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Home devices screen for atrial fibrillation
In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.
KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.
The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
How effective is KardiaMobile at detecting AFib?
Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.1 In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.2
How does the Apple Watch find AFib?
Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.
The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.
In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.3 Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.4,5
What should we do with the results?
It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.
While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.
Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
References
1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.
2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.
3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.
4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.
5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.
In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.
KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.
The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
How effective is KardiaMobile at detecting AFib?
Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.1 In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.2
How does the Apple Watch find AFib?
Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.
The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.
In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.3 Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.4,5
What should we do with the results?
It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.
While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.
Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
References
1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.
2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.
3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.
4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.
5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.
In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.
KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.
The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
How effective is KardiaMobile at detecting AFib?
Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.1 In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.2
How does the Apple Watch find AFib?
Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.
The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.
In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.3 Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.4,5
What should we do with the results?
It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.
While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.
Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
References
1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.
2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.
3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.
4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.
5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.
Coffee lowers heart failure risk in unique study
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
FROM CIRCULATION: HEART FAILURE
Left atrial appendage occlusion, DOAC comparable for AFib
Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.
And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.
“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.
Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).
Observational registry study shows 43% reduction in primary outcome
The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.
The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.
Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.
Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).
Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.
Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.
“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”
Noncompliance to DOAC therapy a concern
In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”
However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.
“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”
Methods ‘severely flawed’
John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.
“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”
Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.
Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.
Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.
Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.
And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.
“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.
Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).
Observational registry study shows 43% reduction in primary outcome
The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.
The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.
Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.
Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).
Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.
Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.
“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”
Noncompliance to DOAC therapy a concern
In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”
However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.
“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”
Methods ‘severely flawed’
John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.
“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”
Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.
Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.
Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.
Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.
And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.
“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.
Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).
Observational registry study shows 43% reduction in primary outcome
The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.
The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.
Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.
Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).
Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.
Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.
“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”
Noncompliance to DOAC therapy a concern
In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”
However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.
“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”
Methods ‘severely flawed’
John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.
“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”
Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.
Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.
Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.
FROM JACC CARDIOVASCULAR INTERVENTION
Urgent recall for Penumbra JET 7 Xtra Flex reperfusion catheters
“All users should stop using this device, and facilities should remove these devices from inventory,” the recall notice, posted on the U.S. Food and Drug Administration website, advises.
The recall covers the JET 7 Xtra Flex catheter, which was cleared for use in June 2019, and the JET 7MAX configuration (which includes the JET 7 Xtra Flex catheter and MAX delivery device), which was cleared in February of this year.
The recall does not apply to the Penumbra JET 7 reperfusion catheter with standard tip.
The FDA says it has received over 200 medical device reports (MDRs) associated with the JET 7 Xtra Flex catheter, including reports of deaths, serious injuries, and malfunctions.
Twenty of these MDRs describe 14 unique patient deaths. Other MDRs describe serious patient injury, such as vessel damage, hemorrhage, and cerebral infarction.
Device malfunctions described in the reports include ballooning, expansion, rupture, breakage or complete separation, and exposure of internal support coils near the distal tip region of the JET 7 Xtra Flex catheter.
According to the FDA, bench testing by the manufacturer, in which the catheter distal tip is plugged and pressurized to failure, indicates that the JET 7 Xtra Flex catheter is not able to withstand the same burst pressures to failure as the manufacturer’s other large-bore aspiration catheters used to remove thrombus for patients with acute ischemic stroke.
Penumbra’s urgent medical device recall letter advises health care providers and facilities to remove and quarantine all unused devices covered by this recall, to complete the product identification and return form, and to return all products to Penumbra in accordance with instructions provided.
For questions regarding this recall, contact Penumbra customer service by phone at 888-272-4606 or by email at [email protected].
A version of this article first appeared on Medscape.com.
“All users should stop using this device, and facilities should remove these devices from inventory,” the recall notice, posted on the U.S. Food and Drug Administration website, advises.
The recall covers the JET 7 Xtra Flex catheter, which was cleared for use in June 2019, and the JET 7MAX configuration (which includes the JET 7 Xtra Flex catheter and MAX delivery device), which was cleared in February of this year.
The recall does not apply to the Penumbra JET 7 reperfusion catheter with standard tip.
The FDA says it has received over 200 medical device reports (MDRs) associated with the JET 7 Xtra Flex catheter, including reports of deaths, serious injuries, and malfunctions.
Twenty of these MDRs describe 14 unique patient deaths. Other MDRs describe serious patient injury, such as vessel damage, hemorrhage, and cerebral infarction.
Device malfunctions described in the reports include ballooning, expansion, rupture, breakage or complete separation, and exposure of internal support coils near the distal tip region of the JET 7 Xtra Flex catheter.
According to the FDA, bench testing by the manufacturer, in which the catheter distal tip is plugged and pressurized to failure, indicates that the JET 7 Xtra Flex catheter is not able to withstand the same burst pressures to failure as the manufacturer’s other large-bore aspiration catheters used to remove thrombus for patients with acute ischemic stroke.
Penumbra’s urgent medical device recall letter advises health care providers and facilities to remove and quarantine all unused devices covered by this recall, to complete the product identification and return form, and to return all products to Penumbra in accordance with instructions provided.
For questions regarding this recall, contact Penumbra customer service by phone at 888-272-4606 or by email at [email protected].
A version of this article first appeared on Medscape.com.
“All users should stop using this device, and facilities should remove these devices from inventory,” the recall notice, posted on the U.S. Food and Drug Administration website, advises.
The recall covers the JET 7 Xtra Flex catheter, which was cleared for use in June 2019, and the JET 7MAX configuration (which includes the JET 7 Xtra Flex catheter and MAX delivery device), which was cleared in February of this year.
The recall does not apply to the Penumbra JET 7 reperfusion catheter with standard tip.
The FDA says it has received over 200 medical device reports (MDRs) associated with the JET 7 Xtra Flex catheter, including reports of deaths, serious injuries, and malfunctions.
Twenty of these MDRs describe 14 unique patient deaths. Other MDRs describe serious patient injury, such as vessel damage, hemorrhage, and cerebral infarction.
Device malfunctions described in the reports include ballooning, expansion, rupture, breakage or complete separation, and exposure of internal support coils near the distal tip region of the JET 7 Xtra Flex catheter.
According to the FDA, bench testing by the manufacturer, in which the catheter distal tip is plugged and pressurized to failure, indicates that the JET 7 Xtra Flex catheter is not able to withstand the same burst pressures to failure as the manufacturer’s other large-bore aspiration catheters used to remove thrombus for patients with acute ischemic stroke.
Penumbra’s urgent medical device recall letter advises health care providers and facilities to remove and quarantine all unused devices covered by this recall, to complete the product identification and return form, and to return all products to Penumbra in accordance with instructions provided.
For questions regarding this recall, contact Penumbra customer service by phone at 888-272-4606 or by email at [email protected].
A version of this article first appeared on Medscape.com.
Disabling stroke reduced with ticagrelor after minor stroke, TIA
Additional results from the THALES trial have shown that 1 month’s dual antiplatelet therapy with ticagrelor (Brilinta; Astra Zeneca) plus aspirin is associated with a reduction in disabling stroke, compared with aspirin alone in patients with minor stroke or high-risk transient ischemic attack (TIA).
Primary results of the THALES trial, published earlier this year in the New England Journal of Medicine, showed a reduction in the primary endpoint of stroke or death within 30 days with the combination of ticagrelor plus aspirin versus aspirin alone, although this was accompanied by an increase in bleeding. In terms of risk/benefit, the main results showed that for every 1,000 patients treatment with ticagrelor on top of aspirin would prevent 11 strokes or deaths at the cost of four severe hemorrhages.
The current exploratory analysis, which focuses on the severity of the strokes occurring in the trial, was published online Nov. 7 in JAMA Neurology to coincide with its presentation at the European Stroke Organisation-World Stroke Organization Conference 2020.
Results showed that, compared with aspirin alone, ticagrelor plus aspirin significantly reduced the 30-day risk for disabling stroke or death (4.0% versus 4.7%), and the total disability burden (the shift analysis of the distribution of modified Rankin scale) following subsequent ischemic stroke was reduced by a significant 23%.
“This new information on disabling stroke underlines the importance of getting patients on dual antiplatelet therapy quickly after a TIA or mild stroke,” said principal investigator of the THALES trial, S. Claiborne Johnston, MD, PhD.
Dr. Johnston, who is dean of Dell Medical School at the University of Texas at Austin, added: “It’s reassuring that ticagrelor has this effect, which was pretty robust. An accompanying editorial to the THALES publication in the NEJM incorrectly stated that ticagrelor did not reduce risk of disabling stroke, so it is good to be able to correct that misconception with this new data.”
Lead author of the exploratory analysis, Pierre Amarenco, MD, professor of neurology at Bichat University Hospital, Paris, added: “The main results showed that ticagrelor on top of aspirin reduced stroke but now we have new information showing reduction in disabling stroke. Obviously, these are the most important types of stroke to prevent. These are the strokes that will impact patients functionally.”
The THALES trial included 11,016 patients with a noncardioembolic, nonsevere ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5) or high-risk TIA, of whom 10,803 had modified Rankin Scale (mRS) functional score recorded at 30 days.
They were randomized within 24 hours of symptom onset to ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for 1 month) or placebo. All patients received aspirin (300-325 mg on day 1 followed by 75-100 mg daily for 1 month).
In the new analysis, time to occurrence of disabling stroke (mRS greater than 1) or death within 30 days occurred in 221 of 5,511 patients (4.0%) randomized to ticagrelor and in 260 of 5,478 patients (4.7%) randomized to placebo (hazard ratio, 0.83; P = .04).
The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; P = .002).
Factors associated with disability were baseline NIHSS score of 4-5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure.
Asked how the current results compared with observations reported in the main NEJM paper of similar incidences of disability (mRS > 1) in the two groups, Dr. Johnston explained that the result in the original paper looked at disability in the overall population, not just those who went on to have a stroke during follow-up.
“The problem with looking at overall disability is that most of it is actually from the index stroke (the one that led to the patient being enrolled in the trial). That creates a lot of noise that overwhelms the benefit in reducing disability due to new stroke, the thing we really care about and the subject of the new paper,” he commented.
Ticagrelor or clopidogrel?
Ticagrelor now becomes the second antiplatelet agent to have shown benefits on top of aspirin in the minor stroke and high-risk TIA population. Clopidogrel also showed a reduction in major ischemic events in the POINT trial as well as in the Chinese CHANCE trial in similar populations.
Dr. Amarenco pointed out, however, that until now the only treatment that has been shown to reduce disabling stroke in the minor stroke/high risk TIA population in a single trial is aspirin. “The CHANCE and POINT trials of clopidogrel did not show a reduction in disabling stroke individually but this was observed when the trials were combined,” he noted.
“Clinicians will now have to choose between ticagrelor and clopidogrel. We don’t have a head-to-head comparison yet but ticagrelor is effective in all patients whereas clopidogrel may not be as effective in the large subgroup of patients who carry the loss of function gene which make up about 20% of the western population and about 40% of the Asian population,” he said.
“It is very important in the acute phase of stroke to know that the antiplatelet drug is immediately effective as the risk of a recurrent event is highest in the first few hours and days.”
Dr. Amarenco acknowledged that some hospitals may favor clopidogrel because of cost, as it is available generically so is much cheaper than ticagrelor. “But we are only talking about 30 days of treatment, so cost is not too much of an issue,” he pointed out.
The Food and Drug Administration recently approved use of ticagrelor in this indication on the basis of the THALES study.
“It is great news that vascular neurologists now have a new player for reducing future stroke in these patients,” Dr. Amarenco said. Clopidogrel is not approved for this indication but is recommended in American Heart Association/American Stroke Association guidelines, he added.
Dr. Johnston, who was also the lead investigator of the POINT trial with clopidogrel, suggested that it is more important to get patients on dual-antiplatelet therapy rather than worrying too much about which agent to use. “I think we can use aspirin plus either ticagrelor or clopidogrel. The effect on disabling stroke was not significant in POINT but it did reach significance in a meta-analysis combining POINT and CHANCE,” he noted.
He said that choosing between ticagrelor and clopidogrel is tricky without head-to-head data. “Differences in the studied populations makes direct comparison of the trials unwise,” he stressed.
Dr. Johnston pointed out that neither of the clopidogrel trials included moderate strokes (NIHSS scores of 4 and 5) in their study population. “We only have data on ticagrelor for this important group, which accounted for 30% of the THALES study population,” he noted.
“Some people are concerned about the limited efficacy of clopidogrel in large subgroups of patients who do not metabolize it to its active form, but on the flip side, clopidogrel is cheaper – though a 21- to 30-day course [of ticagrelor] probably isn’t that costly – and has more data in combination with aspirin,” he added.
Dr. Johnston said that the approval of ticagrelor for this new indication was “reassuring,” and “provides some air cover for practitioners given the risks of hemorrhage.” He added: “We didn’t bother with an FDA submission after POINT because it was an NIH-sponsored trial. The drug company normally prioritizes regulatory approvals for marketing purposes but their interests were limited because clopidogrel has exceeded its patent life.”
Cost-utility analyses are not yet available, but Dr. Johnston noted: “I suspect both drugs will have substantial benefits and be cost saving. Stroke is expensive, particularly disabling stroke.”
Dr. Johnston said that the more important message is: “Get these people on dual-antiplatelet therapy as soon as possible. Too many patients are not getting the right treatment immediately after symptom onset. We have lots of work to do here.”
Reassuring information
Commenting on the research, J. David Spence, MD, professor of neurology at the Robarts Research Institute, London, Ont., who was not involved in the THALES trial, said this new analysis provided useful and important information that should reassure and encourage clinicians to use dual-antiplatelet therapy in this patient population.
He pointed out that the shift analysis gives the most clinically relevant results. “While the number of patients with a disabling stroke defined as an mRS greater than 1 is lower in the ticagrelor group, I am much more interested in the effect on more severe disability levels – those with an mRS score of 3 or more. Those are the disabilities that we really want to prevent. And from examining the shift analysis distribution, we can see that these more severe disabilities are being reduced with ticagrelor.”
Dr. Spence believes the benefit/risk ratio of dual-antiplatelet therapy could be further improved by better control of blood pressure. “The absolute risk of severe hemorrhage was low in this study, but in my view, most of this could have been prevented by better control of hypertension, as 20 of the 28 severe hemorrhages in the ticagrelor group were intracranial bleeds which can be significantly reduced by good blood pressure control.
“In my view, the increased risk of hemorrhage with dual-antiplatelet therapy should not be regarded as inevitable; it can be virtually eliminated with better medical care,” he stated.
Another outside commentator, Peter Rothwell, MD, PhD, professor of neurology, University of Oxford (England), also believes this is an important paper. “The main NEJM report presented the data on overall disability, but did not present a clear analysis of the effect of ticagrelor plus aspirin on disabling recurrent stroke, but disability in all patients is mainly determined by nonvascular premorbid disability and by the effects of the initial prerandomization stroke. It was highly unlikely that ticagrelor plus aspirin would change these pretrial factors. The only thing that treatment could change was the severity of any posttreatment recurrent stroke, which it did,” he said.
“There is evidence that aspirin plus clopidogrel has the same effect on disabling recurrent stroke. So we now know that ticagrelor plus aspirin also has this effect, which informs consideration of the relative merits of the two treatment strategies,” Dr. Rothwell added.
The THALES trial was sponsored by Astra Zeneca. Dr. Johnston reports support from Sanofi and AstraZeneca outside the submitted work. Dr. Amarenco reports grants and personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study.
A version of this article originally appeared on Medscape.com.
Additional results from the THALES trial have shown that 1 month’s dual antiplatelet therapy with ticagrelor (Brilinta; Astra Zeneca) plus aspirin is associated with a reduction in disabling stroke, compared with aspirin alone in patients with minor stroke or high-risk transient ischemic attack (TIA).
Primary results of the THALES trial, published earlier this year in the New England Journal of Medicine, showed a reduction in the primary endpoint of stroke or death within 30 days with the combination of ticagrelor plus aspirin versus aspirin alone, although this was accompanied by an increase in bleeding. In terms of risk/benefit, the main results showed that for every 1,000 patients treatment with ticagrelor on top of aspirin would prevent 11 strokes or deaths at the cost of four severe hemorrhages.
The current exploratory analysis, which focuses on the severity of the strokes occurring in the trial, was published online Nov. 7 in JAMA Neurology to coincide with its presentation at the European Stroke Organisation-World Stroke Organization Conference 2020.
Results showed that, compared with aspirin alone, ticagrelor plus aspirin significantly reduced the 30-day risk for disabling stroke or death (4.0% versus 4.7%), and the total disability burden (the shift analysis of the distribution of modified Rankin scale) following subsequent ischemic stroke was reduced by a significant 23%.
“This new information on disabling stroke underlines the importance of getting patients on dual antiplatelet therapy quickly after a TIA or mild stroke,” said principal investigator of the THALES trial, S. Claiborne Johnston, MD, PhD.
Dr. Johnston, who is dean of Dell Medical School at the University of Texas at Austin, added: “It’s reassuring that ticagrelor has this effect, which was pretty robust. An accompanying editorial to the THALES publication in the NEJM incorrectly stated that ticagrelor did not reduce risk of disabling stroke, so it is good to be able to correct that misconception with this new data.”
Lead author of the exploratory analysis, Pierre Amarenco, MD, professor of neurology at Bichat University Hospital, Paris, added: “The main results showed that ticagrelor on top of aspirin reduced stroke but now we have new information showing reduction in disabling stroke. Obviously, these are the most important types of stroke to prevent. These are the strokes that will impact patients functionally.”
The THALES trial included 11,016 patients with a noncardioembolic, nonsevere ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5) or high-risk TIA, of whom 10,803 had modified Rankin Scale (mRS) functional score recorded at 30 days.
They were randomized within 24 hours of symptom onset to ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for 1 month) or placebo. All patients received aspirin (300-325 mg on day 1 followed by 75-100 mg daily for 1 month).
In the new analysis, time to occurrence of disabling stroke (mRS greater than 1) or death within 30 days occurred in 221 of 5,511 patients (4.0%) randomized to ticagrelor and in 260 of 5,478 patients (4.7%) randomized to placebo (hazard ratio, 0.83; P = .04).
The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; P = .002).
Factors associated with disability were baseline NIHSS score of 4-5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure.
Asked how the current results compared with observations reported in the main NEJM paper of similar incidences of disability (mRS > 1) in the two groups, Dr. Johnston explained that the result in the original paper looked at disability in the overall population, not just those who went on to have a stroke during follow-up.
“The problem with looking at overall disability is that most of it is actually from the index stroke (the one that led to the patient being enrolled in the trial). That creates a lot of noise that overwhelms the benefit in reducing disability due to new stroke, the thing we really care about and the subject of the new paper,” he commented.
Ticagrelor or clopidogrel?
Ticagrelor now becomes the second antiplatelet agent to have shown benefits on top of aspirin in the minor stroke and high-risk TIA population. Clopidogrel also showed a reduction in major ischemic events in the POINT trial as well as in the Chinese CHANCE trial in similar populations.
Dr. Amarenco pointed out, however, that until now the only treatment that has been shown to reduce disabling stroke in the minor stroke/high risk TIA population in a single trial is aspirin. “The CHANCE and POINT trials of clopidogrel did not show a reduction in disabling stroke individually but this was observed when the trials were combined,” he noted.
“Clinicians will now have to choose between ticagrelor and clopidogrel. We don’t have a head-to-head comparison yet but ticagrelor is effective in all patients whereas clopidogrel may not be as effective in the large subgroup of patients who carry the loss of function gene which make up about 20% of the western population and about 40% of the Asian population,” he said.
“It is very important in the acute phase of stroke to know that the antiplatelet drug is immediately effective as the risk of a recurrent event is highest in the first few hours and days.”
Dr. Amarenco acknowledged that some hospitals may favor clopidogrel because of cost, as it is available generically so is much cheaper than ticagrelor. “But we are only talking about 30 days of treatment, so cost is not too much of an issue,” he pointed out.
The Food and Drug Administration recently approved use of ticagrelor in this indication on the basis of the THALES study.
“It is great news that vascular neurologists now have a new player for reducing future stroke in these patients,” Dr. Amarenco said. Clopidogrel is not approved for this indication but is recommended in American Heart Association/American Stroke Association guidelines, he added.
Dr. Johnston, who was also the lead investigator of the POINT trial with clopidogrel, suggested that it is more important to get patients on dual-antiplatelet therapy rather than worrying too much about which agent to use. “I think we can use aspirin plus either ticagrelor or clopidogrel. The effect on disabling stroke was not significant in POINT but it did reach significance in a meta-analysis combining POINT and CHANCE,” he noted.
He said that choosing between ticagrelor and clopidogrel is tricky without head-to-head data. “Differences in the studied populations makes direct comparison of the trials unwise,” he stressed.
Dr. Johnston pointed out that neither of the clopidogrel trials included moderate strokes (NIHSS scores of 4 and 5) in their study population. “We only have data on ticagrelor for this important group, which accounted for 30% of the THALES study population,” he noted.
“Some people are concerned about the limited efficacy of clopidogrel in large subgroups of patients who do not metabolize it to its active form, but on the flip side, clopidogrel is cheaper – though a 21- to 30-day course [of ticagrelor] probably isn’t that costly – and has more data in combination with aspirin,” he added.
Dr. Johnston said that the approval of ticagrelor for this new indication was “reassuring,” and “provides some air cover for practitioners given the risks of hemorrhage.” He added: “We didn’t bother with an FDA submission after POINT because it was an NIH-sponsored trial. The drug company normally prioritizes regulatory approvals for marketing purposes but their interests were limited because clopidogrel has exceeded its patent life.”
Cost-utility analyses are not yet available, but Dr. Johnston noted: “I suspect both drugs will have substantial benefits and be cost saving. Stroke is expensive, particularly disabling stroke.”
Dr. Johnston said that the more important message is: “Get these people on dual-antiplatelet therapy as soon as possible. Too many patients are not getting the right treatment immediately after symptom onset. We have lots of work to do here.”
Reassuring information
Commenting on the research, J. David Spence, MD, professor of neurology at the Robarts Research Institute, London, Ont., who was not involved in the THALES trial, said this new analysis provided useful and important information that should reassure and encourage clinicians to use dual-antiplatelet therapy in this patient population.
He pointed out that the shift analysis gives the most clinically relevant results. “While the number of patients with a disabling stroke defined as an mRS greater than 1 is lower in the ticagrelor group, I am much more interested in the effect on more severe disability levels – those with an mRS score of 3 or more. Those are the disabilities that we really want to prevent. And from examining the shift analysis distribution, we can see that these more severe disabilities are being reduced with ticagrelor.”
Dr. Spence believes the benefit/risk ratio of dual-antiplatelet therapy could be further improved by better control of blood pressure. “The absolute risk of severe hemorrhage was low in this study, but in my view, most of this could have been prevented by better control of hypertension, as 20 of the 28 severe hemorrhages in the ticagrelor group were intracranial bleeds which can be significantly reduced by good blood pressure control.
“In my view, the increased risk of hemorrhage with dual-antiplatelet therapy should not be regarded as inevitable; it can be virtually eliminated with better medical care,” he stated.
Another outside commentator, Peter Rothwell, MD, PhD, professor of neurology, University of Oxford (England), also believes this is an important paper. “The main NEJM report presented the data on overall disability, but did not present a clear analysis of the effect of ticagrelor plus aspirin on disabling recurrent stroke, but disability in all patients is mainly determined by nonvascular premorbid disability and by the effects of the initial prerandomization stroke. It was highly unlikely that ticagrelor plus aspirin would change these pretrial factors. The only thing that treatment could change was the severity of any posttreatment recurrent stroke, which it did,” he said.
“There is evidence that aspirin plus clopidogrel has the same effect on disabling recurrent stroke. So we now know that ticagrelor plus aspirin also has this effect, which informs consideration of the relative merits of the two treatment strategies,” Dr. Rothwell added.
The THALES trial was sponsored by Astra Zeneca. Dr. Johnston reports support from Sanofi and AstraZeneca outside the submitted work. Dr. Amarenco reports grants and personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study.
A version of this article originally appeared on Medscape.com.
Additional results from the THALES trial have shown that 1 month’s dual antiplatelet therapy with ticagrelor (Brilinta; Astra Zeneca) plus aspirin is associated with a reduction in disabling stroke, compared with aspirin alone in patients with minor stroke or high-risk transient ischemic attack (TIA).
Primary results of the THALES trial, published earlier this year in the New England Journal of Medicine, showed a reduction in the primary endpoint of stroke or death within 30 days with the combination of ticagrelor plus aspirin versus aspirin alone, although this was accompanied by an increase in bleeding. In terms of risk/benefit, the main results showed that for every 1,000 patients treatment with ticagrelor on top of aspirin would prevent 11 strokes or deaths at the cost of four severe hemorrhages.
The current exploratory analysis, which focuses on the severity of the strokes occurring in the trial, was published online Nov. 7 in JAMA Neurology to coincide with its presentation at the European Stroke Organisation-World Stroke Organization Conference 2020.
Results showed that, compared with aspirin alone, ticagrelor plus aspirin significantly reduced the 30-day risk for disabling stroke or death (4.0% versus 4.7%), and the total disability burden (the shift analysis of the distribution of modified Rankin scale) following subsequent ischemic stroke was reduced by a significant 23%.
“This new information on disabling stroke underlines the importance of getting patients on dual antiplatelet therapy quickly after a TIA or mild stroke,” said principal investigator of the THALES trial, S. Claiborne Johnston, MD, PhD.
Dr. Johnston, who is dean of Dell Medical School at the University of Texas at Austin, added: “It’s reassuring that ticagrelor has this effect, which was pretty robust. An accompanying editorial to the THALES publication in the NEJM incorrectly stated that ticagrelor did not reduce risk of disabling stroke, so it is good to be able to correct that misconception with this new data.”
Lead author of the exploratory analysis, Pierre Amarenco, MD, professor of neurology at Bichat University Hospital, Paris, added: “The main results showed that ticagrelor on top of aspirin reduced stroke but now we have new information showing reduction in disabling stroke. Obviously, these are the most important types of stroke to prevent. These are the strokes that will impact patients functionally.”
The THALES trial included 11,016 patients with a noncardioembolic, nonsevere ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5) or high-risk TIA, of whom 10,803 had modified Rankin Scale (mRS) functional score recorded at 30 days.
They were randomized within 24 hours of symptom onset to ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for 1 month) or placebo. All patients received aspirin (300-325 mg on day 1 followed by 75-100 mg daily for 1 month).
In the new analysis, time to occurrence of disabling stroke (mRS greater than 1) or death within 30 days occurred in 221 of 5,511 patients (4.0%) randomized to ticagrelor and in 260 of 5,478 patients (4.7%) randomized to placebo (hazard ratio, 0.83; P = .04).
The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; P = .002).
Factors associated with disability were baseline NIHSS score of 4-5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure.
Asked how the current results compared with observations reported in the main NEJM paper of similar incidences of disability (mRS > 1) in the two groups, Dr. Johnston explained that the result in the original paper looked at disability in the overall population, not just those who went on to have a stroke during follow-up.
“The problem with looking at overall disability is that most of it is actually from the index stroke (the one that led to the patient being enrolled in the trial). That creates a lot of noise that overwhelms the benefit in reducing disability due to new stroke, the thing we really care about and the subject of the new paper,” he commented.
Ticagrelor or clopidogrel?
Ticagrelor now becomes the second antiplatelet agent to have shown benefits on top of aspirin in the minor stroke and high-risk TIA population. Clopidogrel also showed a reduction in major ischemic events in the POINT trial as well as in the Chinese CHANCE trial in similar populations.
Dr. Amarenco pointed out, however, that until now the only treatment that has been shown to reduce disabling stroke in the minor stroke/high risk TIA population in a single trial is aspirin. “The CHANCE and POINT trials of clopidogrel did not show a reduction in disabling stroke individually but this was observed when the trials were combined,” he noted.
“Clinicians will now have to choose between ticagrelor and clopidogrel. We don’t have a head-to-head comparison yet but ticagrelor is effective in all patients whereas clopidogrel may not be as effective in the large subgroup of patients who carry the loss of function gene which make up about 20% of the western population and about 40% of the Asian population,” he said.
“It is very important in the acute phase of stroke to know that the antiplatelet drug is immediately effective as the risk of a recurrent event is highest in the first few hours and days.”
Dr. Amarenco acknowledged that some hospitals may favor clopidogrel because of cost, as it is available generically so is much cheaper than ticagrelor. “But we are only talking about 30 days of treatment, so cost is not too much of an issue,” he pointed out.
The Food and Drug Administration recently approved use of ticagrelor in this indication on the basis of the THALES study.
“It is great news that vascular neurologists now have a new player for reducing future stroke in these patients,” Dr. Amarenco said. Clopidogrel is not approved for this indication but is recommended in American Heart Association/American Stroke Association guidelines, he added.
Dr. Johnston, who was also the lead investigator of the POINT trial with clopidogrel, suggested that it is more important to get patients on dual-antiplatelet therapy rather than worrying too much about which agent to use. “I think we can use aspirin plus either ticagrelor or clopidogrel. The effect on disabling stroke was not significant in POINT but it did reach significance in a meta-analysis combining POINT and CHANCE,” he noted.
He said that choosing between ticagrelor and clopidogrel is tricky without head-to-head data. “Differences in the studied populations makes direct comparison of the trials unwise,” he stressed.
Dr. Johnston pointed out that neither of the clopidogrel trials included moderate strokes (NIHSS scores of 4 and 5) in their study population. “We only have data on ticagrelor for this important group, which accounted for 30% of the THALES study population,” he noted.
“Some people are concerned about the limited efficacy of clopidogrel in large subgroups of patients who do not metabolize it to its active form, but on the flip side, clopidogrel is cheaper – though a 21- to 30-day course [of ticagrelor] probably isn’t that costly – and has more data in combination with aspirin,” he added.
Dr. Johnston said that the approval of ticagrelor for this new indication was “reassuring,” and “provides some air cover for practitioners given the risks of hemorrhage.” He added: “We didn’t bother with an FDA submission after POINT because it was an NIH-sponsored trial. The drug company normally prioritizes regulatory approvals for marketing purposes but their interests were limited because clopidogrel has exceeded its patent life.”
Cost-utility analyses are not yet available, but Dr. Johnston noted: “I suspect both drugs will have substantial benefits and be cost saving. Stroke is expensive, particularly disabling stroke.”
Dr. Johnston said that the more important message is: “Get these people on dual-antiplatelet therapy as soon as possible. Too many patients are not getting the right treatment immediately after symptom onset. We have lots of work to do here.”
Reassuring information
Commenting on the research, J. David Spence, MD, professor of neurology at the Robarts Research Institute, London, Ont., who was not involved in the THALES trial, said this new analysis provided useful and important information that should reassure and encourage clinicians to use dual-antiplatelet therapy in this patient population.
He pointed out that the shift analysis gives the most clinically relevant results. “While the number of patients with a disabling stroke defined as an mRS greater than 1 is lower in the ticagrelor group, I am much more interested in the effect on more severe disability levels – those with an mRS score of 3 or more. Those are the disabilities that we really want to prevent. And from examining the shift analysis distribution, we can see that these more severe disabilities are being reduced with ticagrelor.”
Dr. Spence believes the benefit/risk ratio of dual-antiplatelet therapy could be further improved by better control of blood pressure. “The absolute risk of severe hemorrhage was low in this study, but in my view, most of this could have been prevented by better control of hypertension, as 20 of the 28 severe hemorrhages in the ticagrelor group were intracranial bleeds which can be significantly reduced by good blood pressure control.
“In my view, the increased risk of hemorrhage with dual-antiplatelet therapy should not be regarded as inevitable; it can be virtually eliminated with better medical care,” he stated.
Another outside commentator, Peter Rothwell, MD, PhD, professor of neurology, University of Oxford (England), also believes this is an important paper. “The main NEJM report presented the data on overall disability, but did not present a clear analysis of the effect of ticagrelor plus aspirin on disabling recurrent stroke, but disability in all patients is mainly determined by nonvascular premorbid disability and by the effects of the initial prerandomization stroke. It was highly unlikely that ticagrelor plus aspirin would change these pretrial factors. The only thing that treatment could change was the severity of any posttreatment recurrent stroke, which it did,” he said.
“There is evidence that aspirin plus clopidogrel has the same effect on disabling recurrent stroke. So we now know that ticagrelor plus aspirin also has this effect, which informs consideration of the relative merits of the two treatment strategies,” Dr. Rothwell added.
The THALES trial was sponsored by Astra Zeneca. Dr. Johnston reports support from Sanofi and AstraZeneca outside the submitted work. Dr. Amarenco reports grants and personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study.
A version of this article originally appeared on Medscape.com.
COVID-19 and risk of clotting: ‘Be proactive about prevention’
The risk of arterial and venous thrombosis in patients with COVID-19 has been a major issue throughout the pandemic, and how best to manage this risk is the subject of a new review article.
The article, by Gregory Dr. Piazza, MD, and David A. Morrow, MD, Brigham and Women’s Hospital, Boston, was published online in JAMA on Nov. 23.
“Basically we’re saying: ‘Be proactive about prevention,’” Dr. Piazza told this news organization.
There is growing recognition among those on the frontline that there is an increased risk of thrombosis in COVID-19 patients, Dr. Piazza said. The risk is highest in patients in the intensive care unit, but the risk is also increased in patients hospitalized with COVID-19, even those not in ICU.
“We don’t really know what the risk is in nonhospitalized COVID-19 patients, but we think it’s much lower than in those who are hospitalized,” he said. “We are waiting for data on the optimal way of managing this increased risk of thrombosis in COVID patients, but for the time being, we believe a systematic way of addressing this risk is best, with every patient hospitalized with COVID-19 receiving some type of thromboprophylaxis. This would mainly be with anticoagulation, but in patients in whom anticoagulation is contraindicated, then mechanical methods could be used, such as pneumatic compression boots or compression stockings.”
The authors report thrombotic complication rates of 2.6% in noncritically ill hospitalized patients with COVID-19 and 35.3% in critically ill patients from a recent U.S. registry study.
Autopsy findings of microthrombi in multiple organ systems, including the lungs, heart, and kidneys, suggest that thrombosis may contribute to multisystem organ dysfunction in severe COVID-19, they note. Although the pathophysiology is not fully defined, prothrombotic abnormalities have been identified in patients with COVID-19, including elevated levels of D-dimer, fibrinogen, and factor VIII, they add.
“There are several major questions about which COVID-19 patients to treat with thromboprophylaxis, how to treat them in term of levels of anticoagulation, and there are many ongoing clinical trials to try and answer these questions,” Dr. Piazza commented. “We need results from these randomized trials to provide a better compass for COVID-19 patients at risk of clotting.”
At present, clinicians can follow two different sets of guidelines on the issue, one from the American College of Chest Physicians and the other from the International Society on Thrombosis and Hemostasis, the authors note.
“The ACCP guidelines are very conservative and basically follow the evidence base for medical patients, while the ISTH guidelines are more aggressive and recommend increased levels of anticoagulation in both ICU and hospitalized non-ICU patients and also extend prophylaxis after discharge,” Dr. Piazza said.
“There is quite a difference between the two sets of guidelines, which can be a point of confusion,” he added.
Dr. Piazza notes that at his center every hospitalized COVID patient who does not have a contraindication to anticoagulation receives a standard prophylactic dose of a once-daily low-molecular-weight heparin (for example, enoxaparin 40 mg). A once-daily product is used to minimize infection risk to staff.
While all COVID patients in the ICU should automatically receive some anticoagulation, the optimal dose is an area of active investigation, he explained. “There were several early reports of ICU patients developing blood clots despite receiving standard thromboprophylaxis so perhaps we need to use higher doses. There are trials underway looking at this, and we would advise enrolling patients into these trials.”
If patients can’t be enrolled into trials, and clinicians feel higher anticoagulation levels are needed, Dr. Piazza advises following the ISTH guidance, which allows an intermediate dose of low-molecular-weight heparin (up to 1 mg/kg enoxaparin).
“Some experts are suggesting even higher doses may be needed in some ICU patients, such as the full therapeutic dose, but I worry about the risk of bleeding with such a strategy,” he said.
Dr. Piazza says they do not routinely give anticoagulation after discharge, but if this is desired then patients could be switched to an oral agent, and some of the direct-acting oral anticoagulants are approved for prophylactic use in medically ill patients.
Dr. Piazza points out that whether thromboprophylaxis should be used for nonhospitalized COVID patients who have risk factors for clotting such as a prior history of thrombosis or obesity is a pressing question, and he encourages clinicians to enroll these patients in clinical trials evaluating this issue, such as the PREVENT-HD trial.
“If they can’t enroll patents in a trial, then they have to make a decision whether the patient is high-enough risk to justify off-label use of anticoagulant. There is a case to be made for this, but there is no evidence for or against such action at present,” he noted.
At this time, neither the ISTH nor ACCP recommend measuring D-dimer to screen for venous thromboembolism or to determine intensity of prophylaxis or treatment, the authors note.
“Ongoing investigation will determine optimal preventive regimens in COVID-19 in the intensive care unit, at hospital discharge, and in nonhospitalized patients at high risk for thrombosis,” they conclude.
Dr. Piazza reported grants from Bayer, Bristol Myers Squibb, Boston Scientific, Janssen, and Portola, and personal fees from Agile, Amgen, Pfizer, and the Prairie Education and Research Cooperative outside the submitted work. Dr. Morrow reported grants from Abbott Laboratories, Amgen, Anthos Therapeutics, Esai, GlaxoSmithKline, Takeda, and The Medicines Company; grants and personal fees from AstraZeneca, Merck, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma and InCarda outside the submitted work.
A version of this article originally appeared on Medscape.com.
The risk of arterial and venous thrombosis in patients with COVID-19 has been a major issue throughout the pandemic, and how best to manage this risk is the subject of a new review article.
The article, by Gregory Dr. Piazza, MD, and David A. Morrow, MD, Brigham and Women’s Hospital, Boston, was published online in JAMA on Nov. 23.
“Basically we’re saying: ‘Be proactive about prevention,’” Dr. Piazza told this news organization.
There is growing recognition among those on the frontline that there is an increased risk of thrombosis in COVID-19 patients, Dr. Piazza said. The risk is highest in patients in the intensive care unit, but the risk is also increased in patients hospitalized with COVID-19, even those not in ICU.
“We don’t really know what the risk is in nonhospitalized COVID-19 patients, but we think it’s much lower than in those who are hospitalized,” he said. “We are waiting for data on the optimal way of managing this increased risk of thrombosis in COVID patients, but for the time being, we believe a systematic way of addressing this risk is best, with every patient hospitalized with COVID-19 receiving some type of thromboprophylaxis. This would mainly be with anticoagulation, but in patients in whom anticoagulation is contraindicated, then mechanical methods could be used, such as pneumatic compression boots or compression stockings.”
The authors report thrombotic complication rates of 2.6% in noncritically ill hospitalized patients with COVID-19 and 35.3% in critically ill patients from a recent U.S. registry study.
Autopsy findings of microthrombi in multiple organ systems, including the lungs, heart, and kidneys, suggest that thrombosis may contribute to multisystem organ dysfunction in severe COVID-19, they note. Although the pathophysiology is not fully defined, prothrombotic abnormalities have been identified in patients with COVID-19, including elevated levels of D-dimer, fibrinogen, and factor VIII, they add.
“There are several major questions about which COVID-19 patients to treat with thromboprophylaxis, how to treat them in term of levels of anticoagulation, and there are many ongoing clinical trials to try and answer these questions,” Dr. Piazza commented. “We need results from these randomized trials to provide a better compass for COVID-19 patients at risk of clotting.”
At present, clinicians can follow two different sets of guidelines on the issue, one from the American College of Chest Physicians and the other from the International Society on Thrombosis and Hemostasis, the authors note.
“The ACCP guidelines are very conservative and basically follow the evidence base for medical patients, while the ISTH guidelines are more aggressive and recommend increased levels of anticoagulation in both ICU and hospitalized non-ICU patients and also extend prophylaxis after discharge,” Dr. Piazza said.
“There is quite a difference between the two sets of guidelines, which can be a point of confusion,” he added.
Dr. Piazza notes that at his center every hospitalized COVID patient who does not have a contraindication to anticoagulation receives a standard prophylactic dose of a once-daily low-molecular-weight heparin (for example, enoxaparin 40 mg). A once-daily product is used to minimize infection risk to staff.
While all COVID patients in the ICU should automatically receive some anticoagulation, the optimal dose is an area of active investigation, he explained. “There were several early reports of ICU patients developing blood clots despite receiving standard thromboprophylaxis so perhaps we need to use higher doses. There are trials underway looking at this, and we would advise enrolling patients into these trials.”
If patients can’t be enrolled into trials, and clinicians feel higher anticoagulation levels are needed, Dr. Piazza advises following the ISTH guidance, which allows an intermediate dose of low-molecular-weight heparin (up to 1 mg/kg enoxaparin).
“Some experts are suggesting even higher doses may be needed in some ICU patients, such as the full therapeutic dose, but I worry about the risk of bleeding with such a strategy,” he said.
Dr. Piazza says they do not routinely give anticoagulation after discharge, but if this is desired then patients could be switched to an oral agent, and some of the direct-acting oral anticoagulants are approved for prophylactic use in medically ill patients.
Dr. Piazza points out that whether thromboprophylaxis should be used for nonhospitalized COVID patients who have risk factors for clotting such as a prior history of thrombosis or obesity is a pressing question, and he encourages clinicians to enroll these patients in clinical trials evaluating this issue, such as the PREVENT-HD trial.
“If they can’t enroll patents in a trial, then they have to make a decision whether the patient is high-enough risk to justify off-label use of anticoagulant. There is a case to be made for this, but there is no evidence for or against such action at present,” he noted.
At this time, neither the ISTH nor ACCP recommend measuring D-dimer to screen for venous thromboembolism or to determine intensity of prophylaxis or treatment, the authors note.
“Ongoing investigation will determine optimal preventive regimens in COVID-19 in the intensive care unit, at hospital discharge, and in nonhospitalized patients at high risk for thrombosis,” they conclude.
Dr. Piazza reported grants from Bayer, Bristol Myers Squibb, Boston Scientific, Janssen, and Portola, and personal fees from Agile, Amgen, Pfizer, and the Prairie Education and Research Cooperative outside the submitted work. Dr. Morrow reported grants from Abbott Laboratories, Amgen, Anthos Therapeutics, Esai, GlaxoSmithKline, Takeda, and The Medicines Company; grants and personal fees from AstraZeneca, Merck, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma and InCarda outside the submitted work.
A version of this article originally appeared on Medscape.com.
The risk of arterial and venous thrombosis in patients with COVID-19 has been a major issue throughout the pandemic, and how best to manage this risk is the subject of a new review article.
The article, by Gregory Dr. Piazza, MD, and David A. Morrow, MD, Brigham and Women’s Hospital, Boston, was published online in JAMA on Nov. 23.
“Basically we’re saying: ‘Be proactive about prevention,’” Dr. Piazza told this news organization.
There is growing recognition among those on the frontline that there is an increased risk of thrombosis in COVID-19 patients, Dr. Piazza said. The risk is highest in patients in the intensive care unit, but the risk is also increased in patients hospitalized with COVID-19, even those not in ICU.
“We don’t really know what the risk is in nonhospitalized COVID-19 patients, but we think it’s much lower than in those who are hospitalized,” he said. “We are waiting for data on the optimal way of managing this increased risk of thrombosis in COVID patients, but for the time being, we believe a systematic way of addressing this risk is best, with every patient hospitalized with COVID-19 receiving some type of thromboprophylaxis. This would mainly be with anticoagulation, but in patients in whom anticoagulation is contraindicated, then mechanical methods could be used, such as pneumatic compression boots or compression stockings.”
The authors report thrombotic complication rates of 2.6% in noncritically ill hospitalized patients with COVID-19 and 35.3% in critically ill patients from a recent U.S. registry study.
Autopsy findings of microthrombi in multiple organ systems, including the lungs, heart, and kidneys, suggest that thrombosis may contribute to multisystem organ dysfunction in severe COVID-19, they note. Although the pathophysiology is not fully defined, prothrombotic abnormalities have been identified in patients with COVID-19, including elevated levels of D-dimer, fibrinogen, and factor VIII, they add.
“There are several major questions about which COVID-19 patients to treat with thromboprophylaxis, how to treat them in term of levels of anticoagulation, and there are many ongoing clinical trials to try and answer these questions,” Dr. Piazza commented. “We need results from these randomized trials to provide a better compass for COVID-19 patients at risk of clotting.”
At present, clinicians can follow two different sets of guidelines on the issue, one from the American College of Chest Physicians and the other from the International Society on Thrombosis and Hemostasis, the authors note.
“The ACCP guidelines are very conservative and basically follow the evidence base for medical patients, while the ISTH guidelines are more aggressive and recommend increased levels of anticoagulation in both ICU and hospitalized non-ICU patients and also extend prophylaxis after discharge,” Dr. Piazza said.
“There is quite a difference between the two sets of guidelines, which can be a point of confusion,” he added.
Dr. Piazza notes that at his center every hospitalized COVID patient who does not have a contraindication to anticoagulation receives a standard prophylactic dose of a once-daily low-molecular-weight heparin (for example, enoxaparin 40 mg). A once-daily product is used to minimize infection risk to staff.
While all COVID patients in the ICU should automatically receive some anticoagulation, the optimal dose is an area of active investigation, he explained. “There were several early reports of ICU patients developing blood clots despite receiving standard thromboprophylaxis so perhaps we need to use higher doses. There are trials underway looking at this, and we would advise enrolling patients into these trials.”
If patients can’t be enrolled into trials, and clinicians feel higher anticoagulation levels are needed, Dr. Piazza advises following the ISTH guidance, which allows an intermediate dose of low-molecular-weight heparin (up to 1 mg/kg enoxaparin).
“Some experts are suggesting even higher doses may be needed in some ICU patients, such as the full therapeutic dose, but I worry about the risk of bleeding with such a strategy,” he said.
Dr. Piazza says they do not routinely give anticoagulation after discharge, but if this is desired then patients could be switched to an oral agent, and some of the direct-acting oral anticoagulants are approved for prophylactic use in medically ill patients.
Dr. Piazza points out that whether thromboprophylaxis should be used for nonhospitalized COVID patients who have risk factors for clotting such as a prior history of thrombosis or obesity is a pressing question, and he encourages clinicians to enroll these patients in clinical trials evaluating this issue, such as the PREVENT-HD trial.
“If they can’t enroll patents in a trial, then they have to make a decision whether the patient is high-enough risk to justify off-label use of anticoagulant. There is a case to be made for this, but there is no evidence for or against such action at present,” he noted.
At this time, neither the ISTH nor ACCP recommend measuring D-dimer to screen for venous thromboembolism or to determine intensity of prophylaxis or treatment, the authors note.
“Ongoing investigation will determine optimal preventive regimens in COVID-19 in the intensive care unit, at hospital discharge, and in nonhospitalized patients at high risk for thrombosis,” they conclude.
Dr. Piazza reported grants from Bayer, Bristol Myers Squibb, Boston Scientific, Janssen, and Portola, and personal fees from Agile, Amgen, Pfizer, and the Prairie Education and Research Cooperative outside the submitted work. Dr. Morrow reported grants from Abbott Laboratories, Amgen, Anthos Therapeutics, Esai, GlaxoSmithKline, Takeda, and The Medicines Company; grants and personal fees from AstraZeneca, Merck, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma and InCarda outside the submitted work.
A version of this article originally appeared on Medscape.com.
Blood pressure treatment reduces bleeding in ICH
a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.
Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.
“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.
“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”
The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.
Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.
The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.
Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
Variation by drug
A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.
Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.
The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.
Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).
In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.
In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.
They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.
The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
Prevention is essential
Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.
In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.
One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.
In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.
“The main thing is really prevention,” he concluded.
The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.
Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.
“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.
“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”
The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.
Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.
The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.
Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
Variation by drug
A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.
Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.
The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.
Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).
In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.
In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.
They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.
The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
Prevention is essential
Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.
In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.
One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.
In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.
“The main thing is really prevention,” he concluded.
The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.
Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.
“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.
“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”
The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.
Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.
The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.
Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
Variation by drug
A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.
Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.
The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.
Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).
In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.
In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.
They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.
The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
Prevention is essential
Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.
In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.
One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.
In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.
“The main thing is really prevention,” he concluded.
The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM ESO-WSO CONFERENCE 2020
Statins beneficial in elderly, guidelines should be strengthened
Contrary to historical evidence, two new studies show.
“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.
“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.
“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).
The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.
“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.
“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
No RCTs have included patients older than 70
For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.
However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.
Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.
As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
Primary prevention: CV events increase with elevated LDL cholesterol in older age
Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.
Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.
Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.
In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).
Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.
Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).
The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.
“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.
With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.
With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.
“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”
“These robust findings are novel,” he and his colleagues stressed.
Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.
The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
Unequivocal reductions in events in elderly, comparable with younger patients
In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.
The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.
The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.
The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).
Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).
“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.
“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.
“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”
The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”
The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.
A version of this article originally appeared on Medscape.com.
Contrary to historical evidence, two new studies show.
“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.
“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.
“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).
The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.
“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.
“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
No RCTs have included patients older than 70
For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.
However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.
Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.
As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
Primary prevention: CV events increase with elevated LDL cholesterol in older age
Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.
Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.
Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.
In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).
Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.
Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).
The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.
“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.
With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.
With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.
“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”
“These robust findings are novel,” he and his colleagues stressed.
Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.
The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
Unequivocal reductions in events in elderly, comparable with younger patients
In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.
The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.
The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.
The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).
Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).
“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.
“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.
“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”
The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”
The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.
A version of this article originally appeared on Medscape.com.
Contrary to historical evidence, two new studies show.
“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.
“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.
“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).
The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.
“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.
“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
No RCTs have included patients older than 70
For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.
However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.
Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.
As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
Primary prevention: CV events increase with elevated LDL cholesterol in older age
Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.
Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.
Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.
In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).
Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.
Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).
The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.
“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.
With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.
With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.
“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”
“These robust findings are novel,” he and his colleagues stressed.
Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.
The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
Unequivocal reductions in events in elderly, comparable with younger patients
In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.
The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.
The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.
The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).
Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).
“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.
“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.
“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”
The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”
The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.
A version of this article originally appeared on Medscape.com.
Marijuana use tied to repeat MI, stroke after percutaneous coronary intervention
in separate studies.
Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.
Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.
Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
Need for screening and counseling
Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.
She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.
Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.
Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.
That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”
Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”
Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.
“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.
Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.
After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.
However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.
These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
Hospitalized patients with prior MI
Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).
There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.
During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.
Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).
On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.
The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
In-Hospital outcomes after PCI
Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.
In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).
They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).
Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.
Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.
In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.
Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.
The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.
Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
in separate studies.
Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.
Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.
Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
Need for screening and counseling
Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.
She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.
Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.
Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.
That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”
Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”
Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.
“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.
Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.
After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.
However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.
These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
Hospitalized patients with prior MI
Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).
There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.
During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.
Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).
On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.
The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
In-Hospital outcomes after PCI
Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.
In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).
They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).
Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.
Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.
In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.
Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.
The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.
Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
in separate studies.
Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.
Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.
Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
Need for screening and counseling
Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.
She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.
Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.
Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.
That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”
Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”
Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.
“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.
Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.
After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.
However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.
These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
Hospitalized patients with prior MI
Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).
There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.
During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.
Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).
On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.
The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
In-Hospital outcomes after PCI
Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.
In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).
They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).
Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.
Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.
In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.
Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.
The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.
Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
From AHA 2020
Factor XI inhibitor–based anticoagulation strategies gain ground
according to Jeffrey I. Weitz, MD.
These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.
Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.
Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.
“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
Factor XI
That’s where Factor XI (FXI) may come in, Dr. Weitz said.
Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.
The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.
“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”
The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.
Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”
“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”
Potential indications include the following:
Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.
Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.
Secondary stroke prevention.
Prevention or treatment of cancer-associated VTE.
Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.
Agents in development
Of the FXI inhibitors in development, ISIS-FXIRx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXIRx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXIRx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.
The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIRx was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.
This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.
The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.
Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.
Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
Ongoing studies
Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXIRx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.
Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.
Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.
These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.
Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.
Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.
Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.
according to Jeffrey I. Weitz, MD.
These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.
Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.
Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.
“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
Factor XI
That’s where Factor XI (FXI) may come in, Dr. Weitz said.
Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.
The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.
“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”
The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.
Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”
“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”
Potential indications include the following:
Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.
Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.
Secondary stroke prevention.
Prevention or treatment of cancer-associated VTE.
Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.
Agents in development
Of the FXI inhibitors in development, ISIS-FXIRx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXIRx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXIRx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.
The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIRx was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.
This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.
The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.
Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.
Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
Ongoing studies
Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXIRx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.
Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.
Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.
These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.
Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.
Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.
Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.
according to Jeffrey I. Weitz, MD.
These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.
Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.
Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.
“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
Factor XI
That’s where Factor XI (FXI) may come in, Dr. Weitz said.
Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.
The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.
“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”
The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.
Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”
“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”
Potential indications include the following:
Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.
Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.
Secondary stroke prevention.
Prevention or treatment of cancer-associated VTE.
Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.
Agents in development
Of the FXI inhibitors in development, ISIS-FXIRx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXIRx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXIRx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.
The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIRx was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.
This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.
The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.
Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.
Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
Ongoing studies
Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXIRx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.
Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.
Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.
These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.
Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.
Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.
Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.
FROM THE THSNA BIENNIAL SUMMIT