often, however, these symptoms “were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE,” the authors found. “These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement.” These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a “feeling of unreality,” or increased sensory symptoms.
Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression.
Nightmares and Daymares
A third theme centered on disrupted dreaming sleep, nightmares, and “daymares” as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews.
“Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations,” the authors reported. Flare-related nightmares in particular “often involved being attacked, trapped, crushed, or falling.” Patients tended to be more forthcoming about hallucinatory experiences when the term “daymare” was used to describe them, and they often related to the idea of feeling “in-between asleep and awake.”
Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients.
“There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion,” the authors wrote.
Though Dr. Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. “Trauma is a major risk factor for lupus,” Dr. Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. “Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma,” Dr. Kim said.
In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Dr. Kim said, and poor sleep is also associated with lupus. “One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients,” Dr. Kim said.
Misattribution of Neuropsychiatric Symptoms
The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before the lupus diagnosis at age 19 and noticed that the symptoms of one “got under control” when the symptoms of the other did.
“Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions,” the authors reported. “Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself.”
Dr. Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden “the type of symptoms we need to put on our radar pre-diagnosis,” Dr. Kim said. “We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though.”
Dr. Sloan cited earlier work in recommending an “ABC” approach to improving clinician-patient relationships: “Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship.” She noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases.
The research was funded by The Lupus Trust. Three authors reported consultancy, speaker, or advisory fees from Alumis, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, MGP, Novartis, Pfizer, Sanofi, UCB, Vifor, and/or Werfen Group. The other authors, including Dr. Sloan, had no industry-related disclosures. Dr. Kim reported research support from AstraZeneca, GlaxoSmithKline, and Novartis; speaking fees from Exagen Diagnostics and GlaxoSmithKline; and consulting fees from AbbVie, Amgen, ANI Pharmaceuticals, AstraZeneca, Atara Bio, Aurinia Pharmaceuticals, Cargo Therapeutics, Exagen Diagnostics, Hinge Bio, GlaxoSmithKline, Kypha, Miltenyi Biotec, Synthekine, and Tectonic Therapeutic.
A version of this article appeared on Medscape.com.
Neuropsychiatric symptoms, including nightmares and hallucinatory “daymares,” may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science’s eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare.
“For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought,” lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in England, told this news organization.
“If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage,” Dr. Sloan said. “Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms.”
Alfred Kim, MD, PhD, associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition.
“There is some controversy about whether the neuropsychiatric manifestations that we have long attributed to lupus actually are due to lupus,” Dr. Kim told this news organization. Dr. Kim was part of a group that published a review on potential mechanisms underlying neuropsychiatric symptoms described by a committee of the American College of Rheumatology.
Since that committee’s findings, “we have long assumed that if we saw these symptoms, the best explanation was lupus,” Dr. Kim said. “The problem is that, in the real world, we can see many of these manifestations in patients with lupus that do not get better with lupus meds. This opens up the very real possibility that another etiology is at play.”
Dr. Kim noted that mood disorders such as depression and anxiety may be part of the neuropsychiatric SLE criteria, but they failed to correlate with overall lupus disease activity in a cohort he evaluated. That makes it hard to distinguish whether those neuropsychiatric symptoms can actually be attributed to lupus. “Probably the more accurate interpretation is that there may be certain symptoms, such as nightmares, that indicated a prodrome of lupus,” he said. “Whether these are actually lupus symptoms is debatable to me.”
There remains value in initiating discussions about these symptoms with patients, however, because the stigma associated with neuropsychiatric symptoms may prevent patients from bringing them up themselves.
“It is important to remember that many of these patients, in common with other chronic diseases, will often have had long and traumatic journeys to diagnosis,” including having been misdiagnosed with a psychiatric condition, Dr. Sloan said. “Many of the patients then lose trust in doctors and are reluctant to report symptoms that may lead to another misdiagnosis.”
Clinicians may also be reluctant to bring up these symptoms, but for different reasons. Their reluctance may stem from insufficient time to discuss the symptoms or not having the support available to help the patients with these particular problems, Dr. Sloan said. The invisible nature of these symptoms, which lack biomarkers, makes them harder to identify and makes listening to patients more important, she added.
Study Details
In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). “The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution,” the authors reported.
During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%).
The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%).
The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. “Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these,” the authors wrote.
The researchers also conducted video conference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term “daymare” was used to discuss possible hallucinations.
Linking Neuropsychiatric Symptoms and Disease
Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an “established theory” that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms.
Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked.
A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. “For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more ‘reactive’ low mood that could be more attributable to a consequence of psychological distress,” the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue.
Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an “early warning system.” Often, however, these symptoms “were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE,” the authors found. “These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement.” These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a “feeling of unreality,” or increased sensory symptoms.
Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression.
Nightmares and Daymares
A third theme centered on disrupted dreaming sleep, nightmares, and “daymares” as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews.
“Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations,” the authors reported. Flare-related nightmares in particular “often involved being attacked, trapped, crushed, or falling.” Patients tended to be more forthcoming about hallucinatory experiences when the term “daymare” was used to describe them, and they often related to the idea of feeling “in-between asleep and awake.”
Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients.
“There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion,” the authors wrote.
Though Dr. Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. “Trauma is a major risk factor for lupus,” Dr. Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. “Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma,” Dr. Kim said.
In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Dr. Kim said, and poor sleep is also associated with lupus. “One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients,” Dr. Kim said.
Misattribution of Neuropsychiatric Symptoms
The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before the lupus diagnosis at age 19 and noticed that the symptoms of one “got under control” when the symptoms of the other did.
“Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions,” the authors reported. “Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself.”
Dr. Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden “the type of symptoms we need to put on our radar pre-diagnosis,” Dr. Kim said. “We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though.”
Dr. Sloan cited earlier work in recommending an “ABC” approach to improving clinician-patient relationships: “Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship.” She noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases.
The research was funded by The Lupus Trust. Three authors reported consultancy, speaker, or advisory fees from Alumis, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, MGP, Novartis, Pfizer, Sanofi, UCB, Vifor, and/or Werfen Group. The other authors, including Dr. Sloan, had no industry-related disclosures. Dr. Kim reported research support from AstraZeneca, GlaxoSmithKline, and Novartis; speaking fees from Exagen Diagnostics and GlaxoSmithKline; and consulting fees from AbbVie, Amgen, ANI Pharmaceuticals, AstraZeneca, Atara Bio, Aurinia Pharmaceuticals, Cargo Therapeutics, Exagen Diagnostics, Hinge Bio, GlaxoSmithKline, Kypha, Miltenyi Biotec, Synthekine, and Tectonic Therapeutic.
A version of this article appeared on Medscape.com.
Neuropsychiatric symptoms, including nightmares and hallucinatory “daymares,” may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science’s eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare.
“For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought,” lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in England, told this news organization.
“If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage,” Dr. Sloan said. “Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms.”
Alfred Kim, MD, PhD, associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition.
“There is some controversy about whether the neuropsychiatric manifestations that we have long attributed to lupus actually are due to lupus,” Dr. Kim told this news organization. Dr. Kim was part of a group that published a review on potential mechanisms underlying neuropsychiatric symptoms described by a committee of the American College of Rheumatology.
Since that committee’s findings, “we have long assumed that if we saw these symptoms, the best explanation was lupus,” Dr. Kim said. “The problem is that, in the real world, we can see many of these manifestations in patients with lupus that do not get better with lupus meds. This opens up the very real possibility that another etiology is at play.”
Dr. Kim noted that mood disorders such as depression and anxiety may be part of the neuropsychiatric SLE criteria, but they failed to correlate with overall lupus disease activity in a cohort he evaluated. That makes it hard to distinguish whether those neuropsychiatric symptoms can actually be attributed to lupus. “Probably the more accurate interpretation is that there may be certain symptoms, such as nightmares, that indicated a prodrome of lupus,” he said. “Whether these are actually lupus symptoms is debatable to me.”
There remains value in initiating discussions about these symptoms with patients, however, because the stigma associated with neuropsychiatric symptoms may prevent patients from bringing them up themselves.
“It is important to remember that many of these patients, in common with other chronic diseases, will often have had long and traumatic journeys to diagnosis,” including having been misdiagnosed with a psychiatric condition, Dr. Sloan said. “Many of the patients then lose trust in doctors and are reluctant to report symptoms that may lead to another misdiagnosis.”
Clinicians may also be reluctant to bring up these symptoms, but for different reasons. Their reluctance may stem from insufficient time to discuss the symptoms or not having the support available to help the patients with these particular problems, Dr. Sloan said. The invisible nature of these symptoms, which lack biomarkers, makes them harder to identify and makes listening to patients more important, she added.
Study Details
In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). “The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution,” the authors reported.
During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%).
The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%).
The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. “Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these,” the authors wrote.
The researchers also conducted video conference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term “daymare” was used to discuss possible hallucinations.
Linking Neuropsychiatric Symptoms and Disease
Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an “established theory” that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms.
Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked.
A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. “For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more ‘reactive’ low mood that could be more attributable to a consequence of psychological distress,” the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue.
Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an “early warning system.” Often, however, these symptoms “were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE,” the authors found. “These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement.” These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a “feeling of unreality,” or increased sensory symptoms.
Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression.
Nightmares and Daymares
A third theme centered on disrupted dreaming sleep, nightmares, and “daymares” as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews.
“Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations,” the authors reported. Flare-related nightmares in particular “often involved being attacked, trapped, crushed, or falling.” Patients tended to be more forthcoming about hallucinatory experiences when the term “daymare” was used to describe them, and they often related to the idea of feeling “in-between asleep and awake.”
Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients.
“There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion,” the authors wrote.
Though Dr. Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. “Trauma is a major risk factor for lupus,” Dr. Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. “Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma,” Dr. Kim said.
In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Dr. Kim said, and poor sleep is also associated with lupus. “One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients,” Dr. Kim said.
Misattribution of Neuropsychiatric Symptoms
The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before the lupus diagnosis at age 19 and noticed that the symptoms of one “got under control” when the symptoms of the other did.
“Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions,” the authors reported. “Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself.”
Dr. Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden “the type of symptoms we need to put on our radar pre-diagnosis,” Dr. Kim said. “We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though.”
Dr. Sloan cited earlier work in recommending an “ABC” approach to improving clinician-patient relationships: “Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship.” She noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases.
The research was funded by The Lupus Trust. Three authors reported consultancy, speaker, or advisory fees from Alumis, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, MGP, Novartis, Pfizer, Sanofi, UCB, Vifor, and/or Werfen Group. The other authors, including Dr. Sloan, had no industry-related disclosures. Dr. Kim reported research support from AstraZeneca, GlaxoSmithKline, and Novartis; speaking fees from Exagen Diagnostics and GlaxoSmithKline; and consulting fees from AbbVie, Amgen, ANI Pharmaceuticals, AstraZeneca, Atara Bio, Aurinia Pharmaceuticals, Cargo Therapeutics, Exagen Diagnostics, Hinge Bio, GlaxoSmithKline, Kypha, Miltenyi Biotec, Synthekine, and Tectonic Therapeutic.
A version of this article appeared on Medscape.com.
FROM ECLINICALMEDICINE
Guidelines on Rapid Blood Pressure Reduction in Acute Ischemic Stroke Challenged
BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.
The observational cluster study showed that , even though this meant fewer patient received thrombolysis.
“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands.
“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.
The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology.
Guidelines Without Evidence?
Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines.
Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital.
“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted.
However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.
For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy.
Baseline characteristics of participants in the two groups were similar.
Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68).
This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering).
Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
Reconsider Guidelines?
These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.
“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said.
But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.
Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients.
“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added.
Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis.
“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
Caution Advised
Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”
Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding.
“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said.
In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”
But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.
He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy.
“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said.
“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.
INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed.
“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said.
The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.
The observational cluster study showed that , even though this meant fewer patient received thrombolysis.
“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands.
“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.
The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology.
Guidelines Without Evidence?
Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines.
Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital.
“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted.
However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.
For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy.
Baseline characteristics of participants in the two groups were similar.
Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68).
This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering).
Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
Reconsider Guidelines?
These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.
“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said.
But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.
Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients.
“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added.
Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis.
“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
Caution Advised
Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”
Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding.
“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said.
In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”
But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.
He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy.
“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said.
“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.
INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed.
“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said.
The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.
The observational cluster study showed that , even though this meant fewer patient received thrombolysis.
“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands.
“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.
The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology.
Guidelines Without Evidence?
Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines.
Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital.
“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted.
However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.
For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy.
Baseline characteristics of participants in the two groups were similar.
Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68).
This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering).
Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
Reconsider Guidelines?
These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.
“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said.
But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.
Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients.
“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added.
Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis.
“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
Caution Advised
Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”
Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding.
“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said.
In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”
But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.
He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy.
“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said.
“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.
INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed.
“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said.
The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.
A version of this article appeared on Medscape.com.
FROM ESOC 2024
IV Thrombolysis Offers No Benefit for Mild Stroke
BASEL, SWITZERLAND — , a new trial has concluded.
Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.
The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.
“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.
“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”
The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
Very Little Data
Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.
Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.
However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.
Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.
The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.
The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.
Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).
The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.
The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).
Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.
More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).
There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).
The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.
Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.
Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.
Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
More Trials Needed
Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”
In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.
Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.
Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.
While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.
“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.
This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — , a new trial has concluded.
Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.
The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.
“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.
“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”
The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
Very Little Data
Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.
Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.
However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.
Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.
The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.
The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.
Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).
The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.
The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).
Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.
More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).
There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).
The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.
Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.
Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.
Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
More Trials Needed
Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”
In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.
Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.
Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.
While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.
“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.
This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — , a new trial has concluded.
Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.
The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.
“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.
“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”
The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
Very Little Data
Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.
Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.
However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.
Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.
The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.
The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.
Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).
The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.
The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).
Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.
More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).
There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).
The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.
Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.
Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.
Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
More Trials Needed
Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”
In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.
Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.
Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.
While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.
“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.
This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.
A version of this article appeared on Medscape.com.
FROM ESOC 2024
New Data to Change Practice on BP Control in Acute Stroke: INTERACT4
BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients.
“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia.
“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.
The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine.
A Test of Early BP Control
The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke.
The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis.
For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).
The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg.
Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke.
At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group.
The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days.
Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar.
But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke.
‘Slam-Dunk’ Effect
Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.
“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”
The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.
The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said.
“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.”
Challenging Ischemic Stroke Guidelines
The INTERACT4 results in ischemic stroke patients are likely to be more controversial.
“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said.
Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly.
“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.”
He said the mechanisms behind the different stroke types would explain the results.
“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”
Accurate Diagnosis Necessary
Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance.
“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”
Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice.
“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated.
Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions.
In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke.
“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote.
The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients.
“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia.
“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.
The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine.
A Test of Early BP Control
The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke.
The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis.
For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).
The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg.
Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke.
At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group.
The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days.
Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar.
But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke.
‘Slam-Dunk’ Effect
Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.
“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”
The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.
The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said.
“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.”
Challenging Ischemic Stroke Guidelines
The INTERACT4 results in ischemic stroke patients are likely to be more controversial.
“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said.
Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly.
“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.”
He said the mechanisms behind the different stroke types would explain the results.
“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”
Accurate Diagnosis Necessary
Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance.
“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”
Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice.
“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated.
Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions.
In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke.
“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote.
The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients.
“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia.
“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.
The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine.
A Test of Early BP Control
The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke.
The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis.
For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).
The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg.
Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke.
At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group.
The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days.
Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar.
But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke.
‘Slam-Dunk’ Effect
Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.
“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”
The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.
The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said.
“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.”
Challenging Ischemic Stroke Guidelines
The INTERACT4 results in ischemic stroke patients are likely to be more controversial.
“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said.
Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly.
“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.”
He said the mechanisms behind the different stroke types would explain the results.
“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”
Accurate Diagnosis Necessary
Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance.
“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”
Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice.
“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated.
Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions.
In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke.
“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote.
The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.
A version of this article appeared on Medscape.com.
‘Big Breakthrough’: New Low-Field MRI Is Safer and Easier
For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.
Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.
In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.
The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.
Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.
If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.
But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
Improving Access to MRI
One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.
While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.
A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.
Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.
“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
Challenges and the Future
The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.
One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.
Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.
That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
A version of this article appeared on Medscape.com.
For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.
Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.
In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.
The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.
Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.
If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.
But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
Improving Access to MRI
One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.
While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.
A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.
Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.
“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
Challenges and the Future
The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.
One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.
Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.
That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
A version of this article appeared on Medscape.com.
For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.
Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.
In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.
The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.
Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.
If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.
But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
Improving Access to MRI
One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.
While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.
A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.
Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.
“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
Challenges and the Future
The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.
One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.
Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.
That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
A version of this article appeared on Medscape.com.
CVD Risk Rises With Higher NSAID Doses in Ankylosing Spondylitis
TOPLINE:
Higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and congestive heart failure in patients with ankylosing spondylitis (AS) compared with lower doses.
METHODOLOGY:
- NSAIDs can suppress inflammation and relieve pain in patients with AS, but long-term treatment with NSAIDs poses concerns regarding gastrointestinal and renal toxicities and increased CVD risk.
- This nationwide cohort study used data from the Korean National Health Insurance database to investigate the risk for CVD associated with an increasing NSAID dosage in a real-world AS cohort.
- Investigators recruited 19,775 patients (mean age, 36.1 years; 75% men) with newly diagnosed AS and without any prior CVD between January 2010 and December 2018, among whom 99.7% received NSAID treatment and 30.2% received tumor necrosis factor inhibitor treatment.
- A time-varying approach was used to assess the NSAID exposure, wherein periods of NSAID use were defined as “NSAID-exposed” and periods longer than 1 month without NSAID use were defined as “NSAID-unexposed.”
- The primary outcome was the composite outcome of ischemic heart disease, stroke, or congestive heart failure.
TAKEAWAY:
- During the follow-up period of 98,290 person-years, 1663 cases of CVD were identified, which included 1157 cases of ischemic heart disease, 301 cases of stroke, and 613 cases of congestive heart failure.
- After adjusting for confounders, each defined daily dose increase in NSAIDs raised the risk for incident CVD by 10% (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.08-1.13).
- Similarly, increasing the dose of NSAIDs was associated with an increased risk for ischemic heart disease (aHR, 1.08; 95% CI, 1.05-1.11), stroke (aHR, 1.09; 95% CI, 1.04-1.15), and congestive heart failure (aHR, 1.12; 95% CI, 1.08-1.16).
- The association between increasing NSAID dose and increased CVD risk was consistent across various subgroups, with NSAIDs posing a greater threat to cardiovascular health in women than in men.
IN PRACTICE:
The authors wrote, “Taken together, these results suggest that increasing the dose of NSAIDs is associated with a higher cardiovascular risk in AS, but that the increased risk might be lower than that in the general population.”
SOURCE:
First author Ji-Won Kim, MD, PhD, of the Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, the Republic of Korea, and colleagues had their work published online on April 9 in Annals of the Rheumatic Diseases.
LIMITATIONS:
The study was of retrospective nature. The levels of acute phase reactants and AS disease activity could not be determined owing to a lack of data in the National Health Insurance database. The accuracy of the diagnosis of cardiovascular outcomes on the basis of the International Classification of Disease codes was also questionable.
DISCLOSURES:
The study was supported by the National Research Foundation of Korea. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and congestive heart failure in patients with ankylosing spondylitis (AS) compared with lower doses.
METHODOLOGY:
- NSAIDs can suppress inflammation and relieve pain in patients with AS, but long-term treatment with NSAIDs poses concerns regarding gastrointestinal and renal toxicities and increased CVD risk.
- This nationwide cohort study used data from the Korean National Health Insurance database to investigate the risk for CVD associated with an increasing NSAID dosage in a real-world AS cohort.
- Investigators recruited 19,775 patients (mean age, 36.1 years; 75% men) with newly diagnosed AS and without any prior CVD between January 2010 and December 2018, among whom 99.7% received NSAID treatment and 30.2% received tumor necrosis factor inhibitor treatment.
- A time-varying approach was used to assess the NSAID exposure, wherein periods of NSAID use were defined as “NSAID-exposed” and periods longer than 1 month without NSAID use were defined as “NSAID-unexposed.”
- The primary outcome was the composite outcome of ischemic heart disease, stroke, or congestive heart failure.
TAKEAWAY:
- During the follow-up period of 98,290 person-years, 1663 cases of CVD were identified, which included 1157 cases of ischemic heart disease, 301 cases of stroke, and 613 cases of congestive heart failure.
- After adjusting for confounders, each defined daily dose increase in NSAIDs raised the risk for incident CVD by 10% (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.08-1.13).
- Similarly, increasing the dose of NSAIDs was associated with an increased risk for ischemic heart disease (aHR, 1.08; 95% CI, 1.05-1.11), stroke (aHR, 1.09; 95% CI, 1.04-1.15), and congestive heart failure (aHR, 1.12; 95% CI, 1.08-1.16).
- The association between increasing NSAID dose and increased CVD risk was consistent across various subgroups, with NSAIDs posing a greater threat to cardiovascular health in women than in men.
IN PRACTICE:
The authors wrote, “Taken together, these results suggest that increasing the dose of NSAIDs is associated with a higher cardiovascular risk in AS, but that the increased risk might be lower than that in the general population.”
SOURCE:
First author Ji-Won Kim, MD, PhD, of the Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, the Republic of Korea, and colleagues had their work published online on April 9 in Annals of the Rheumatic Diseases.
LIMITATIONS:
The study was of retrospective nature. The levels of acute phase reactants and AS disease activity could not be determined owing to a lack of data in the National Health Insurance database. The accuracy of the diagnosis of cardiovascular outcomes on the basis of the International Classification of Disease codes was also questionable.
DISCLOSURES:
The study was supported by the National Research Foundation of Korea. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and congestive heart failure in patients with ankylosing spondylitis (AS) compared with lower doses.
METHODOLOGY:
- NSAIDs can suppress inflammation and relieve pain in patients with AS, but long-term treatment with NSAIDs poses concerns regarding gastrointestinal and renal toxicities and increased CVD risk.
- This nationwide cohort study used data from the Korean National Health Insurance database to investigate the risk for CVD associated with an increasing NSAID dosage in a real-world AS cohort.
- Investigators recruited 19,775 patients (mean age, 36.1 years; 75% men) with newly diagnosed AS and without any prior CVD between January 2010 and December 2018, among whom 99.7% received NSAID treatment and 30.2% received tumor necrosis factor inhibitor treatment.
- A time-varying approach was used to assess the NSAID exposure, wherein periods of NSAID use were defined as “NSAID-exposed” and periods longer than 1 month without NSAID use were defined as “NSAID-unexposed.”
- The primary outcome was the composite outcome of ischemic heart disease, stroke, or congestive heart failure.
TAKEAWAY:
- During the follow-up period of 98,290 person-years, 1663 cases of CVD were identified, which included 1157 cases of ischemic heart disease, 301 cases of stroke, and 613 cases of congestive heart failure.
- After adjusting for confounders, each defined daily dose increase in NSAIDs raised the risk for incident CVD by 10% (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.08-1.13).
- Similarly, increasing the dose of NSAIDs was associated with an increased risk for ischemic heart disease (aHR, 1.08; 95% CI, 1.05-1.11), stroke (aHR, 1.09; 95% CI, 1.04-1.15), and congestive heart failure (aHR, 1.12; 95% CI, 1.08-1.16).
- The association between increasing NSAID dose and increased CVD risk was consistent across various subgroups, with NSAIDs posing a greater threat to cardiovascular health in women than in men.
IN PRACTICE:
The authors wrote, “Taken together, these results suggest that increasing the dose of NSAIDs is associated with a higher cardiovascular risk in AS, but that the increased risk might be lower than that in the general population.”
SOURCE:
First author Ji-Won Kim, MD, PhD, of the Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, the Republic of Korea, and colleagues had their work published online on April 9 in Annals of the Rheumatic Diseases.
LIMITATIONS:
The study was of retrospective nature. The levels of acute phase reactants and AS disease activity could not be determined owing to a lack of data in the National Health Insurance database. The accuracy of the diagnosis of cardiovascular outcomes on the basis of the International Classification of Disease codes was also questionable.
DISCLOSURES:
The study was supported by the National Research Foundation of Korea. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.