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Apixaban cuts stroke but ups bleeding in subclinical AFib: ARTESIA
in the ARTESIA study.
The results appear to contrast somewhat with the recently reported NOAH-AFNET 6 trial, which failed to show a reduction in stroke with the anticoagulant edoxaban versus placebo in a similar patient group, but that trial was stopped early and so was underpowered.
However, the lead investigators of both trials say the studies actually show consistent results – both found a lower rate of stroke than expected in this population, but the confidence intervals for stroke reduction with anticoagulation overlap, suggesting there is likely some effect, albeit less than that in clinical AFib.
The big question is whether the reduction in stroke with anticoagulation outweighs the increase in major bleeding.
A new meta-analysis of the two trials showed that “oral anticoagulation with edoxaban or apixaban reduces the risk of ischemic stroke by approximately one-third and increases major bleeding by roughly double.”
In absolute numbers, there were three fewer ischemic strokes per 1,000 patient-years with anticoagulation in the two trials combined, at the cost of seven more major bleeds.
The lead investigators of the two trials have somewhat different opinions on how these findings may translate into clinical practice.
Jeff Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ont., lead investigator of the ARTESIA trial, believes that the risks and benefits need to be assessed in individual patients, but there should be some patient groups that will benefit from anticoagulation treatment.
“In patients with pacemakers or implantable loop recorders with continuous monitoring, subclinical AF[ib] is detected in about one third of patients, so this is extremely common,” he said in an interview. “The question is whether this is just a normal feature of getting older or is this like AF[ib] that we see in the clinic which increases stroke risk, and I think we can conclude from ARTESIA that this subclinical AF[ib] is associated with an increased risk of stroke, although that is lower than the risk with clinical AF[ib], and that it can be reduced by anticoagulation.”
Until recently it hasn’t been possible to quantify the risk associated with subclinical AFib, he noted. “But now we have a rich dataset to use to see if we can tease out some specifics on this. Future analyses of this dataset will help define patients where the benefits outweigh the risks of bleeding. For now, I think we can look at the data in a qualitative way and consider the totality of risk factors in each patient – their bleeding risk, stroke risk, how much AF[ib] they have, and make a decision as to whether to give anticoagulation or not.”
But Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), lead investigator of the NOAH-AFNET 6 trial said: “Both trials showed the stroke rate is low in these patients – about 1% per year – and that anticoagulation can reduce it a bit further at the expense of increasing major bleeding. I don’t believe the AF[ib] episodes picked up on these devices constitute a sufficient stroke risk to warrant anticoagulation, given the bleeding risk.”
Dr. Kirchhof suggests an alternate approach of performing further traditional AFib monitoring on these patients.
“I think going forward in my practice, when we come across this device-detected AF[ib], we will do further investigations with an established method for detecting AF[ib] involving surface ECG monitoring – maybe a 3-day or 7-day Holter. If that shows AF[ib], then we will be on firm ground to start anticoagulation. If that doesn’t show AF[ib], we will probably not use anticoagulation.”
The ARTESIA trial and the meta-analysis of the two trials were both presented at the annual scientific sessions of the American Heart Association. Both studies were also simultaneously published online – ARTESIA in the New England Journal of Medicine and the meta-analysis in Circulation.
ARTESIA
For the ARTESIA study, 4012 patients with device-detected AFib and other clinical risk factors for stroke were randomly assigned to treatment with apixaban (5 mg twice daily) or aspirin (81 mg daily).
After a mean follow-up of 3.5 years, the primary endpoint – stroke or systemic embolism – occurred in 55 patients in the apixaban group (0.78% per patient-year), compared with 86 patients in the aspirin group (1.24% per patient-year), giving a hazard ratio of 0.63 (95% confidence interval, 0.45-0.88; P = .007).
“The risk of stroke or systemic embolism was lower by 37% with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49%,” Dr. Healey reported.
In the “on-treatment” population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001).
Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.
One of the main findings of the trial is the lower-than-expected risk of ischemic stroke in this population – about 1% per year in the aspirin group, which was reduced to 0.64% per year in the apixaban group.
The authors noted that “simply counting strokes as compared with bleeding events might suggest a neutral overall effect. With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis.”
However, they pointed out that strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery, which was the case in this study.
“Thus, on the basis of the considerably greater severity of the stroke events prevented than the bleeding events caused, we believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops,” they concluded.
First well-powered trial addressing this question
Discussing the ARTESIA trial at an AHA press conference, Christine Albert, MD, Cedars-Sinai Medical Center, Los Angeles, said: “I want to emphasize how important this trial is.”
She explained that current guidelines do not recommend any treatment for patients with device-detected AFib that is not shown on ECG, even though it is known this confers some excess risk of stroke.
“ARTESIA is the first well-powered, long-term trial looking at this question,” she said. “It found a clear reduction in the risk of stroke/systemic embolism with apixaban vs aspirin, but there was also a significant amount of bleeding – about an 80% increase. The question is whether the benefit on stroke is worth it given the bleeding risk.”
Dr. Albert highlighted the low absolute risk of stroke in this study population of around 1.2%, pointing out that even with the 37% relative reduction with anticoagulation, stroke is only reduced in absolute terms by 0.4%.
“We are going to have to take this back to committees and guidelines and look at the balance between the benefit on stroke and the increase in bleeding,” she concluded.
Noting that observational studies have shown that the duration of AFib impacts the risk of stroke, Dr. Albert suggested that patients with longer-duration AFib may benefit from anticoagulation to a greater extent; and given that the bleeding seen in ARTESIA was mainly GI bleeding, it might be possible to screen out patients at high risk of GI bleeding.
She also pointed out that a lot of patients discontinued anticoagulation treatment in both ARTESIA and NOAH-AFNET 6, showing that this is not an easy strategy for elderly patients.
In an editorial accompanying publication of the ARTESIA trial, Emma Svennberg, MD, Karolinska Institute, Stockholm, also concluded that, “going forward, we must balance the increased bleeding risks with the risk for disabling strokes,” and that “future substudies and meta-analyses may provide further insights regarding treatment benefits in specific subgroups.”
NOAH-AFNET 6: New subgroup analysis
The previously reported NOAH-AFNET 6 study randomly assigned 2,538 patients with subclinical AFib and additional risk factors for stroke to anticoagulation with edoxaban or placebo. The trial was stopped early, so it was underpowered – but it found no difference between groups in the incidence of the composite endpoint of stroke, systemic embolism, or death from cardiovascular causes or in the incidence of stroke, although there was higher risk of major bleeding.
Again, there was a low rate of stroke in this trial with just 49 strokes in total in the whole study. The NOAH-AFNET-6 investigators concluded that these patients should not receive anticoagulation because the risk of bleeding outweighed any potential benefits.
A new subanalysis of the 259 patients who had durations of subclinical AFib of 24 hours or longer in the NOAH-AFNET 6 trial was presented at the AHA meeting, and simultaneously published online in the European Heart Journal.
This showed that the rate of stroke also appeared low in patients with these long durations of subclinical AFib, and that there was no interaction between the duration of subclinical AFib and the efficacy and safety of oral anticoagulation.
But with such a low number of events in the study as a whole and in the long duration subclinical AFib subgroup (in which there were just two strokes in each treatment group), this analysis was unlikely to show a difference, Dr. Kirchhof commented.
The subgroup analysis did, however, show that patients experiencing subclinical AFib durations of 24 hours or more were more likely to develop clinical AFib over time than those with shorter durations, suggesting the need for regular ECGs in these patients.
Dr. Kirchhof said better methods are needed to detect patients with subclinical AFib at high risk of stroke. “I don’t think our clinical stroke risk factor scores such as CHA2DS2-VASc are sufficient to detect high-risk patients. Patients in both NOAH-AFNET 6 and ARTESIA had a median CHA2DS2-VASc score of 4, but they had a stroke rate of just 1% per year,” he noted.
The meta-analysis of the two trials showed that the results from both are consistent, with an overall reduction in ischemic stroke with oral anticoagulation (relative risk, 0.68). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85).
There was no significant difference in cardiovascular death (RR, 0.95) or all-cause mortality (RR, 1.08), but anticoagulation significantly increased major bleeding (RR, 1.62).
Aspirin use complicates results
Dr. Healey said further analyses of the ARTESIA data will try to tease out the effect of concomitant aspirin use in the trial.
He explained that patients in this trial were allowed to take a single antiplatelet agent on top of study therapy.
“It is difficult to work out the exact use of antiplatelet therapy as it changed throughout the study,” he said. “About two-thirds were taking antiplatelet agents at the time of enrollment into the trial, but this decreased throughout the study. Many clinicians stopped open-label antiplatelet therapy during the trial when new evidence came out to suggest that there was no added benefit of adding aspirin on top of anticoagulants.
“We need to look carefully as to what impact that may have had,” Dr. Healey added. “We know from other studies that adding an antiplatelet on top of an anticoagulant doesn’t do much to thromboembolic events, but it approximately doubles the risk of major bleeding.”
In contrast, the NOAH-AFNET trial did not allow aspirin use in the anticoagulation group and aspirin was taken by around half the patients in the placebo group who had an indication for its use.
The authors of the meta-analysis pointed out that the omission of aspirin in nearly half of the control patients in NOAH-AFNET 6 and the early termination of the trial may have led to a slightly higher estimate for excess major bleeding with anticoagulation.
The ARTESIA study was supported by the Canadian Institutes for Health Research, the Bristol Myers Squibb-Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Advancing Clinical Trials Network and the Population Health Research Institute. Dr. Healey reported research grants and speaking fees from BMS/Pfizer Alliance, Servier, Novartis, Boston Scientific, Medtronic; and acts as a consultant to Bayer, Servier and Boston Scientific. The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.
A version of this article first appeared on Medscape.com.
in the ARTESIA study.
The results appear to contrast somewhat with the recently reported NOAH-AFNET 6 trial, which failed to show a reduction in stroke with the anticoagulant edoxaban versus placebo in a similar patient group, but that trial was stopped early and so was underpowered.
However, the lead investigators of both trials say the studies actually show consistent results – both found a lower rate of stroke than expected in this population, but the confidence intervals for stroke reduction with anticoagulation overlap, suggesting there is likely some effect, albeit less than that in clinical AFib.
The big question is whether the reduction in stroke with anticoagulation outweighs the increase in major bleeding.
A new meta-analysis of the two trials showed that “oral anticoagulation with edoxaban or apixaban reduces the risk of ischemic stroke by approximately one-third and increases major bleeding by roughly double.”
In absolute numbers, there were three fewer ischemic strokes per 1,000 patient-years with anticoagulation in the two trials combined, at the cost of seven more major bleeds.
The lead investigators of the two trials have somewhat different opinions on how these findings may translate into clinical practice.
Jeff Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ont., lead investigator of the ARTESIA trial, believes that the risks and benefits need to be assessed in individual patients, but there should be some patient groups that will benefit from anticoagulation treatment.
“In patients with pacemakers or implantable loop recorders with continuous monitoring, subclinical AF[ib] is detected in about one third of patients, so this is extremely common,” he said in an interview. “The question is whether this is just a normal feature of getting older or is this like AF[ib] that we see in the clinic which increases stroke risk, and I think we can conclude from ARTESIA that this subclinical AF[ib] is associated with an increased risk of stroke, although that is lower than the risk with clinical AF[ib], and that it can be reduced by anticoagulation.”
Until recently it hasn’t been possible to quantify the risk associated with subclinical AFib, he noted. “But now we have a rich dataset to use to see if we can tease out some specifics on this. Future analyses of this dataset will help define patients where the benefits outweigh the risks of bleeding. For now, I think we can look at the data in a qualitative way and consider the totality of risk factors in each patient – their bleeding risk, stroke risk, how much AF[ib] they have, and make a decision as to whether to give anticoagulation or not.”
But Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), lead investigator of the NOAH-AFNET 6 trial said: “Both trials showed the stroke rate is low in these patients – about 1% per year – and that anticoagulation can reduce it a bit further at the expense of increasing major bleeding. I don’t believe the AF[ib] episodes picked up on these devices constitute a sufficient stroke risk to warrant anticoagulation, given the bleeding risk.”
Dr. Kirchhof suggests an alternate approach of performing further traditional AFib monitoring on these patients.
“I think going forward in my practice, when we come across this device-detected AF[ib], we will do further investigations with an established method for detecting AF[ib] involving surface ECG monitoring – maybe a 3-day or 7-day Holter. If that shows AF[ib], then we will be on firm ground to start anticoagulation. If that doesn’t show AF[ib], we will probably not use anticoagulation.”
The ARTESIA trial and the meta-analysis of the two trials were both presented at the annual scientific sessions of the American Heart Association. Both studies were also simultaneously published online – ARTESIA in the New England Journal of Medicine and the meta-analysis in Circulation.
ARTESIA
For the ARTESIA study, 4012 patients with device-detected AFib and other clinical risk factors for stroke were randomly assigned to treatment with apixaban (5 mg twice daily) or aspirin (81 mg daily).
After a mean follow-up of 3.5 years, the primary endpoint – stroke or systemic embolism – occurred in 55 patients in the apixaban group (0.78% per patient-year), compared with 86 patients in the aspirin group (1.24% per patient-year), giving a hazard ratio of 0.63 (95% confidence interval, 0.45-0.88; P = .007).
“The risk of stroke or systemic embolism was lower by 37% with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49%,” Dr. Healey reported.
In the “on-treatment” population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001).
Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.
One of the main findings of the trial is the lower-than-expected risk of ischemic stroke in this population – about 1% per year in the aspirin group, which was reduced to 0.64% per year in the apixaban group.
The authors noted that “simply counting strokes as compared with bleeding events might suggest a neutral overall effect. With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis.”
However, they pointed out that strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery, which was the case in this study.
“Thus, on the basis of the considerably greater severity of the stroke events prevented than the bleeding events caused, we believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops,” they concluded.
First well-powered trial addressing this question
Discussing the ARTESIA trial at an AHA press conference, Christine Albert, MD, Cedars-Sinai Medical Center, Los Angeles, said: “I want to emphasize how important this trial is.”
She explained that current guidelines do not recommend any treatment for patients with device-detected AFib that is not shown on ECG, even though it is known this confers some excess risk of stroke.
“ARTESIA is the first well-powered, long-term trial looking at this question,” she said. “It found a clear reduction in the risk of stroke/systemic embolism with apixaban vs aspirin, but there was also a significant amount of bleeding – about an 80% increase. The question is whether the benefit on stroke is worth it given the bleeding risk.”
Dr. Albert highlighted the low absolute risk of stroke in this study population of around 1.2%, pointing out that even with the 37% relative reduction with anticoagulation, stroke is only reduced in absolute terms by 0.4%.
“We are going to have to take this back to committees and guidelines and look at the balance between the benefit on stroke and the increase in bleeding,” she concluded.
Noting that observational studies have shown that the duration of AFib impacts the risk of stroke, Dr. Albert suggested that patients with longer-duration AFib may benefit from anticoagulation to a greater extent; and given that the bleeding seen in ARTESIA was mainly GI bleeding, it might be possible to screen out patients at high risk of GI bleeding.
She also pointed out that a lot of patients discontinued anticoagulation treatment in both ARTESIA and NOAH-AFNET 6, showing that this is not an easy strategy for elderly patients.
In an editorial accompanying publication of the ARTESIA trial, Emma Svennberg, MD, Karolinska Institute, Stockholm, also concluded that, “going forward, we must balance the increased bleeding risks with the risk for disabling strokes,” and that “future substudies and meta-analyses may provide further insights regarding treatment benefits in specific subgroups.”
NOAH-AFNET 6: New subgroup analysis
The previously reported NOAH-AFNET 6 study randomly assigned 2,538 patients with subclinical AFib and additional risk factors for stroke to anticoagulation with edoxaban or placebo. The trial was stopped early, so it was underpowered – but it found no difference between groups in the incidence of the composite endpoint of stroke, systemic embolism, or death from cardiovascular causes or in the incidence of stroke, although there was higher risk of major bleeding.
Again, there was a low rate of stroke in this trial with just 49 strokes in total in the whole study. The NOAH-AFNET-6 investigators concluded that these patients should not receive anticoagulation because the risk of bleeding outweighed any potential benefits.
A new subanalysis of the 259 patients who had durations of subclinical AFib of 24 hours or longer in the NOAH-AFNET 6 trial was presented at the AHA meeting, and simultaneously published online in the European Heart Journal.
This showed that the rate of stroke also appeared low in patients with these long durations of subclinical AFib, and that there was no interaction between the duration of subclinical AFib and the efficacy and safety of oral anticoagulation.
But with such a low number of events in the study as a whole and in the long duration subclinical AFib subgroup (in which there were just two strokes in each treatment group), this analysis was unlikely to show a difference, Dr. Kirchhof commented.
The subgroup analysis did, however, show that patients experiencing subclinical AFib durations of 24 hours or more were more likely to develop clinical AFib over time than those with shorter durations, suggesting the need for regular ECGs in these patients.
Dr. Kirchhof said better methods are needed to detect patients with subclinical AFib at high risk of stroke. “I don’t think our clinical stroke risk factor scores such as CHA2DS2-VASc are sufficient to detect high-risk patients. Patients in both NOAH-AFNET 6 and ARTESIA had a median CHA2DS2-VASc score of 4, but they had a stroke rate of just 1% per year,” he noted.
The meta-analysis of the two trials showed that the results from both are consistent, with an overall reduction in ischemic stroke with oral anticoagulation (relative risk, 0.68). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85).
There was no significant difference in cardiovascular death (RR, 0.95) or all-cause mortality (RR, 1.08), but anticoagulation significantly increased major bleeding (RR, 1.62).
Aspirin use complicates results
Dr. Healey said further analyses of the ARTESIA data will try to tease out the effect of concomitant aspirin use in the trial.
He explained that patients in this trial were allowed to take a single antiplatelet agent on top of study therapy.
“It is difficult to work out the exact use of antiplatelet therapy as it changed throughout the study,” he said. “About two-thirds were taking antiplatelet agents at the time of enrollment into the trial, but this decreased throughout the study. Many clinicians stopped open-label antiplatelet therapy during the trial when new evidence came out to suggest that there was no added benefit of adding aspirin on top of anticoagulants.
“We need to look carefully as to what impact that may have had,” Dr. Healey added. “We know from other studies that adding an antiplatelet on top of an anticoagulant doesn’t do much to thromboembolic events, but it approximately doubles the risk of major bleeding.”
In contrast, the NOAH-AFNET trial did not allow aspirin use in the anticoagulation group and aspirin was taken by around half the patients in the placebo group who had an indication for its use.
The authors of the meta-analysis pointed out that the omission of aspirin in nearly half of the control patients in NOAH-AFNET 6 and the early termination of the trial may have led to a slightly higher estimate for excess major bleeding with anticoagulation.
The ARTESIA study was supported by the Canadian Institutes for Health Research, the Bristol Myers Squibb-Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Advancing Clinical Trials Network and the Population Health Research Institute. Dr. Healey reported research grants and speaking fees from BMS/Pfizer Alliance, Servier, Novartis, Boston Scientific, Medtronic; and acts as a consultant to Bayer, Servier and Boston Scientific. The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.
A version of this article first appeared on Medscape.com.
in the ARTESIA study.
The results appear to contrast somewhat with the recently reported NOAH-AFNET 6 trial, which failed to show a reduction in stroke with the anticoagulant edoxaban versus placebo in a similar patient group, but that trial was stopped early and so was underpowered.
However, the lead investigators of both trials say the studies actually show consistent results – both found a lower rate of stroke than expected in this population, but the confidence intervals for stroke reduction with anticoagulation overlap, suggesting there is likely some effect, albeit less than that in clinical AFib.
The big question is whether the reduction in stroke with anticoagulation outweighs the increase in major bleeding.
A new meta-analysis of the two trials showed that “oral anticoagulation with edoxaban or apixaban reduces the risk of ischemic stroke by approximately one-third and increases major bleeding by roughly double.”
In absolute numbers, there were three fewer ischemic strokes per 1,000 patient-years with anticoagulation in the two trials combined, at the cost of seven more major bleeds.
The lead investigators of the two trials have somewhat different opinions on how these findings may translate into clinical practice.
Jeff Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ont., lead investigator of the ARTESIA trial, believes that the risks and benefits need to be assessed in individual patients, but there should be some patient groups that will benefit from anticoagulation treatment.
“In patients with pacemakers or implantable loop recorders with continuous monitoring, subclinical AF[ib] is detected in about one third of patients, so this is extremely common,” he said in an interview. “The question is whether this is just a normal feature of getting older or is this like AF[ib] that we see in the clinic which increases stroke risk, and I think we can conclude from ARTESIA that this subclinical AF[ib] is associated with an increased risk of stroke, although that is lower than the risk with clinical AF[ib], and that it can be reduced by anticoagulation.”
Until recently it hasn’t been possible to quantify the risk associated with subclinical AFib, he noted. “But now we have a rich dataset to use to see if we can tease out some specifics on this. Future analyses of this dataset will help define patients where the benefits outweigh the risks of bleeding. For now, I think we can look at the data in a qualitative way and consider the totality of risk factors in each patient – their bleeding risk, stroke risk, how much AF[ib] they have, and make a decision as to whether to give anticoagulation or not.”
But Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), lead investigator of the NOAH-AFNET 6 trial said: “Both trials showed the stroke rate is low in these patients – about 1% per year – and that anticoagulation can reduce it a bit further at the expense of increasing major bleeding. I don’t believe the AF[ib] episodes picked up on these devices constitute a sufficient stroke risk to warrant anticoagulation, given the bleeding risk.”
Dr. Kirchhof suggests an alternate approach of performing further traditional AFib monitoring on these patients.
“I think going forward in my practice, when we come across this device-detected AF[ib], we will do further investigations with an established method for detecting AF[ib] involving surface ECG monitoring – maybe a 3-day or 7-day Holter. If that shows AF[ib], then we will be on firm ground to start anticoagulation. If that doesn’t show AF[ib], we will probably not use anticoagulation.”
The ARTESIA trial and the meta-analysis of the two trials were both presented at the annual scientific sessions of the American Heart Association. Both studies were also simultaneously published online – ARTESIA in the New England Journal of Medicine and the meta-analysis in Circulation.
ARTESIA
For the ARTESIA study, 4012 patients with device-detected AFib and other clinical risk factors for stroke were randomly assigned to treatment with apixaban (5 mg twice daily) or aspirin (81 mg daily).
After a mean follow-up of 3.5 years, the primary endpoint – stroke or systemic embolism – occurred in 55 patients in the apixaban group (0.78% per patient-year), compared with 86 patients in the aspirin group (1.24% per patient-year), giving a hazard ratio of 0.63 (95% confidence interval, 0.45-0.88; P = .007).
“The risk of stroke or systemic embolism was lower by 37% with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49%,” Dr. Healey reported.
In the “on-treatment” population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001).
Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.
One of the main findings of the trial is the lower-than-expected risk of ischemic stroke in this population – about 1% per year in the aspirin group, which was reduced to 0.64% per year in the apixaban group.
The authors noted that “simply counting strokes as compared with bleeding events might suggest a neutral overall effect. With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis.”
However, they pointed out that strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery, which was the case in this study.
“Thus, on the basis of the considerably greater severity of the stroke events prevented than the bleeding events caused, we believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops,” they concluded.
First well-powered trial addressing this question
Discussing the ARTESIA trial at an AHA press conference, Christine Albert, MD, Cedars-Sinai Medical Center, Los Angeles, said: “I want to emphasize how important this trial is.”
She explained that current guidelines do not recommend any treatment for patients with device-detected AFib that is not shown on ECG, even though it is known this confers some excess risk of stroke.
“ARTESIA is the first well-powered, long-term trial looking at this question,” she said. “It found a clear reduction in the risk of stroke/systemic embolism with apixaban vs aspirin, but there was also a significant amount of bleeding – about an 80% increase. The question is whether the benefit on stroke is worth it given the bleeding risk.”
Dr. Albert highlighted the low absolute risk of stroke in this study population of around 1.2%, pointing out that even with the 37% relative reduction with anticoagulation, stroke is only reduced in absolute terms by 0.4%.
“We are going to have to take this back to committees and guidelines and look at the balance between the benefit on stroke and the increase in bleeding,” she concluded.
Noting that observational studies have shown that the duration of AFib impacts the risk of stroke, Dr. Albert suggested that patients with longer-duration AFib may benefit from anticoagulation to a greater extent; and given that the bleeding seen in ARTESIA was mainly GI bleeding, it might be possible to screen out patients at high risk of GI bleeding.
She also pointed out that a lot of patients discontinued anticoagulation treatment in both ARTESIA and NOAH-AFNET 6, showing that this is not an easy strategy for elderly patients.
In an editorial accompanying publication of the ARTESIA trial, Emma Svennberg, MD, Karolinska Institute, Stockholm, also concluded that, “going forward, we must balance the increased bleeding risks with the risk for disabling strokes,” and that “future substudies and meta-analyses may provide further insights regarding treatment benefits in specific subgroups.”
NOAH-AFNET 6: New subgroup analysis
The previously reported NOAH-AFNET 6 study randomly assigned 2,538 patients with subclinical AFib and additional risk factors for stroke to anticoagulation with edoxaban or placebo. The trial was stopped early, so it was underpowered – but it found no difference between groups in the incidence of the composite endpoint of stroke, systemic embolism, or death from cardiovascular causes or in the incidence of stroke, although there was higher risk of major bleeding.
Again, there was a low rate of stroke in this trial with just 49 strokes in total in the whole study. The NOAH-AFNET-6 investigators concluded that these patients should not receive anticoagulation because the risk of bleeding outweighed any potential benefits.
A new subanalysis of the 259 patients who had durations of subclinical AFib of 24 hours or longer in the NOAH-AFNET 6 trial was presented at the AHA meeting, and simultaneously published online in the European Heart Journal.
This showed that the rate of stroke also appeared low in patients with these long durations of subclinical AFib, and that there was no interaction between the duration of subclinical AFib and the efficacy and safety of oral anticoagulation.
But with such a low number of events in the study as a whole and in the long duration subclinical AFib subgroup (in which there were just two strokes in each treatment group), this analysis was unlikely to show a difference, Dr. Kirchhof commented.
The subgroup analysis did, however, show that patients experiencing subclinical AFib durations of 24 hours or more were more likely to develop clinical AFib over time than those with shorter durations, suggesting the need for regular ECGs in these patients.
Dr. Kirchhof said better methods are needed to detect patients with subclinical AFib at high risk of stroke. “I don’t think our clinical stroke risk factor scores such as CHA2DS2-VASc are sufficient to detect high-risk patients. Patients in both NOAH-AFNET 6 and ARTESIA had a median CHA2DS2-VASc score of 4, but they had a stroke rate of just 1% per year,” he noted.
The meta-analysis of the two trials showed that the results from both are consistent, with an overall reduction in ischemic stroke with oral anticoagulation (relative risk, 0.68). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85).
There was no significant difference in cardiovascular death (RR, 0.95) or all-cause mortality (RR, 1.08), but anticoagulation significantly increased major bleeding (RR, 1.62).
Aspirin use complicates results
Dr. Healey said further analyses of the ARTESIA data will try to tease out the effect of concomitant aspirin use in the trial.
He explained that patients in this trial were allowed to take a single antiplatelet agent on top of study therapy.
“It is difficult to work out the exact use of antiplatelet therapy as it changed throughout the study,” he said. “About two-thirds were taking antiplatelet agents at the time of enrollment into the trial, but this decreased throughout the study. Many clinicians stopped open-label antiplatelet therapy during the trial when new evidence came out to suggest that there was no added benefit of adding aspirin on top of anticoagulants.
“We need to look carefully as to what impact that may have had,” Dr. Healey added. “We know from other studies that adding an antiplatelet on top of an anticoagulant doesn’t do much to thromboembolic events, but it approximately doubles the risk of major bleeding.”
In contrast, the NOAH-AFNET trial did not allow aspirin use in the anticoagulation group and aspirin was taken by around half the patients in the placebo group who had an indication for its use.
The authors of the meta-analysis pointed out that the omission of aspirin in nearly half of the control patients in NOAH-AFNET 6 and the early termination of the trial may have led to a slightly higher estimate for excess major bleeding with anticoagulation.
The ARTESIA study was supported by the Canadian Institutes for Health Research, the Bristol Myers Squibb-Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Advancing Clinical Trials Network and the Population Health Research Institute. Dr. Healey reported research grants and speaking fees from BMS/Pfizer Alliance, Servier, Novartis, Boston Scientific, Medtronic; and acts as a consultant to Bayer, Servier and Boston Scientific. The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.
A version of this article first appeared on Medscape.com.
FROM AHA 2023
Does taking BP medicine at night (vs morning) result in fewer cardiovascular events?
Evidence summary
Recent UK study shows no difference by timing
A 2022 UK prospective, randomized, multicenter trial assigned 21,104 predominantly White adults (58% men) with hypertension to take their usual antihypertensive medication either in the morning (6
All patient baseline characteristics were equivalent between groups. If troubled by nocturia, patients in the evening group taking diuretics were told to take only the diuretic earlier (6
The median follow-up was 5.2 years. Data were collected at regular intervals through patient completion of online questionnaires and researcher analysis of National Health Service data on hospitalization and death. The intention-to-treat analysis showed no difference in the primary outcome (a composite of vascular death, nonfatal myocardial infarction, or nonfatal stroke) between the evening and morning administration groups (0.69 events vs 0.72 events per 100 person-years; hazard ratio [HR] = 0.95; 95% CI, 0.83-1.10; P = .53).
The controversial Hygia Project favored evening
Prior to the UK study was the Hygia Chronotherapy Trial, a prospective, controlled, multicenter study conducted within the primary care setting in Spain. Caucasian Spanish adults (N = 19,168; mean age, 61 years; 56% men) with hypertension were randomly assigned to take all prescribed antihypertensive medication either at bedtime or upon waking.2
The Hygia Project initially sought to establish the value of ambulatory blood pressure monitoring (ABPM) compared to office blood pressure (BP) monitoring and to explore the prognostic value of sleeping BP.3 The study objectives evolved over time. The randomization process was not clearly described,2,3 but multiple randomizations were alluded to. The authors stated that “for any of these chronotherapy trials” randomizations were done separately for “each participating center” and “randomization of participants to treatment-time regimen is done separately for each hypertension medication or combination being tested.”
The baseline characteristics of patients in the evening and morning administration groups were similar, but statistically significant differences existed in BMI (29.6 vs 29.7; P = .030) and sleep-time systolic BP percent decline (9.3 vs 9.0; P < .001). Mean baseline 48-hour BP was 132/77 mm Hg. Hypertension was defined as an awake systolic BP ≥
Prescribers were free to prescribe medicines from 5 classes (diuretic, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or beta-blocker) as they thought appropriate, were encouraged to use fixed-dose combination pills, and were told not to use split (eg, twice per day) dosing. Annual 48-hour ABPM was completed, and patients’ electronic health records were analyzed by blinded investigators. Median follow-up was 6.3 years, and only 84 participants failed to complete the minimum 1-year participation requirement.
Continue to: The primary outcome...
The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): cardiovascular death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63).
The complicated, layered study design and randomization methods limit the ability to critically appraise the study.
Smaller Spanish study also supported evening administration
A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.4 The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.
After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).
Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.
Recommendations from others
A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.5 Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.6
Editor’s takeaway
I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.
1. Mackenzie IS, Rogers A, Poulter NR, et al; TIME Study Group. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022;400:1417-1425. doi: 10.1016/S0140-6736(22)01786-X
2. Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al; Hygia Project Investigators. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2020;41:4565-4576. doi: 10.1093/eurheartj/ehz754
3. Hermida RC. Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: rationale and design of the Hygia Project. Chronobiol Int. 2016;33:906-936. doi: 10.1080/07420528.2016.1181078
4. Hermida RC, Ayala DE, Mojón A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27:1629-1651. doi: 10.3109/07420528.2010.510230
5. Stergiou G, Brunström M, MacDonald T, et al. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension. J Hypertens. 2022;40:1847-1858. doi: 10.1097/HJH.0000000000003240
6. Brunström M, Kjeldsen SE, Kreutz R, et al. Missing verification of source data in hypertension research: The HYGIA PROJECT in Perspective. Hypertension. 2021;78:555-558. doi: 10.1161/HYPERTENSIONAHA.121.17356
Evidence summary
Recent UK study shows no difference by timing
A 2022 UK prospective, randomized, multicenter trial assigned 21,104 predominantly White adults (58% men) with hypertension to take their usual antihypertensive medication either in the morning (6
All patient baseline characteristics were equivalent between groups. If troubled by nocturia, patients in the evening group taking diuretics were told to take only the diuretic earlier (6
The median follow-up was 5.2 years. Data were collected at regular intervals through patient completion of online questionnaires and researcher analysis of National Health Service data on hospitalization and death. The intention-to-treat analysis showed no difference in the primary outcome (a composite of vascular death, nonfatal myocardial infarction, or nonfatal stroke) between the evening and morning administration groups (0.69 events vs 0.72 events per 100 person-years; hazard ratio [HR] = 0.95; 95% CI, 0.83-1.10; P = .53).
The controversial Hygia Project favored evening
Prior to the UK study was the Hygia Chronotherapy Trial, a prospective, controlled, multicenter study conducted within the primary care setting in Spain. Caucasian Spanish adults (N = 19,168; mean age, 61 years; 56% men) with hypertension were randomly assigned to take all prescribed antihypertensive medication either at bedtime or upon waking.2
The Hygia Project initially sought to establish the value of ambulatory blood pressure monitoring (ABPM) compared to office blood pressure (BP) monitoring and to explore the prognostic value of sleeping BP.3 The study objectives evolved over time. The randomization process was not clearly described,2,3 but multiple randomizations were alluded to. The authors stated that “for any of these chronotherapy trials” randomizations were done separately for “each participating center” and “randomization of participants to treatment-time regimen is done separately for each hypertension medication or combination being tested.”
The baseline characteristics of patients in the evening and morning administration groups were similar, but statistically significant differences existed in BMI (29.6 vs 29.7; P = .030) and sleep-time systolic BP percent decline (9.3 vs 9.0; P < .001). Mean baseline 48-hour BP was 132/77 mm Hg. Hypertension was defined as an awake systolic BP ≥
Prescribers were free to prescribe medicines from 5 classes (diuretic, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or beta-blocker) as they thought appropriate, were encouraged to use fixed-dose combination pills, and were told not to use split (eg, twice per day) dosing. Annual 48-hour ABPM was completed, and patients’ electronic health records were analyzed by blinded investigators. Median follow-up was 6.3 years, and only 84 participants failed to complete the minimum 1-year participation requirement.
Continue to: The primary outcome...
The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): cardiovascular death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63).
The complicated, layered study design and randomization methods limit the ability to critically appraise the study.
Smaller Spanish study also supported evening administration
A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.4 The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.
After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).
Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.
Recommendations from others
A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.5 Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.6
Editor’s takeaway
I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.
Evidence summary
Recent UK study shows no difference by timing
A 2022 UK prospective, randomized, multicenter trial assigned 21,104 predominantly White adults (58% men) with hypertension to take their usual antihypertensive medication either in the morning (6
All patient baseline characteristics were equivalent between groups. If troubled by nocturia, patients in the evening group taking diuretics were told to take only the diuretic earlier (6
The median follow-up was 5.2 years. Data were collected at regular intervals through patient completion of online questionnaires and researcher analysis of National Health Service data on hospitalization and death. The intention-to-treat analysis showed no difference in the primary outcome (a composite of vascular death, nonfatal myocardial infarction, or nonfatal stroke) between the evening and morning administration groups (0.69 events vs 0.72 events per 100 person-years; hazard ratio [HR] = 0.95; 95% CI, 0.83-1.10; P = .53).
The controversial Hygia Project favored evening
Prior to the UK study was the Hygia Chronotherapy Trial, a prospective, controlled, multicenter study conducted within the primary care setting in Spain. Caucasian Spanish adults (N = 19,168; mean age, 61 years; 56% men) with hypertension were randomly assigned to take all prescribed antihypertensive medication either at bedtime or upon waking.2
The Hygia Project initially sought to establish the value of ambulatory blood pressure monitoring (ABPM) compared to office blood pressure (BP) monitoring and to explore the prognostic value of sleeping BP.3 The study objectives evolved over time. The randomization process was not clearly described,2,3 but multiple randomizations were alluded to. The authors stated that “for any of these chronotherapy trials” randomizations were done separately for “each participating center” and “randomization of participants to treatment-time regimen is done separately for each hypertension medication or combination being tested.”
The baseline characteristics of patients in the evening and morning administration groups were similar, but statistically significant differences existed in BMI (29.6 vs 29.7; P = .030) and sleep-time systolic BP percent decline (9.3 vs 9.0; P < .001). Mean baseline 48-hour BP was 132/77 mm Hg. Hypertension was defined as an awake systolic BP ≥
Prescribers were free to prescribe medicines from 5 classes (diuretic, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or beta-blocker) as they thought appropriate, were encouraged to use fixed-dose combination pills, and were told not to use split (eg, twice per day) dosing. Annual 48-hour ABPM was completed, and patients’ electronic health records were analyzed by blinded investigators. Median follow-up was 6.3 years, and only 84 participants failed to complete the minimum 1-year participation requirement.
Continue to: The primary outcome...
The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): cardiovascular death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63).
The complicated, layered study design and randomization methods limit the ability to critically appraise the study.
Smaller Spanish study also supported evening administration
A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.4 The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.
After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).
Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.
Recommendations from others
A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.5 Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.6
Editor’s takeaway
I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.
1. Mackenzie IS, Rogers A, Poulter NR, et al; TIME Study Group. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022;400:1417-1425. doi: 10.1016/S0140-6736(22)01786-X
2. Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al; Hygia Project Investigators. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2020;41:4565-4576. doi: 10.1093/eurheartj/ehz754
3. Hermida RC. Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: rationale and design of the Hygia Project. Chronobiol Int. 2016;33:906-936. doi: 10.1080/07420528.2016.1181078
4. Hermida RC, Ayala DE, Mojón A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27:1629-1651. doi: 10.3109/07420528.2010.510230
5. Stergiou G, Brunström M, MacDonald T, et al. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension. J Hypertens. 2022;40:1847-1858. doi: 10.1097/HJH.0000000000003240
6. Brunström M, Kjeldsen SE, Kreutz R, et al. Missing verification of source data in hypertension research: The HYGIA PROJECT in Perspective. Hypertension. 2021;78:555-558. doi: 10.1161/HYPERTENSIONAHA.121.17356
1. Mackenzie IS, Rogers A, Poulter NR, et al; TIME Study Group. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022;400:1417-1425. doi: 10.1016/S0140-6736(22)01786-X
2. Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al; Hygia Project Investigators. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2020;41:4565-4576. doi: 10.1093/eurheartj/ehz754
3. Hermida RC. Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: rationale and design of the Hygia Project. Chronobiol Int. 2016;33:906-936. doi: 10.1080/07420528.2016.1181078
4. Hermida RC, Ayala DE, Mojón A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27:1629-1651. doi: 10.3109/07420528.2010.510230
5. Stergiou G, Brunström M, MacDonald T, et al. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension. J Hypertens. 2022;40:1847-1858. doi: 10.1097/HJH.0000000000003240
6. Brunström M, Kjeldsen SE, Kreutz R, et al. Missing verification of source data in hypertension research: The HYGIA PROJECT in Perspective. Hypertension. 2021;78:555-558. doi: 10.1161/HYPERTENSIONAHA.121.17356
EVIDENCE-BASED ANSWER:
Impressive bleeding profile with factor XI inhibitor in AFib: AZALEA
; the risk of stroke was moderate to high.
The trial was stopped earlier this year because of an “overwhelming” reduction in bleeding with abelacimab in comparison to rivaroxaban. Abelacimab is a monoclonal antibody given by subcutaneous injection once a month.
“Details of the bleeding results have now shown that the 150-mg dose of abelacimab, which is the dose being carried forward to phase 3 trials, was associated with a 67% reduction in major or clinically relevant nonmajor bleeding, the primary endpoint of the study.”
In addition, major bleeding was reduced by 74%, and major gastrointestinal bleeding was reduced by 93%.
“We are seeing really profound reductions in bleeding with this agent vs. a NOAC [novel oral anticoagulant],” lead AZALEA investigator Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, said in an interview.
“Major bleeding – effectively the type of bleeding that results in hospitalization – is reduced by more than two-thirds, and major GI bleeding – which is the most common type of bleeding experienced by AF patients on anticoagulants – is almost eliminated. This gives us real hope that we have finally found an anticoagulant that is remarkably safe and will allow us to use anticoagulation in our most vulnerable patients,” he said.
Dr. Ruff presented the full results from the AZALEA trial at the American Heart Association scientific sessions.
He noted that AFib is one of the most common medical conditions in the world and that it confers an increased risk of stroke. Anticoagulants reduce this risk very effectively, and while the NOACS, such as apixaban and rivaroxaban, are safer than warfarin, significant bleeding still occurs, and “shockingly,” he said, between 30% and 60% of patients are not prescribed an anticoagulant or discontinue treatment because of bleeding concerns.
“Clearly, we need safer anticoagulants to protect these patients. Factor XI inhibitors, of which abelacimab is one, have emerged as the most promising agents, as they are thought to provide precision anticoagulation,” Dr. Ruff said.
He explained that factor XI appears to be involved in the formation of thrombus, which blocks arteries and causes strokes and myocardial infarction (thrombosis), but not in the healing process of blood vessels after injury (hemostasis). So, it is believed that inhibiting factor XI should reduce thrombotic events without causing excess bleeding.
AZALEA, which is the largest and longest trial of a factor XI inhibitor to date, enrolled 1,287 adults with AF who were at moderate to high risk of stroke.
They were randomly assigned to receive one of three treatments: oral rivaroxaban 20 mg daily; abelacimab 90 mg; or abelacimab 150 mg. Abelacimab was given monthly by injection.
Both doses of abelacimab inhibited factor XI almost completely; 97% inhibition was achieved with the 90-mg dose, and 99% inhibition was achieved with the 150-mg dose.
Results showed that after a median follow-up of 1.8 years, there was a clear reduction in all bleeding endpoints with both doses of abelacimab, compared with rivaroxaban.
Dr. Ruff explained that the trial was powered to detect differences in bleeding, not stroke, but the investigators approached this in an exploratory way.
“As expected, the numbers were low, with just 25 strokes (23 ischemic strokes) across all three groups in the trial. So, because of this very low rate, we are really not able to compare how abelacimab compares with rivaroxaban in reducing stroke,” he commented.
He did, however, suggest that the low stroke rate in the study was encouraging.
“If we look at the same population without anticoagulation, the stroke rate would be about 7% per year. And we see here in this trial that in all three arms, the stroke rate was just above 1% per year. I think this shows that all the patients in the trial were getting highly effective anticoagulation,” he said.
“But what this trial doesn’t answer – because the numbers are so low – is exactly how effective factor XI inhibition with abelacimab is, compared to NOACs in reducing stroke rates. That requires dedicated phase 3 trials.”
Dr. Ruff pointed out that there are some reassuring data from phase 2 trials in venous thromboembolism (VTE), in which the 150-mg dose of abelacimab was associated with an 80% reduction in VTE, compared with enoxaparin. “Historically in the development of anticoagulants, efficacy in VTE has translated into efficacy in stroke prevention, so that is very encouraging,” he commented.
“So, I think our results along with the VTE results are encouraging, but the precision regarding the relative efficacy compared to NOACs is still an open question that needs to be clarified in phase 3 trials,” he concluded.
Several phase 3 trials are now underway with abelacimab and two other small-molecule orally available factor XI inhibitors, milvexian (BMS/Janssen) and asundexian (Bayer).
The designated discussant of the AZALEA study at the AHA meeting, Manesh Patel. MD, Duke University, Durham, N.C., described the results as “an important step forward.”
“This trial, with the prior data in this field, show that factor XI inhibition as a target is biologically possible (studies showing > 95% inhibition), significantly less bleeding than NOACS. We await the phase 3 studies, but having significantly less bleeding and similar or less stroke would be a substantial step forward for the field,” he said.
John Alexander, MD, also from Duke University, said: “There were clinically important reductions in bleeding with both doses of abelacimab, compared with rivaroxaban. This is consistent to what we’ve seen with comparisons between other factor XI inhibitors and other factor Xa inhibitors.”
On the exploratory efficacy results, Dr. Alexander agreed with Dr. Ruff that it was not possible to get any idea of how abelacimab compared with rivaroxaban in reducing stroke. “The hazard ratio and confidence intervals comparing abelacimab and rivaroxaban include substantial lower rates, no difference, and substantially higher rates,” he noted.
“We need to wait for the results of phase 3 trials, with abelacimab and other factor XI inhibitors, to understand how well factor XI inhibition prevents stroke and systemic embolism in patients with atrial fibrillation,” Dr. Alexander added. “These trials are ongoing.”
Dr. Ruff concluded: “Assuming the data from ongoing phase 3 trials confirm the benefit of factor XI inhibitors for stroke prevention in people with AF, it will really be transformative for the field of cardiology.
“Our first mission in treating people with AF is to prevent stroke, and our ability to do this with a remarkably safe anticoagulant such as abelacimab would be an incredible advance,” he concluded.
Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AF executive committee for BMS/Janssen (milvexian), and has been on an advisory board for Bayer (asundexian). Dr. Patel has received grants from and acts as an advisor to Bayer and Janssen. Dr. Alexander receives research funding from Bayer.
A version of this article first appeared on Medscape.com.
; the risk of stroke was moderate to high.
The trial was stopped earlier this year because of an “overwhelming” reduction in bleeding with abelacimab in comparison to rivaroxaban. Abelacimab is a monoclonal antibody given by subcutaneous injection once a month.
“Details of the bleeding results have now shown that the 150-mg dose of abelacimab, which is the dose being carried forward to phase 3 trials, was associated with a 67% reduction in major or clinically relevant nonmajor bleeding, the primary endpoint of the study.”
In addition, major bleeding was reduced by 74%, and major gastrointestinal bleeding was reduced by 93%.
“We are seeing really profound reductions in bleeding with this agent vs. a NOAC [novel oral anticoagulant],” lead AZALEA investigator Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, said in an interview.
“Major bleeding – effectively the type of bleeding that results in hospitalization – is reduced by more than two-thirds, and major GI bleeding – which is the most common type of bleeding experienced by AF patients on anticoagulants – is almost eliminated. This gives us real hope that we have finally found an anticoagulant that is remarkably safe and will allow us to use anticoagulation in our most vulnerable patients,” he said.
Dr. Ruff presented the full results from the AZALEA trial at the American Heart Association scientific sessions.
He noted that AFib is one of the most common medical conditions in the world and that it confers an increased risk of stroke. Anticoagulants reduce this risk very effectively, and while the NOACS, such as apixaban and rivaroxaban, are safer than warfarin, significant bleeding still occurs, and “shockingly,” he said, between 30% and 60% of patients are not prescribed an anticoagulant or discontinue treatment because of bleeding concerns.
“Clearly, we need safer anticoagulants to protect these patients. Factor XI inhibitors, of which abelacimab is one, have emerged as the most promising agents, as they are thought to provide precision anticoagulation,” Dr. Ruff said.
He explained that factor XI appears to be involved in the formation of thrombus, which blocks arteries and causes strokes and myocardial infarction (thrombosis), but not in the healing process of blood vessels after injury (hemostasis). So, it is believed that inhibiting factor XI should reduce thrombotic events without causing excess bleeding.
AZALEA, which is the largest and longest trial of a factor XI inhibitor to date, enrolled 1,287 adults with AF who were at moderate to high risk of stroke.
They were randomly assigned to receive one of three treatments: oral rivaroxaban 20 mg daily; abelacimab 90 mg; or abelacimab 150 mg. Abelacimab was given monthly by injection.
Both doses of abelacimab inhibited factor XI almost completely; 97% inhibition was achieved with the 90-mg dose, and 99% inhibition was achieved with the 150-mg dose.
Results showed that after a median follow-up of 1.8 years, there was a clear reduction in all bleeding endpoints with both doses of abelacimab, compared with rivaroxaban.
Dr. Ruff explained that the trial was powered to detect differences in bleeding, not stroke, but the investigators approached this in an exploratory way.
“As expected, the numbers were low, with just 25 strokes (23 ischemic strokes) across all three groups in the trial. So, because of this very low rate, we are really not able to compare how abelacimab compares with rivaroxaban in reducing stroke,” he commented.
He did, however, suggest that the low stroke rate in the study was encouraging.
“If we look at the same population without anticoagulation, the stroke rate would be about 7% per year. And we see here in this trial that in all three arms, the stroke rate was just above 1% per year. I think this shows that all the patients in the trial were getting highly effective anticoagulation,” he said.
“But what this trial doesn’t answer – because the numbers are so low – is exactly how effective factor XI inhibition with abelacimab is, compared to NOACs in reducing stroke rates. That requires dedicated phase 3 trials.”
Dr. Ruff pointed out that there are some reassuring data from phase 2 trials in venous thromboembolism (VTE), in which the 150-mg dose of abelacimab was associated with an 80% reduction in VTE, compared with enoxaparin. “Historically in the development of anticoagulants, efficacy in VTE has translated into efficacy in stroke prevention, so that is very encouraging,” he commented.
“So, I think our results along with the VTE results are encouraging, but the precision regarding the relative efficacy compared to NOACs is still an open question that needs to be clarified in phase 3 trials,” he concluded.
Several phase 3 trials are now underway with abelacimab and two other small-molecule orally available factor XI inhibitors, milvexian (BMS/Janssen) and asundexian (Bayer).
The designated discussant of the AZALEA study at the AHA meeting, Manesh Patel. MD, Duke University, Durham, N.C., described the results as “an important step forward.”
“This trial, with the prior data in this field, show that factor XI inhibition as a target is biologically possible (studies showing > 95% inhibition), significantly less bleeding than NOACS. We await the phase 3 studies, but having significantly less bleeding and similar or less stroke would be a substantial step forward for the field,” he said.
John Alexander, MD, also from Duke University, said: “There were clinically important reductions in bleeding with both doses of abelacimab, compared with rivaroxaban. This is consistent to what we’ve seen with comparisons between other factor XI inhibitors and other factor Xa inhibitors.”
On the exploratory efficacy results, Dr. Alexander agreed with Dr. Ruff that it was not possible to get any idea of how abelacimab compared with rivaroxaban in reducing stroke. “The hazard ratio and confidence intervals comparing abelacimab and rivaroxaban include substantial lower rates, no difference, and substantially higher rates,” he noted.
“We need to wait for the results of phase 3 trials, with abelacimab and other factor XI inhibitors, to understand how well factor XI inhibition prevents stroke and systemic embolism in patients with atrial fibrillation,” Dr. Alexander added. “These trials are ongoing.”
Dr. Ruff concluded: “Assuming the data from ongoing phase 3 trials confirm the benefit of factor XI inhibitors for stroke prevention in people with AF, it will really be transformative for the field of cardiology.
“Our first mission in treating people with AF is to prevent stroke, and our ability to do this with a remarkably safe anticoagulant such as abelacimab would be an incredible advance,” he concluded.
Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AF executive committee for BMS/Janssen (milvexian), and has been on an advisory board for Bayer (asundexian). Dr. Patel has received grants from and acts as an advisor to Bayer and Janssen. Dr. Alexander receives research funding from Bayer.
A version of this article first appeared on Medscape.com.
; the risk of stroke was moderate to high.
The trial was stopped earlier this year because of an “overwhelming” reduction in bleeding with abelacimab in comparison to rivaroxaban. Abelacimab is a monoclonal antibody given by subcutaneous injection once a month.
“Details of the bleeding results have now shown that the 150-mg dose of abelacimab, which is the dose being carried forward to phase 3 trials, was associated with a 67% reduction in major or clinically relevant nonmajor bleeding, the primary endpoint of the study.”
In addition, major bleeding was reduced by 74%, and major gastrointestinal bleeding was reduced by 93%.
“We are seeing really profound reductions in bleeding with this agent vs. a NOAC [novel oral anticoagulant],” lead AZALEA investigator Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, said in an interview.
“Major bleeding – effectively the type of bleeding that results in hospitalization – is reduced by more than two-thirds, and major GI bleeding – which is the most common type of bleeding experienced by AF patients on anticoagulants – is almost eliminated. This gives us real hope that we have finally found an anticoagulant that is remarkably safe and will allow us to use anticoagulation in our most vulnerable patients,” he said.
Dr. Ruff presented the full results from the AZALEA trial at the American Heart Association scientific sessions.
He noted that AFib is one of the most common medical conditions in the world and that it confers an increased risk of stroke. Anticoagulants reduce this risk very effectively, and while the NOACS, such as apixaban and rivaroxaban, are safer than warfarin, significant bleeding still occurs, and “shockingly,” he said, between 30% and 60% of patients are not prescribed an anticoagulant or discontinue treatment because of bleeding concerns.
“Clearly, we need safer anticoagulants to protect these patients. Factor XI inhibitors, of which abelacimab is one, have emerged as the most promising agents, as they are thought to provide precision anticoagulation,” Dr. Ruff said.
He explained that factor XI appears to be involved in the formation of thrombus, which blocks arteries and causes strokes and myocardial infarction (thrombosis), but not in the healing process of blood vessels after injury (hemostasis). So, it is believed that inhibiting factor XI should reduce thrombotic events without causing excess bleeding.
AZALEA, which is the largest and longest trial of a factor XI inhibitor to date, enrolled 1,287 adults with AF who were at moderate to high risk of stroke.
They were randomly assigned to receive one of three treatments: oral rivaroxaban 20 mg daily; abelacimab 90 mg; or abelacimab 150 mg. Abelacimab was given monthly by injection.
Both doses of abelacimab inhibited factor XI almost completely; 97% inhibition was achieved with the 90-mg dose, and 99% inhibition was achieved with the 150-mg dose.
Results showed that after a median follow-up of 1.8 years, there was a clear reduction in all bleeding endpoints with both doses of abelacimab, compared with rivaroxaban.
Dr. Ruff explained that the trial was powered to detect differences in bleeding, not stroke, but the investigators approached this in an exploratory way.
“As expected, the numbers were low, with just 25 strokes (23 ischemic strokes) across all three groups in the trial. So, because of this very low rate, we are really not able to compare how abelacimab compares with rivaroxaban in reducing stroke,” he commented.
He did, however, suggest that the low stroke rate in the study was encouraging.
“If we look at the same population without anticoagulation, the stroke rate would be about 7% per year. And we see here in this trial that in all three arms, the stroke rate was just above 1% per year. I think this shows that all the patients in the trial were getting highly effective anticoagulation,” he said.
“But what this trial doesn’t answer – because the numbers are so low – is exactly how effective factor XI inhibition with abelacimab is, compared to NOACs in reducing stroke rates. That requires dedicated phase 3 trials.”
Dr. Ruff pointed out that there are some reassuring data from phase 2 trials in venous thromboembolism (VTE), in which the 150-mg dose of abelacimab was associated with an 80% reduction in VTE, compared with enoxaparin. “Historically in the development of anticoagulants, efficacy in VTE has translated into efficacy in stroke prevention, so that is very encouraging,” he commented.
“So, I think our results along with the VTE results are encouraging, but the precision regarding the relative efficacy compared to NOACs is still an open question that needs to be clarified in phase 3 trials,” he concluded.
Several phase 3 trials are now underway with abelacimab and two other small-molecule orally available factor XI inhibitors, milvexian (BMS/Janssen) and asundexian (Bayer).
The designated discussant of the AZALEA study at the AHA meeting, Manesh Patel. MD, Duke University, Durham, N.C., described the results as “an important step forward.”
“This trial, with the prior data in this field, show that factor XI inhibition as a target is biologically possible (studies showing > 95% inhibition), significantly less bleeding than NOACS. We await the phase 3 studies, but having significantly less bleeding and similar or less stroke would be a substantial step forward for the field,” he said.
John Alexander, MD, also from Duke University, said: “There were clinically important reductions in bleeding with both doses of abelacimab, compared with rivaroxaban. This is consistent to what we’ve seen with comparisons between other factor XI inhibitors and other factor Xa inhibitors.”
On the exploratory efficacy results, Dr. Alexander agreed with Dr. Ruff that it was not possible to get any idea of how abelacimab compared with rivaroxaban in reducing stroke. “The hazard ratio and confidence intervals comparing abelacimab and rivaroxaban include substantial lower rates, no difference, and substantially higher rates,” he noted.
“We need to wait for the results of phase 3 trials, with abelacimab and other factor XI inhibitors, to understand how well factor XI inhibition prevents stroke and systemic embolism in patients with atrial fibrillation,” Dr. Alexander added. “These trials are ongoing.”
Dr. Ruff concluded: “Assuming the data from ongoing phase 3 trials confirm the benefit of factor XI inhibitors for stroke prevention in people with AF, it will really be transformative for the field of cardiology.
“Our first mission in treating people with AF is to prevent stroke, and our ability to do this with a remarkably safe anticoagulant such as abelacimab would be an incredible advance,” he concluded.
Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AF executive committee for BMS/Janssen (milvexian), and has been on an advisory board for Bayer (asundexian). Dr. Patel has received grants from and acts as an advisor to Bayer and Janssen. Dr. Alexander receives research funding from Bayer.
A version of this article first appeared on Medscape.com.
FROM AHA 2023
Atrial fibrillation linked to dementia, especially when diagnosed before age 65 years
TOPLINE:
Adults with atrial fibrillation (AFib) are at increased risk for dementia, especially when AFib occurs before age 65 years, new research shows. Investigators note the findings highlight the importance of monitoring cognitive function in adults with AF.
METHODOLOGY:
- This prospective, population-based cohort study leveraged data from 433,746 UK Biobank participants (55% women), including 30,601 with AFib, who were followed for a median of 12.6 years
- Incident cases of dementia were determined through linkage from multiple databases.
- Cox proportional hazards models and propensity score matching were used to estimate the association between age at onset of AFib and incident dementia.
TAKEAWAY:
- During follow-up, new-onset dementia occurred in 5,898 participants (2,546 with Alzheimer’s disease [AD] and 1,211 with vascular dementia [VD]), of which, 1,031 had AFib (350 with AD; 320 with VD).
- Compared with participants without AFib, those with AFib had a 42% higher risk for all-cause dementia (adjusted hazard ratio, 1.42; P < .001) and more than double the risk for VD (aHR, 2.06; P < .001), but no significantly higher risk for AD.
- Younger age at AFib onset was associated with higher risks for all-cause dementia, AD and VD, with aHRs per 10-year decrease of 1.23, 1.27, and 1.35, respectively (P < .001 for all).
- After propensity score matching, AFib onset before age 65 years had the highest risk for all-cause dementia (aHR, 1.82; P < .001), followed by AF onset at age 65-74 years (aHR, 1.47; P < .001). Similar results were seen in AD and VD.
IN PRACTICE:
“The findings indicate that careful monitoring of cognitive function for patients with a younger [AFib] onset age, particularly those diagnosed with [AFib] before age 65 years, is important to attenuate the risk of subsequent dementia,” the authors write.
SOURCE:
The study, with first author Wenya Zhang, with the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, was published online in JAMA Network Open.
LIMITATIONS:
Because the study was observational, a cause-effect relationship cannot be established. Despite the adjustment for many underlying confounders, residual unidentified confounders may still exist. The vast majority of participants were White. The analyses did not consider the potential impact of effective treatment of AFib on dementia risk.
DISCLOSURES:
The study had no commercial funding. The authors have declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Adults with atrial fibrillation (AFib) are at increased risk for dementia, especially when AFib occurs before age 65 years, new research shows. Investigators note the findings highlight the importance of monitoring cognitive function in adults with AF.
METHODOLOGY:
- This prospective, population-based cohort study leveraged data from 433,746 UK Biobank participants (55% women), including 30,601 with AFib, who were followed for a median of 12.6 years
- Incident cases of dementia were determined through linkage from multiple databases.
- Cox proportional hazards models and propensity score matching were used to estimate the association between age at onset of AFib and incident dementia.
TAKEAWAY:
- During follow-up, new-onset dementia occurred in 5,898 participants (2,546 with Alzheimer’s disease [AD] and 1,211 with vascular dementia [VD]), of which, 1,031 had AFib (350 with AD; 320 with VD).
- Compared with participants without AFib, those with AFib had a 42% higher risk for all-cause dementia (adjusted hazard ratio, 1.42; P < .001) and more than double the risk for VD (aHR, 2.06; P < .001), but no significantly higher risk for AD.
- Younger age at AFib onset was associated with higher risks for all-cause dementia, AD and VD, with aHRs per 10-year decrease of 1.23, 1.27, and 1.35, respectively (P < .001 for all).
- After propensity score matching, AFib onset before age 65 years had the highest risk for all-cause dementia (aHR, 1.82; P < .001), followed by AF onset at age 65-74 years (aHR, 1.47; P < .001). Similar results were seen in AD and VD.
IN PRACTICE:
“The findings indicate that careful monitoring of cognitive function for patients with a younger [AFib] onset age, particularly those diagnosed with [AFib] before age 65 years, is important to attenuate the risk of subsequent dementia,” the authors write.
SOURCE:
The study, with first author Wenya Zhang, with the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, was published online in JAMA Network Open.
LIMITATIONS:
Because the study was observational, a cause-effect relationship cannot be established. Despite the adjustment for many underlying confounders, residual unidentified confounders may still exist. The vast majority of participants were White. The analyses did not consider the potential impact of effective treatment of AFib on dementia risk.
DISCLOSURES:
The study had no commercial funding. The authors have declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Adults with atrial fibrillation (AFib) are at increased risk for dementia, especially when AFib occurs before age 65 years, new research shows. Investigators note the findings highlight the importance of monitoring cognitive function in adults with AF.
METHODOLOGY:
- This prospective, population-based cohort study leveraged data from 433,746 UK Biobank participants (55% women), including 30,601 with AFib, who were followed for a median of 12.6 years
- Incident cases of dementia were determined through linkage from multiple databases.
- Cox proportional hazards models and propensity score matching were used to estimate the association between age at onset of AFib and incident dementia.
TAKEAWAY:
- During follow-up, new-onset dementia occurred in 5,898 participants (2,546 with Alzheimer’s disease [AD] and 1,211 with vascular dementia [VD]), of which, 1,031 had AFib (350 with AD; 320 with VD).
- Compared with participants without AFib, those with AFib had a 42% higher risk for all-cause dementia (adjusted hazard ratio, 1.42; P < .001) and more than double the risk for VD (aHR, 2.06; P < .001), but no significantly higher risk for AD.
- Younger age at AFib onset was associated with higher risks for all-cause dementia, AD and VD, with aHRs per 10-year decrease of 1.23, 1.27, and 1.35, respectively (P < .001 for all).
- After propensity score matching, AFib onset before age 65 years had the highest risk for all-cause dementia (aHR, 1.82; P < .001), followed by AF onset at age 65-74 years (aHR, 1.47; P < .001). Similar results were seen in AD and VD.
IN PRACTICE:
“The findings indicate that careful monitoring of cognitive function for patients with a younger [AFib] onset age, particularly those diagnosed with [AFib] before age 65 years, is important to attenuate the risk of subsequent dementia,” the authors write.
SOURCE:
The study, with first author Wenya Zhang, with the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, was published online in JAMA Network Open.
LIMITATIONS:
Because the study was observational, a cause-effect relationship cannot be established. Despite the adjustment for many underlying confounders, residual unidentified confounders may still exist. The vast majority of participants were White. The analyses did not consider the potential impact of effective treatment of AFib on dementia risk.
DISCLOSURES:
The study had no commercial funding. The authors have declared no conflicts of interest.
A version of this article appeared on Medscape.com.
Blood pressure lowering reduces dementia risk
Results of a trial using an intensive, 4-year program aimed at blood pressure lowering showed that intervention reduced not only blood pressure, but also significantly reduced the risk of total dementia over that period.
and cognitive impairment no dementia (CIND), a secondary outcome, was also significantly reduced by 16%.
“Blood pressure reduction is effective in reducing the risk of dementia in patients with hypertension,” concluded Jiang He, MD, PhD, professor of epidemiology and medicine and director of Tulane University’s Translational Science Institute, New Orleans. “This proven, effective intervention should be widely scaled up to reduce the global burden of dementia.”
He presented these results from the China Rural Hypertension Control Project (CRHCP) at the annual scientific sessions of the American Heart Association.
Target organ damage
Keith Ferdinand, MD, also from Tulane University, commented on the findings during a press conference at the meeting, noting that the result “opens our opportunity to recognize that the target organ damage of hypertension also now includes dementia.”
The researchers were able to “rigorously lower blood pressure from 157 to 127.6 in the intervention, 155 to 147 in the controls – 22 mg Hg – and if you look at the P values for all the various outcomes, they were very robust,” Dr. Ferdinand said.
Another interesting feature about the strategy used in this trial is that “this was true team-based care,” he pointed out. The trained interventionists in the study, called village doctors, collaborated with primary care physicians and initiated medications. “They stayed on a simple treatment protocol, and they were able to assist patients to ensure they had free medications, health coaching for lifestyle, home blood pressure measurement, and ensuring adherence.”
So, Dr. Ferdinand added, “one of the questions is whether this is a model we can use in other places around the globe, in places with low resources, and in the United States in disadvantaged populations.”
Public health priority
It’s estimated that the global number of those living with dementia will increase from 57.4 million in 2019 to 152.8 million by 2050, Dr. He said. “In the absence of curative treatment, the primary prevention of dementia through risk factor reduction, such as blood pressure lowering, becomes a public health priority.”
Previous randomized trials have lacked sample size and duration but have reported a nonsignificant reduction in dementia associated with antihypertensive treatment in patients with hypertension or a history of stroke, Dr. He noted.
This new trial aimed to test the effectiveness of intensive BP intervention to reduce the risk of all-cause dementia and cognitive impairment over a 48-month intervention period versus usual care.
It was an open-label, blinded-endpoint, cluster-randomized trial, and included 33,995 individual patients from 325 villages in China, aged 40 years and older, with untreated hypertension. The villages were randomly assigned to an intervention group or usual care, stratified by province, county, and township.
Patients were eligible if they had mean untreated systolic BP greater than 140 mm Hg and/or diastolic BP greater than 90 mm Hg or mean treated systolic BP of greater than 130 and/or diastolic greater than 80 mm Hg. Patients with a history of cardiovascular disease, chronic kidney disease, or diabetes and a mean systolic BP greater than 130 mm Hg and/or diastolic BP greater than 80 mm Hg from six measures on two different days were also eligible.
All were enrolled in the China New Rural Cooperative Medical Scheme, which covers 99% of rural residents for health care services, Dr. He noted.
The intervention was a simple stepped-care protocol for hypertension treatment, aimed at achieving a target systolic BP of less than 130 mm Hg and diastolic of less than 80 mm Hg.
Village doctors started and titrated antihypertensive treatment based on a protocol and were able to deliver discounted and free medications to patients. They also did health coaching on lifestyle modification and adherence to medication, and instructed patients on home BP monitoring.
Patients were provided training, supervision, and consultation by primary care physicians and hypertension specialists.
At the month 48 follow-up visit, the participants were assessed by neurologists who were blinded to randomization assignments. Neurologists did a variety of tests and assessments including collecting data on the patient’s medical and psychiatric history and risk factors for dementia, as well as neurologic assessment using the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Quick Dementia Rating System.
The primary outcome was all-cause dementia, defined according to recommendations from the National Institute on Aging–Alzheimer’s Association work groups on diagnostic guidelines for Alzheimer’s disease.
Secondary outcomes included CIND, a composite outcome of dementia or CIND, and a composite of dementia or deaths.
The final diagnosis of all-cause dementia or CIND was made by an expert adjudication panel blinded to the intervention assignment.
At 48 months, 91.3% of patients completed the follow-up for clinical outcomes. Participants were an average of 63 years of age, 61% were female, and 23% had less than a primary school education, Dr. He noted.
The net group differences in systolic and diastolic BP reduction were 22 and 9.3 mm Hg, respectively (P < .0001).
Significant differences were also seen between the groups in the primary outcome of all-cause dementia, as well as secondary outcomes of CIND, dementia or cognitive impairment, or dementia or deaths.
Serious adverse events were more common in the usual care group, and there was no difference between groups in the occurrence of falls or syncope.
The effect was consistent across subgroups, Dr. He said, including age, sex, education, cigarette smoking, body mass index, systolic BP, and fasting plasma glucose at baseline.
First definitive evidence
Invited discussant for the trial, Daniel W. Jones, MD, University of Mississippi Medical Center, Jackson, and past president of the AHA, pointed out that previous results from CRHCP on cardiovascular outcomes, reported earlier in 2023 in The Lancet, showed that, similar to results of the large SPRINT trial, lowering systolic BP to a goal of less than 130 mm Hg reduced a composite endpoint of MI, stroke, heart failure requiring hospitalization, and cardiovascular disease death over the 36-month follow-up.
The SPRINT findings also suggested a possible reduction in dementia, Dr. Jones said.
Now, in these new CRHCP results, “there was a clear benefit for intensive BP control in reducing risk for dementia and cognitive dysfunction,” he said. “This is, importantly, the first definitive evidence of dementia risk reduction demonstrated in a randomized controlled clinical trial. This outcome supports observational data that shows a strong relationship between BP and dementia.”
Since it is the first of its kind though, replication of the results will be important, he noted.
The study also showed that the intervention, using minimally trained village doctors, sustained BP control for 48 months. “This model could be used in any setting with modifications, including in the United States,” Dr. Jones said.
The study was supported by the Ministry of Science and Technology of China; U.S. investigators did not receive financial support from this study. The researchers and Dr. Jones disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Results of a trial using an intensive, 4-year program aimed at blood pressure lowering showed that intervention reduced not only blood pressure, but also significantly reduced the risk of total dementia over that period.
and cognitive impairment no dementia (CIND), a secondary outcome, was also significantly reduced by 16%.
“Blood pressure reduction is effective in reducing the risk of dementia in patients with hypertension,” concluded Jiang He, MD, PhD, professor of epidemiology and medicine and director of Tulane University’s Translational Science Institute, New Orleans. “This proven, effective intervention should be widely scaled up to reduce the global burden of dementia.”
He presented these results from the China Rural Hypertension Control Project (CRHCP) at the annual scientific sessions of the American Heart Association.
Target organ damage
Keith Ferdinand, MD, also from Tulane University, commented on the findings during a press conference at the meeting, noting that the result “opens our opportunity to recognize that the target organ damage of hypertension also now includes dementia.”
The researchers were able to “rigorously lower blood pressure from 157 to 127.6 in the intervention, 155 to 147 in the controls – 22 mg Hg – and if you look at the P values for all the various outcomes, they were very robust,” Dr. Ferdinand said.
Another interesting feature about the strategy used in this trial is that “this was true team-based care,” he pointed out. The trained interventionists in the study, called village doctors, collaborated with primary care physicians and initiated medications. “They stayed on a simple treatment protocol, and they were able to assist patients to ensure they had free medications, health coaching for lifestyle, home blood pressure measurement, and ensuring adherence.”
So, Dr. Ferdinand added, “one of the questions is whether this is a model we can use in other places around the globe, in places with low resources, and in the United States in disadvantaged populations.”
Public health priority
It’s estimated that the global number of those living with dementia will increase from 57.4 million in 2019 to 152.8 million by 2050, Dr. He said. “In the absence of curative treatment, the primary prevention of dementia through risk factor reduction, such as blood pressure lowering, becomes a public health priority.”
Previous randomized trials have lacked sample size and duration but have reported a nonsignificant reduction in dementia associated with antihypertensive treatment in patients with hypertension or a history of stroke, Dr. He noted.
This new trial aimed to test the effectiveness of intensive BP intervention to reduce the risk of all-cause dementia and cognitive impairment over a 48-month intervention period versus usual care.
It was an open-label, blinded-endpoint, cluster-randomized trial, and included 33,995 individual patients from 325 villages in China, aged 40 years and older, with untreated hypertension. The villages were randomly assigned to an intervention group or usual care, stratified by province, county, and township.
Patients were eligible if they had mean untreated systolic BP greater than 140 mm Hg and/or diastolic BP greater than 90 mm Hg or mean treated systolic BP of greater than 130 and/or diastolic greater than 80 mm Hg. Patients with a history of cardiovascular disease, chronic kidney disease, or diabetes and a mean systolic BP greater than 130 mm Hg and/or diastolic BP greater than 80 mm Hg from six measures on two different days were also eligible.
All were enrolled in the China New Rural Cooperative Medical Scheme, which covers 99% of rural residents for health care services, Dr. He noted.
The intervention was a simple stepped-care protocol for hypertension treatment, aimed at achieving a target systolic BP of less than 130 mm Hg and diastolic of less than 80 mm Hg.
Village doctors started and titrated antihypertensive treatment based on a protocol and were able to deliver discounted and free medications to patients. They also did health coaching on lifestyle modification and adherence to medication, and instructed patients on home BP monitoring.
Patients were provided training, supervision, and consultation by primary care physicians and hypertension specialists.
At the month 48 follow-up visit, the participants were assessed by neurologists who were blinded to randomization assignments. Neurologists did a variety of tests and assessments including collecting data on the patient’s medical and psychiatric history and risk factors for dementia, as well as neurologic assessment using the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Quick Dementia Rating System.
The primary outcome was all-cause dementia, defined according to recommendations from the National Institute on Aging–Alzheimer’s Association work groups on diagnostic guidelines for Alzheimer’s disease.
Secondary outcomes included CIND, a composite outcome of dementia or CIND, and a composite of dementia or deaths.
The final diagnosis of all-cause dementia or CIND was made by an expert adjudication panel blinded to the intervention assignment.
At 48 months, 91.3% of patients completed the follow-up for clinical outcomes. Participants were an average of 63 years of age, 61% were female, and 23% had less than a primary school education, Dr. He noted.
The net group differences in systolic and diastolic BP reduction were 22 and 9.3 mm Hg, respectively (P < .0001).
Significant differences were also seen between the groups in the primary outcome of all-cause dementia, as well as secondary outcomes of CIND, dementia or cognitive impairment, or dementia or deaths.
Serious adverse events were more common in the usual care group, and there was no difference between groups in the occurrence of falls or syncope.
The effect was consistent across subgroups, Dr. He said, including age, sex, education, cigarette smoking, body mass index, systolic BP, and fasting plasma glucose at baseline.
First definitive evidence
Invited discussant for the trial, Daniel W. Jones, MD, University of Mississippi Medical Center, Jackson, and past president of the AHA, pointed out that previous results from CRHCP on cardiovascular outcomes, reported earlier in 2023 in The Lancet, showed that, similar to results of the large SPRINT trial, lowering systolic BP to a goal of less than 130 mm Hg reduced a composite endpoint of MI, stroke, heart failure requiring hospitalization, and cardiovascular disease death over the 36-month follow-up.
The SPRINT findings also suggested a possible reduction in dementia, Dr. Jones said.
Now, in these new CRHCP results, “there was a clear benefit for intensive BP control in reducing risk for dementia and cognitive dysfunction,” he said. “This is, importantly, the first definitive evidence of dementia risk reduction demonstrated in a randomized controlled clinical trial. This outcome supports observational data that shows a strong relationship between BP and dementia.”
Since it is the first of its kind though, replication of the results will be important, he noted.
The study also showed that the intervention, using minimally trained village doctors, sustained BP control for 48 months. “This model could be used in any setting with modifications, including in the United States,” Dr. Jones said.
The study was supported by the Ministry of Science and Technology of China; U.S. investigators did not receive financial support from this study. The researchers and Dr. Jones disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Results of a trial using an intensive, 4-year program aimed at blood pressure lowering showed that intervention reduced not only blood pressure, but also significantly reduced the risk of total dementia over that period.
and cognitive impairment no dementia (CIND), a secondary outcome, was also significantly reduced by 16%.
“Blood pressure reduction is effective in reducing the risk of dementia in patients with hypertension,” concluded Jiang He, MD, PhD, professor of epidemiology and medicine and director of Tulane University’s Translational Science Institute, New Orleans. “This proven, effective intervention should be widely scaled up to reduce the global burden of dementia.”
He presented these results from the China Rural Hypertension Control Project (CRHCP) at the annual scientific sessions of the American Heart Association.
Target organ damage
Keith Ferdinand, MD, also from Tulane University, commented on the findings during a press conference at the meeting, noting that the result “opens our opportunity to recognize that the target organ damage of hypertension also now includes dementia.”
The researchers were able to “rigorously lower blood pressure from 157 to 127.6 in the intervention, 155 to 147 in the controls – 22 mg Hg – and if you look at the P values for all the various outcomes, they were very robust,” Dr. Ferdinand said.
Another interesting feature about the strategy used in this trial is that “this was true team-based care,” he pointed out. The trained interventionists in the study, called village doctors, collaborated with primary care physicians and initiated medications. “They stayed on a simple treatment protocol, and they were able to assist patients to ensure they had free medications, health coaching for lifestyle, home blood pressure measurement, and ensuring adherence.”
So, Dr. Ferdinand added, “one of the questions is whether this is a model we can use in other places around the globe, in places with low resources, and in the United States in disadvantaged populations.”
Public health priority
It’s estimated that the global number of those living with dementia will increase from 57.4 million in 2019 to 152.8 million by 2050, Dr. He said. “In the absence of curative treatment, the primary prevention of dementia through risk factor reduction, such as blood pressure lowering, becomes a public health priority.”
Previous randomized trials have lacked sample size and duration but have reported a nonsignificant reduction in dementia associated with antihypertensive treatment in patients with hypertension or a history of stroke, Dr. He noted.
This new trial aimed to test the effectiveness of intensive BP intervention to reduce the risk of all-cause dementia and cognitive impairment over a 48-month intervention period versus usual care.
It was an open-label, blinded-endpoint, cluster-randomized trial, and included 33,995 individual patients from 325 villages in China, aged 40 years and older, with untreated hypertension. The villages were randomly assigned to an intervention group or usual care, stratified by province, county, and township.
Patients were eligible if they had mean untreated systolic BP greater than 140 mm Hg and/or diastolic BP greater than 90 mm Hg or mean treated systolic BP of greater than 130 and/or diastolic greater than 80 mm Hg. Patients with a history of cardiovascular disease, chronic kidney disease, or diabetes and a mean systolic BP greater than 130 mm Hg and/or diastolic BP greater than 80 mm Hg from six measures on two different days were also eligible.
All were enrolled in the China New Rural Cooperative Medical Scheme, which covers 99% of rural residents for health care services, Dr. He noted.
The intervention was a simple stepped-care protocol for hypertension treatment, aimed at achieving a target systolic BP of less than 130 mm Hg and diastolic of less than 80 mm Hg.
Village doctors started and titrated antihypertensive treatment based on a protocol and were able to deliver discounted and free medications to patients. They also did health coaching on lifestyle modification and adherence to medication, and instructed patients on home BP monitoring.
Patients were provided training, supervision, and consultation by primary care physicians and hypertension specialists.
At the month 48 follow-up visit, the participants were assessed by neurologists who were blinded to randomization assignments. Neurologists did a variety of tests and assessments including collecting data on the patient’s medical and psychiatric history and risk factors for dementia, as well as neurologic assessment using the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Quick Dementia Rating System.
The primary outcome was all-cause dementia, defined according to recommendations from the National Institute on Aging–Alzheimer’s Association work groups on diagnostic guidelines for Alzheimer’s disease.
Secondary outcomes included CIND, a composite outcome of dementia or CIND, and a composite of dementia or deaths.
The final diagnosis of all-cause dementia or CIND was made by an expert adjudication panel blinded to the intervention assignment.
At 48 months, 91.3% of patients completed the follow-up for clinical outcomes. Participants were an average of 63 years of age, 61% were female, and 23% had less than a primary school education, Dr. He noted.
The net group differences in systolic and diastolic BP reduction were 22 and 9.3 mm Hg, respectively (P < .0001).
Significant differences were also seen between the groups in the primary outcome of all-cause dementia, as well as secondary outcomes of CIND, dementia or cognitive impairment, or dementia or deaths.
Serious adverse events were more common in the usual care group, and there was no difference between groups in the occurrence of falls or syncope.
The effect was consistent across subgroups, Dr. He said, including age, sex, education, cigarette smoking, body mass index, systolic BP, and fasting plasma glucose at baseline.
First definitive evidence
Invited discussant for the trial, Daniel W. Jones, MD, University of Mississippi Medical Center, Jackson, and past president of the AHA, pointed out that previous results from CRHCP on cardiovascular outcomes, reported earlier in 2023 in The Lancet, showed that, similar to results of the large SPRINT trial, lowering systolic BP to a goal of less than 130 mm Hg reduced a composite endpoint of MI, stroke, heart failure requiring hospitalization, and cardiovascular disease death over the 36-month follow-up.
The SPRINT findings also suggested a possible reduction in dementia, Dr. Jones said.
Now, in these new CRHCP results, “there was a clear benefit for intensive BP control in reducing risk for dementia and cognitive dysfunction,” he said. “This is, importantly, the first definitive evidence of dementia risk reduction demonstrated in a randomized controlled clinical trial. This outcome supports observational data that shows a strong relationship between BP and dementia.”
Since it is the first of its kind though, replication of the results will be important, he noted.
The study also showed that the intervention, using minimally trained village doctors, sustained BP control for 48 months. “This model could be used in any setting with modifications, including in the United States,” Dr. Jones said.
The study was supported by the Ministry of Science and Technology of China; U.S. investigators did not receive financial support from this study. The researchers and Dr. Jones disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM AHA 2023
Classification identifies four stages of heart attack
Relying on more than 50 years of data on acute MI with reperfusion therapy, the society has identified the following four stages of progressively worsening myocardial tissue injury:
- Aborted MI (no or minimal myocardial necrosis).
- MI with significant cardiomyocyte necrosis but without microvascular injury.
- Cardiomyocyte necrosis and microvascular dysfunction leading to microvascular obstruction (that is, “no reflow”).
- Cardiomyocyte and microvascular necrosis leading to reperfusion hemorrhage.
The classification is described in an expert consensus statement that was published in the Canadian Journal of Cardiology.
The new classification will allow for better risk stratification and more appropriate treatment and provide refined endpoints for clinical trials and translational research, according to the authors.
Currently, all patients with acute MI receive the same treatment, even though they may have different levels of tissue injury severity, statement author Andreas Kumar, MD, chair of the writing group and associate professor of medicine at Northern Ontario School of Medicine University, Sudbury, said in an interview.
“In some cases, treatment for a mild stage 1 acute MI may be deadly for someone with stage 4 hemorrhagic MI,” said Dr. Kumar.
Technological advances
The classification is based on decades of data. “The initial data were obtained with pathology studies in the 1970s. When cardiac MRI came around, around the year 2000, suddenly there was a noninvasive imaging method where we could investigate patients in vivo,” said Dr. Kumar. “We learned a lot about tissue changes in acute MI. And especially in the last 2 to 5 years, we have learned a lot about hemorrhagic MI. So, this then gave us enough knowledge to come up with this new classification.”
The idea of classifying acute MI came to Dr. Kumar and senior author Rohan Dharmakumar, PhD, executive director of the Krannert Cardiovascular Research Center at Indiana University, Indianapolis, when both were at the University of Toronto.
“This work has been years in the making,” Dr. Dharmakumar said in an interview. “We’ve been thinking about this for a long time, but we needed to get substantial layers of evidence to support the classification. We had a feeling about these stages for a long time, but that feeling needed to be substantiated.”
In 2022, Dr. Dharmakumar and Dr. Kumar observed that damage to the heart from MI was not only a result of ischemia caused by a blocked artery, but also a result of bleeding in the myocardium after the artery had been opened. Their findings were published in the Journal of the American College of Cardiology.
The author of an accompanying editorial lauded the investigators “for providing new, mechanistic insights into a difficult clinical problem that has an unmet therapeutic need.”
“Hemorrhagic MI is a very dangerous injury because hemorrhage itself causes a lot of problems,” said Dr. Kumar. “We reported that there is infarct expansion after reperfusion, so once you open up the vessel, the heart attack actually gets larger. We also showed that the remodeling of these hearts is worse. These patients take a second hit with hemorrhage occurring in the myocardium.”
Classification and staging
“The standard guideline therapy for somebody who comes into the hospital is to put in a stent, open the artery, have the patient stay in the hospital for 48-72 hours, and then be released home,” said Dr. Dharmukumar. “But here’s the problem. These two patients who are going back home have different levels of injury, yet they are taking the same medications. Even inside the hospital, we have heterogeneity in mortality risk. But we are not paying attention to one patient differently than the other, even though we should, because their injuries are very different.”
The CCS classification may provide endpoints and outcome measures beyond the commonly used clinical markers, which could lead to improved treatments to help patients recover from their cardiac events.
“We have this issue of rampant heart failure in acute MI survivors. We’ve gotten really good at saving patients from immediate death, but now we are just postponing some of the serious problems survivors are going to face, said Dr. Dharmukumar. “What are we doing for these patients who are really at risk? We’ve been treating every single patient the same way and we have not been paying attention to the very different stages of injury.”
In an accompanying editorial, Prakriti Gaba, MD, a clinical fellow in medicine at Brigham and Women’s Hospital, Boston, and Deepak L. Bhatt, MD, MPH, director of the Mount Sinai Fuster Heart Hospital, New York, wrote: “There is no doubt that the classification system proposed by the investigators is important and timely, as acute MI continues to account for substantial morbidity and mortality worldwide.”
Imaging and staging could be useful in guiding appropriate therapy, Bhatt said in an interview. “The authors’ hope, which I think is a very laudable one, is that more finely characterizing exactly what the extent of damage is and what the mechanism of damage is in a heart attack will make it possible to develop therapies that are particularly targeted to each of the stages,” he said.
“It is quite common to have the ability to do cardiac MRI at experienced cardiovascular centers, although this may not be true for smaller community hospitals,” Dr. Bhatt added. “But at least at larger hospitals, this will allow for much finer evaluation and assessment of exactly what is going on in that particular patient and how extensive the heart muscle damage is. Eventually, this will facilitate the development of therapies that are specifically targeted to treat each stage.”
Dr. Kumar is partly supported by a research grant from the Northern Ontario Academic Medicine Association. Dr. Dharmakumar was funded in part by grants from the U.S. National Institutes of Health. Dr. Dharmakumar has an ownership interest in Cardio-Theranostics. Dr. Bhatt has served on advisory boards for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys. He is a member of the board of directors of or holds stock in Angiowave, Boston VA Research Institute, Bristol-Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft. He has worked as a consultant for Broadview Ventures, and Hims. He has received honoraria from the American College of Cardiology, Arnold and Porter law firm, Baim Institute for Clinical Research, Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, and Wiley.
A version of this article appeared on Medscape.com.
Relying on more than 50 years of data on acute MI with reperfusion therapy, the society has identified the following four stages of progressively worsening myocardial tissue injury:
- Aborted MI (no or minimal myocardial necrosis).
- MI with significant cardiomyocyte necrosis but without microvascular injury.
- Cardiomyocyte necrosis and microvascular dysfunction leading to microvascular obstruction (that is, “no reflow”).
- Cardiomyocyte and microvascular necrosis leading to reperfusion hemorrhage.
The classification is described in an expert consensus statement that was published in the Canadian Journal of Cardiology.
The new classification will allow for better risk stratification and more appropriate treatment and provide refined endpoints for clinical trials and translational research, according to the authors.
Currently, all patients with acute MI receive the same treatment, even though they may have different levels of tissue injury severity, statement author Andreas Kumar, MD, chair of the writing group and associate professor of medicine at Northern Ontario School of Medicine University, Sudbury, said in an interview.
“In some cases, treatment for a mild stage 1 acute MI may be deadly for someone with stage 4 hemorrhagic MI,” said Dr. Kumar.
Technological advances
The classification is based on decades of data. “The initial data were obtained with pathology studies in the 1970s. When cardiac MRI came around, around the year 2000, suddenly there was a noninvasive imaging method where we could investigate patients in vivo,” said Dr. Kumar. “We learned a lot about tissue changes in acute MI. And especially in the last 2 to 5 years, we have learned a lot about hemorrhagic MI. So, this then gave us enough knowledge to come up with this new classification.”
The idea of classifying acute MI came to Dr. Kumar and senior author Rohan Dharmakumar, PhD, executive director of the Krannert Cardiovascular Research Center at Indiana University, Indianapolis, when both were at the University of Toronto.
“This work has been years in the making,” Dr. Dharmakumar said in an interview. “We’ve been thinking about this for a long time, but we needed to get substantial layers of evidence to support the classification. We had a feeling about these stages for a long time, but that feeling needed to be substantiated.”
In 2022, Dr. Dharmakumar and Dr. Kumar observed that damage to the heart from MI was not only a result of ischemia caused by a blocked artery, but also a result of bleeding in the myocardium after the artery had been opened. Their findings were published in the Journal of the American College of Cardiology.
The author of an accompanying editorial lauded the investigators “for providing new, mechanistic insights into a difficult clinical problem that has an unmet therapeutic need.”
“Hemorrhagic MI is a very dangerous injury because hemorrhage itself causes a lot of problems,” said Dr. Kumar. “We reported that there is infarct expansion after reperfusion, so once you open up the vessel, the heart attack actually gets larger. We also showed that the remodeling of these hearts is worse. These patients take a second hit with hemorrhage occurring in the myocardium.”
Classification and staging
“The standard guideline therapy for somebody who comes into the hospital is to put in a stent, open the artery, have the patient stay in the hospital for 48-72 hours, and then be released home,” said Dr. Dharmukumar. “But here’s the problem. These two patients who are going back home have different levels of injury, yet they are taking the same medications. Even inside the hospital, we have heterogeneity in mortality risk. But we are not paying attention to one patient differently than the other, even though we should, because their injuries are very different.”
The CCS classification may provide endpoints and outcome measures beyond the commonly used clinical markers, which could lead to improved treatments to help patients recover from their cardiac events.
“We have this issue of rampant heart failure in acute MI survivors. We’ve gotten really good at saving patients from immediate death, but now we are just postponing some of the serious problems survivors are going to face, said Dr. Dharmukumar. “What are we doing for these patients who are really at risk? We’ve been treating every single patient the same way and we have not been paying attention to the very different stages of injury.”
In an accompanying editorial, Prakriti Gaba, MD, a clinical fellow in medicine at Brigham and Women’s Hospital, Boston, and Deepak L. Bhatt, MD, MPH, director of the Mount Sinai Fuster Heart Hospital, New York, wrote: “There is no doubt that the classification system proposed by the investigators is important and timely, as acute MI continues to account for substantial morbidity and mortality worldwide.”
Imaging and staging could be useful in guiding appropriate therapy, Bhatt said in an interview. “The authors’ hope, which I think is a very laudable one, is that more finely characterizing exactly what the extent of damage is and what the mechanism of damage is in a heart attack will make it possible to develop therapies that are particularly targeted to each of the stages,” he said.
“It is quite common to have the ability to do cardiac MRI at experienced cardiovascular centers, although this may not be true for smaller community hospitals,” Dr. Bhatt added. “But at least at larger hospitals, this will allow for much finer evaluation and assessment of exactly what is going on in that particular patient and how extensive the heart muscle damage is. Eventually, this will facilitate the development of therapies that are specifically targeted to treat each stage.”
Dr. Kumar is partly supported by a research grant from the Northern Ontario Academic Medicine Association. Dr. Dharmakumar was funded in part by grants from the U.S. National Institutes of Health. Dr. Dharmakumar has an ownership interest in Cardio-Theranostics. Dr. Bhatt has served on advisory boards for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys. He is a member of the board of directors of or holds stock in Angiowave, Boston VA Research Institute, Bristol-Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft. He has worked as a consultant for Broadview Ventures, and Hims. He has received honoraria from the American College of Cardiology, Arnold and Porter law firm, Baim Institute for Clinical Research, Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, and Wiley.
A version of this article appeared on Medscape.com.
Relying on more than 50 years of data on acute MI with reperfusion therapy, the society has identified the following four stages of progressively worsening myocardial tissue injury:
- Aborted MI (no or minimal myocardial necrosis).
- MI with significant cardiomyocyte necrosis but without microvascular injury.
- Cardiomyocyte necrosis and microvascular dysfunction leading to microvascular obstruction (that is, “no reflow”).
- Cardiomyocyte and microvascular necrosis leading to reperfusion hemorrhage.
The classification is described in an expert consensus statement that was published in the Canadian Journal of Cardiology.
The new classification will allow for better risk stratification and more appropriate treatment and provide refined endpoints for clinical trials and translational research, according to the authors.
Currently, all patients with acute MI receive the same treatment, even though they may have different levels of tissue injury severity, statement author Andreas Kumar, MD, chair of the writing group and associate professor of medicine at Northern Ontario School of Medicine University, Sudbury, said in an interview.
“In some cases, treatment for a mild stage 1 acute MI may be deadly for someone with stage 4 hemorrhagic MI,” said Dr. Kumar.
Technological advances
The classification is based on decades of data. “The initial data were obtained with pathology studies in the 1970s. When cardiac MRI came around, around the year 2000, suddenly there was a noninvasive imaging method where we could investigate patients in vivo,” said Dr. Kumar. “We learned a lot about tissue changes in acute MI. And especially in the last 2 to 5 years, we have learned a lot about hemorrhagic MI. So, this then gave us enough knowledge to come up with this new classification.”
The idea of classifying acute MI came to Dr. Kumar and senior author Rohan Dharmakumar, PhD, executive director of the Krannert Cardiovascular Research Center at Indiana University, Indianapolis, when both were at the University of Toronto.
“This work has been years in the making,” Dr. Dharmakumar said in an interview. “We’ve been thinking about this for a long time, but we needed to get substantial layers of evidence to support the classification. We had a feeling about these stages for a long time, but that feeling needed to be substantiated.”
In 2022, Dr. Dharmakumar and Dr. Kumar observed that damage to the heart from MI was not only a result of ischemia caused by a blocked artery, but also a result of bleeding in the myocardium after the artery had been opened. Their findings were published in the Journal of the American College of Cardiology.
The author of an accompanying editorial lauded the investigators “for providing new, mechanistic insights into a difficult clinical problem that has an unmet therapeutic need.”
“Hemorrhagic MI is a very dangerous injury because hemorrhage itself causes a lot of problems,” said Dr. Kumar. “We reported that there is infarct expansion after reperfusion, so once you open up the vessel, the heart attack actually gets larger. We also showed that the remodeling of these hearts is worse. These patients take a second hit with hemorrhage occurring in the myocardium.”
Classification and staging
“The standard guideline therapy for somebody who comes into the hospital is to put in a stent, open the artery, have the patient stay in the hospital for 48-72 hours, and then be released home,” said Dr. Dharmukumar. “But here’s the problem. These two patients who are going back home have different levels of injury, yet they are taking the same medications. Even inside the hospital, we have heterogeneity in mortality risk. But we are not paying attention to one patient differently than the other, even though we should, because their injuries are very different.”
The CCS classification may provide endpoints and outcome measures beyond the commonly used clinical markers, which could lead to improved treatments to help patients recover from their cardiac events.
“We have this issue of rampant heart failure in acute MI survivors. We’ve gotten really good at saving patients from immediate death, but now we are just postponing some of the serious problems survivors are going to face, said Dr. Dharmukumar. “What are we doing for these patients who are really at risk? We’ve been treating every single patient the same way and we have not been paying attention to the very different stages of injury.”
In an accompanying editorial, Prakriti Gaba, MD, a clinical fellow in medicine at Brigham and Women’s Hospital, Boston, and Deepak L. Bhatt, MD, MPH, director of the Mount Sinai Fuster Heart Hospital, New York, wrote: “There is no doubt that the classification system proposed by the investigators is important and timely, as acute MI continues to account for substantial morbidity and mortality worldwide.”
Imaging and staging could be useful in guiding appropriate therapy, Bhatt said in an interview. “The authors’ hope, which I think is a very laudable one, is that more finely characterizing exactly what the extent of damage is and what the mechanism of damage is in a heart attack will make it possible to develop therapies that are particularly targeted to each of the stages,” he said.
“It is quite common to have the ability to do cardiac MRI at experienced cardiovascular centers, although this may not be true for smaller community hospitals,” Dr. Bhatt added. “But at least at larger hospitals, this will allow for much finer evaluation and assessment of exactly what is going on in that particular patient and how extensive the heart muscle damage is. Eventually, this will facilitate the development of therapies that are specifically targeted to treat each stage.”
Dr. Kumar is partly supported by a research grant from the Northern Ontario Academic Medicine Association. Dr. Dharmakumar was funded in part by grants from the U.S. National Institutes of Health. Dr. Dharmakumar has an ownership interest in Cardio-Theranostics. Dr. Bhatt has served on advisory boards for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys. He is a member of the board of directors of or holds stock in Angiowave, Boston VA Research Institute, Bristol-Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft. He has worked as a consultant for Broadview Ventures, and Hims. He has received honoraria from the American College of Cardiology, Arnold and Porter law firm, Baim Institute for Clinical Research, Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, and Wiley.
A version of this article appeared on Medscape.com.
FROM THE CANADIAN JOURNAL OF CARDIOLOGY
Potential dapagliflozin benefit post MI is not a ‘mandate’
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
AT AHA 2023
Semaglutide ‘a new pathway’ to CVD risk reduction: SELECT
over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.
“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview.
“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.
The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m2 or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.
Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.
The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).
Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.
However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.
The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).
The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.
Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.
The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.
Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity.
“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.
Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.
“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.
On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.
“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”
But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
‘A new era’ for patients with obesity
Outside experts in the field were also impressed with the data.
Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.
“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.
Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.
She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.
Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”
“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.
“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”
Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.
“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”
Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”
Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”
He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”
On the more robust reduction in all-cause death, compared with cardiovascular death,
Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
Effect on clinical practice
With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.
Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”
He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.
“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”
Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
‘A welcome treatment option’
In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.
But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”
However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many.
They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.
The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.
over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.
“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview.
“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.
The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m2 or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.
Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.
The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).
Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.
However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.
The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).
The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.
Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.
The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.
Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity.
“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.
Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.
“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.
On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.
“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”
But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
‘A new era’ for patients with obesity
Outside experts in the field were also impressed with the data.
Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.
“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.
Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.
She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.
Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”
“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.
“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”
Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.
“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”
Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”
Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”
He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”
On the more robust reduction in all-cause death, compared with cardiovascular death,
Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
Effect on clinical practice
With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.
Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”
He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.
“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”
Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
‘A welcome treatment option’
In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.
But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”
However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many.
They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.
The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.
over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.
“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview.
“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.
The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m2 or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.
Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.
The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).
Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.
However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.
The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).
The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.
Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.
The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.
Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity.
“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.
Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.
“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.
On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.
“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”
But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
‘A new era’ for patients with obesity
Outside experts in the field were also impressed with the data.
Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.
“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.
Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.
She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.
Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”
“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.
“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”
Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.
“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”
Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”
Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”
He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”
On the more robust reduction in all-cause death, compared with cardiovascular death,
Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
Effect on clinical practice
With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.
Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”
He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.
“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”
Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
‘A welcome treatment option’
In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.
But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”
However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many.
They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.
The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.
FROM AHA 2023
Does vaginal estrogen use increase the risk for adverse cardiovascular outcomes?
Evidence summary
Cohort studies demonstrate no adverse CV outcomes
A 2020 systematic review and meta-analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.1 The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE1). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use.
Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.2 Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined.
The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.3 The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability.
A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).4 Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.
Recommendations from others
In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.5 They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.
Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.6
A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.7
Editor’s takeaway
The available evidence on vaginal estrogen replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.
1. Kim JE, Chang JH, Jeong MJ, et al. A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases. Sci Rep. 2020;10:20631. doi: 10.1038/s41598-020-77534-9
2. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the WHI Observational Study. Menopause. 2018;25:11-20. doi: 10.1097/GME.0000000000000956
3. Bhupathiraju SN, Grodstein F, Stampfer MJ, et al. Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause. 2018;26:603-610. doi: 10.1097/GME.0000000000001284
4. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Vaginal estrogen use and the risk for cardiovascular mortality. Human Reproduction. 2016;31:804-809. doi: 10.1093/humrep/dew014
5. North American Menopause Society. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
6. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:3975-4011. doi: 10.1210/jc.2015-2236
7. American College of Obstetricians and Gynecologists. Committee Opinion No 565: hormone therapy and heart disease. Obstet Gynecol. 2013;121:1407-1410. doi: 10.1097/01.AOG.0000431053.33593.2d
Evidence summary
Cohort studies demonstrate no adverse CV outcomes
A 2020 systematic review and meta-analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.1 The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE1). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use.
Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.2 Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined.
The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.3 The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability.
A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).4 Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.
Recommendations from others
In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.5 They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.
Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.6
A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.7
Editor’s takeaway
The available evidence on vaginal estrogen replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.
Evidence summary
Cohort studies demonstrate no adverse CV outcomes
A 2020 systematic review and meta-analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.1 The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE1). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use.
Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.2 Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined.
The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.3 The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability.
A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).4 Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.
Recommendations from others
In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.5 They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.
Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.6
A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.7
Editor’s takeaway
The available evidence on vaginal estrogen replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.
1. Kim JE, Chang JH, Jeong MJ, et al. A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases. Sci Rep. 2020;10:20631. doi: 10.1038/s41598-020-77534-9
2. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the WHI Observational Study. Menopause. 2018;25:11-20. doi: 10.1097/GME.0000000000000956
3. Bhupathiraju SN, Grodstein F, Stampfer MJ, et al. Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause. 2018;26:603-610. doi: 10.1097/GME.0000000000001284
4. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Vaginal estrogen use and the risk for cardiovascular mortality. Human Reproduction. 2016;31:804-809. doi: 10.1093/humrep/dew014
5. North American Menopause Society. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
6. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:3975-4011. doi: 10.1210/jc.2015-2236
7. American College of Obstetricians and Gynecologists. Committee Opinion No 565: hormone therapy and heart disease. Obstet Gynecol. 2013;121:1407-1410. doi: 10.1097/01.AOG.0000431053.33593.2d
1. Kim JE, Chang JH, Jeong MJ, et al. A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases. Sci Rep. 2020;10:20631. doi: 10.1038/s41598-020-77534-9
2. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the WHI Observational Study. Menopause. 2018;25:11-20. doi: 10.1097/GME.0000000000000956
3. Bhupathiraju SN, Grodstein F, Stampfer MJ, et al. Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause. 2018;26:603-610. doi: 10.1097/GME.0000000000001284
4. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Vaginal estrogen use and the risk for cardiovascular mortality. Human Reproduction. 2016;31:804-809. doi: 10.1093/humrep/dew014
5. North American Menopause Society. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
6. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:3975-4011. doi: 10.1210/jc.2015-2236
7. American College of Obstetricians and Gynecologists. Committee Opinion No 565: hormone therapy and heart disease. Obstet Gynecol. 2013;121:1407-1410. doi: 10.1097/01.AOG.0000431053.33593.2d
EVIDENCE-BASED ANSWER:
NO. In general, nonoral estrogen use for menopausal symptoms is associated with a lower cardiovascular (CV) risk profile than oral estrogen use (strength of recommendation [SOR], B; meta-analysis of cohort studies). Vaginal estrogen use is associated with lower risk for coronary heart disease (CHD) and similar risk for myocardial infarction (MI), stroke, and deep vein thrombosis/pulmonary embolism (DVT/PE) compared with nonuse (SOR, B; cohort studies). Vaginal estrogen therapy also is associated with lower CV-related mortality for 3 to 5 years compared with nonuse (SOR, B; cohort study). No high-quality randomized trials address this topic.
In MI with anemia, results may favor liberal transfusion: MINT
In patients with myocardial infarction and anemia, a “liberal” red blood cell transfusion strategy did not significantly reduce the risk of recurrent MI or death within 30 days, compared with a “restrictive” transfusion strategy, in the 3,500-patient MINT trial.
Jeffrey L. Carson, MD, from Robert Wood Johnson Medical School, New Brunswick, N.J., said in a press briefing.
He presented the study in a late-breaking trial session at the annual scientific sessions of the American Heart Association, and it was simultaneously published online in the New England Journal of Medicine.
“Whether to transfuse is an everyday decision faced by clinicians caring for patients with acute MI,” Dr. Carson said.
“We cannot claim that a liberal transfusion strategy is definitively superior based on our primary outcome,” he said, but “the 95% confidence interval is consistent with treatment effects corresponding to no difference between the two transfusion strategies and to a clinically relevant benefit with the liberal strategy.”
“In contrast to other trials in other settings,” such as anemia and cardiac surgery, Dr. Carson said, “the results suggest that a liberal transfusion strategy has the potential for clinical benefit with an acceptable risk of harm.”
“A liberal transfusion strategy may be the most prudent approach to transfusion in anemic patients with MI,” he added.
Not a home run
Others agreed with this interpretation. Martin B. Leon, MD, from Columbia University, New York, the study discussant in the press briefing, said the study “addresses a question that is common” in clinical practice. It was well conducted, and international (although most patients were in the United States and Canada), in a very broad group of patients, designed to make the results more generalizable. The 98% follow-up was extremely good, Dr. Leon added, and the trialists achieved their goal in that they did show a difference between the two transfusion strategies.
The number needed to treat was 40 to see a benefit in the combined outcome of death or recurrent MI at 30 days, Dr. Leon said. The P value for this was .07, “right on the edge” of statistical significance.
This study is “not a home run,” for the primary outcome, he noted; however, many of the outcomes tended to be in favor of a liberal transfusion strategy. Notably, cardiovascular death, which was not a specified outcome, was significantly lower in the group who received a liberal transfusion strategy.
Although a liberal transfusion strategy was “not definitely superior” in these patients with MI and anemia, Dr. Carson said, he thinks the trial will be interpreted as favoring a liberal transfusion strategy.
C. Michael Gibson, MD, professor of medicine at Harvard Medical School, Boston, and CEO of Harvard’s Baim and PERFUSE institutes for clinical research, voiced similar views.
“Given the lack of acute harm associated with liberal transfusion and the preponderance of evidence favoring liberal transfusion in the largest trial to date,” concluded Dr. Gibson, the assigned discussant at the session, “liberal transfusion appears to be a viable management strategy, particularly among patients with non-STEMI type 1 MI and as clinical judgment dictates.”
Only three small randomized controlled trials have compared transfusion thresholds in a total of 820 patients with MI and anemia, Dr. Gibson said, a point that the trial investigators also made. The results were inconsistent between trials: the CRIT trial (n = 45) favored a restrictive strategy, the MINT pilot study (n = 110) favored a liberal one, and the REALITY trial (n = 668) showed noninferiority of a restrictive strategy, compared with a liberal strategy in 30-day MACE.
The MINT trial was four times larger than all prior studies combined. However, most outcomes were negative or of borderline significance for benefit.
Cardiac death was more common in the restrictive group at 5.5% than the liberal group at 3.2% (risk ratio, 1.74, 95% CI, 1.26-2.40), but this was nonadjudicated, and not designated as a primary, secondary, or tertiary outcome – which the researchers also noted. Fewer than half of the deaths were classified as cardiac, which was “odd,” Dr. Gibson observed.
A restrictive transfusion strategy was associated with increased events among participants with type 1 MI (RR, 1.32, 95% CI, 1.04-1.67), he noted.
Study strengths included that 45.5% of participants were women, Dr. Gibson said. Limitations included that the trial was “somewhat underpowered.” Also, even in the restrictive group, participants received a mean of 0.7 units of packed red blood cells.
Adherence to the 10 g/dL threshold in the liberal transfusion group was moderate (86.3% at hospital discharge), which the researchers acknowledged. They noted that this was frequently caused by clinical discretion, such as concern about fluid overload, and to the timing of hospital discharge. In addition, long-term potential for harm (microchimerism) is not known.
“There was a consistent nonsignificant acute benefit for liberal transfusion and a nominal reduction in CV mortality and improved outcomes in patients with type 1 MI in exploratory analyses, in a trial that ended up underpowered,” Dr. Gibson summarized. “Long-term follow up would be helpful to evaluate chronic outcomes.”
This is a very well-conducted, high-quality, important study that will be considered a landmark trial, C. David Mazer, MD, University of Toronto and St. Michael’s Hospital, also in Toronto, said in an interview.
Unfortunately, “it was not as definitive as hoped for,” Dr. Mazer lamented. Nevertheless, “I think people may interpret it as providing support for a liberal transfusion strategy” in patients with anemia and MI, he said.
Dr. Mazer, who was not involved with this research, was a principal investigator on the TRICS-3 trial, which disputed a liberal RBC transfusion strategy in patients with anemia undergoing cardiac surgery, as previously reported.
The “Red Blood Cell Transfusion: 2023 AABB International Guidelines,” led by Dr. Carson and published in JAMA, recommend a restrictive strategy in stable patients, although these guidelines did not include the current study, Dr. Mazer observed.
In the REALITY trial, there were fewer major adverse cardiac events (MACE) events in the restrictive strategy, he noted.
MINT can be viewed as comparing a high versus low hemoglobin threshold. “It is possible that the best is in between,” he said.
Dr. Mazer also noted that MINT may have achieved significance if it was designed with a larger enrollment and a higher power (for example, 90% instead of 80%) to detect between-group difference for the primary outcome.
Study rationale, design, and findings
Anemia, or low RBC count, is common in patients with MI, Dr. Carson noted. A normal hemoglobin is 13 g/dL in men and 12 g/dL in women. Administering a packed RBC transfusion only when a patient’s hemoglobin falls below 7 or 8 g/dL has been widely adopted, but it is unclear if patients with acute MI may benefit from a higher hemoglobin level.
“Blood transfusion may decrease ischemic injury by improving oxygen delivery to myocardial tissues and reduce the risk of reinfarction or death,” the researchers wrote. “Alternatively, administering more blood could result in more frequent heart failure from fluid overload, infection from immunosuppression, thrombosis from higher viscosity, and inflammation.”
From 2017 to 2023, investigators enrolled 3,504 adults aged 18 and older at 144 sites in the United States (2,157 patients), Canada (885), France (323), Brazil (105), New Zealand (25), and Australia (9).
The participants had ST-elevation or non–ST-elevation MI and hemoglobin less than 10 g/dL within 24 hours. Patients with type 1 (atherosclerotic plaque disruption), type 2 (supply-demand mismatch without atherothrombotic plaque disruption), type 4b, or type 4c MI were eligible.
They were randomly assigned to receive:
- A ‘restrictive’ transfusion strategy (1,749 patients): Transfusion was permitted but not required when a patient’s hemoglobin was less than 8 g/dL and was strongly recommended when it was less than 7 g/dL or when anginal symptoms were not controlled with medications.
- A ‘liberal’ transfusion strategy (1,755 patients): One unit of RBCs was administered after randomization, and RBCs were transfused to maintain hemoglobin 10 g/dL or higher until hospital discharge or 30 days.
The patients had a mean age of 72 years and 46% were women. More than three-quarters (78%) were White and 14% were Black. They had frequent coexisting illnesses, about a third had a history of MI, percutaneous coronary intervention, or heart failure; 14% were on a ventilator and 12% had renal dialysis. The median duration of hospitalization was 5 days in the two groups.
At baseline, the mean hemoglobin was 8.6 g/dL in both groups. At days 1, 2, and 3, the mean hemoglobin was 8.8, 8.9, and 8.9 g/dL, respectively, in the restrictive transfusion group, and 10.1, 10.4, and 10.5 g/dL, respectively, in the liberal transfusion group.
The mean number of transfused blood units was 0.7 units in the restrictive strategy group and 2.5 units in the liberal strategy group, roughly a 3.5-fold difference.
After adjustment for site and incomplete follow-up in 57 patients (20 with the restrictive strategy and 37 with the liberal strategy), the estimated RR for the primary outcome in the restrictive group versus the liberal group was 1.15 (P = .07).
“We observed that the 95% confidence interval contains values that suggest a clinical benefit for the liberal transfusion strategy and does not include values that suggest a benefit for the more restrictive transfusion strategy,” the researchers wrote. Heart failure and other safety outcomes were comparable in the two groups.
The trial was supported by grants from the National Heart, Lung, and Blood Institute and by the Canadian Blood Services and Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health. Dr. Carson, Dr. Leon, Dr. Gibson, and Dr. Mazer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In patients with myocardial infarction and anemia, a “liberal” red blood cell transfusion strategy did not significantly reduce the risk of recurrent MI or death within 30 days, compared with a “restrictive” transfusion strategy, in the 3,500-patient MINT trial.
Jeffrey L. Carson, MD, from Robert Wood Johnson Medical School, New Brunswick, N.J., said in a press briefing.
He presented the study in a late-breaking trial session at the annual scientific sessions of the American Heart Association, and it was simultaneously published online in the New England Journal of Medicine.
“Whether to transfuse is an everyday decision faced by clinicians caring for patients with acute MI,” Dr. Carson said.
“We cannot claim that a liberal transfusion strategy is definitively superior based on our primary outcome,” he said, but “the 95% confidence interval is consistent with treatment effects corresponding to no difference between the two transfusion strategies and to a clinically relevant benefit with the liberal strategy.”
“In contrast to other trials in other settings,” such as anemia and cardiac surgery, Dr. Carson said, “the results suggest that a liberal transfusion strategy has the potential for clinical benefit with an acceptable risk of harm.”
“A liberal transfusion strategy may be the most prudent approach to transfusion in anemic patients with MI,” he added.
Not a home run
Others agreed with this interpretation. Martin B. Leon, MD, from Columbia University, New York, the study discussant in the press briefing, said the study “addresses a question that is common” in clinical practice. It was well conducted, and international (although most patients were in the United States and Canada), in a very broad group of patients, designed to make the results more generalizable. The 98% follow-up was extremely good, Dr. Leon added, and the trialists achieved their goal in that they did show a difference between the two transfusion strategies.
The number needed to treat was 40 to see a benefit in the combined outcome of death or recurrent MI at 30 days, Dr. Leon said. The P value for this was .07, “right on the edge” of statistical significance.
This study is “not a home run,” for the primary outcome, he noted; however, many of the outcomes tended to be in favor of a liberal transfusion strategy. Notably, cardiovascular death, which was not a specified outcome, was significantly lower in the group who received a liberal transfusion strategy.
Although a liberal transfusion strategy was “not definitely superior” in these patients with MI and anemia, Dr. Carson said, he thinks the trial will be interpreted as favoring a liberal transfusion strategy.
C. Michael Gibson, MD, professor of medicine at Harvard Medical School, Boston, and CEO of Harvard’s Baim and PERFUSE institutes for clinical research, voiced similar views.
“Given the lack of acute harm associated with liberal transfusion and the preponderance of evidence favoring liberal transfusion in the largest trial to date,” concluded Dr. Gibson, the assigned discussant at the session, “liberal transfusion appears to be a viable management strategy, particularly among patients with non-STEMI type 1 MI and as clinical judgment dictates.”
Only three small randomized controlled trials have compared transfusion thresholds in a total of 820 patients with MI and anemia, Dr. Gibson said, a point that the trial investigators also made. The results were inconsistent between trials: the CRIT trial (n = 45) favored a restrictive strategy, the MINT pilot study (n = 110) favored a liberal one, and the REALITY trial (n = 668) showed noninferiority of a restrictive strategy, compared with a liberal strategy in 30-day MACE.
The MINT trial was four times larger than all prior studies combined. However, most outcomes were negative or of borderline significance for benefit.
Cardiac death was more common in the restrictive group at 5.5% than the liberal group at 3.2% (risk ratio, 1.74, 95% CI, 1.26-2.40), but this was nonadjudicated, and not designated as a primary, secondary, or tertiary outcome – which the researchers also noted. Fewer than half of the deaths were classified as cardiac, which was “odd,” Dr. Gibson observed.
A restrictive transfusion strategy was associated with increased events among participants with type 1 MI (RR, 1.32, 95% CI, 1.04-1.67), he noted.
Study strengths included that 45.5% of participants were women, Dr. Gibson said. Limitations included that the trial was “somewhat underpowered.” Also, even in the restrictive group, participants received a mean of 0.7 units of packed red blood cells.
Adherence to the 10 g/dL threshold in the liberal transfusion group was moderate (86.3% at hospital discharge), which the researchers acknowledged. They noted that this was frequently caused by clinical discretion, such as concern about fluid overload, and to the timing of hospital discharge. In addition, long-term potential for harm (microchimerism) is not known.
“There was a consistent nonsignificant acute benefit for liberal transfusion and a nominal reduction in CV mortality and improved outcomes in patients with type 1 MI in exploratory analyses, in a trial that ended up underpowered,” Dr. Gibson summarized. “Long-term follow up would be helpful to evaluate chronic outcomes.”
This is a very well-conducted, high-quality, important study that will be considered a landmark trial, C. David Mazer, MD, University of Toronto and St. Michael’s Hospital, also in Toronto, said in an interview.
Unfortunately, “it was not as definitive as hoped for,” Dr. Mazer lamented. Nevertheless, “I think people may interpret it as providing support for a liberal transfusion strategy” in patients with anemia and MI, he said.
Dr. Mazer, who was not involved with this research, was a principal investigator on the TRICS-3 trial, which disputed a liberal RBC transfusion strategy in patients with anemia undergoing cardiac surgery, as previously reported.
The “Red Blood Cell Transfusion: 2023 AABB International Guidelines,” led by Dr. Carson and published in JAMA, recommend a restrictive strategy in stable patients, although these guidelines did not include the current study, Dr. Mazer observed.
In the REALITY trial, there were fewer major adverse cardiac events (MACE) events in the restrictive strategy, he noted.
MINT can be viewed as comparing a high versus low hemoglobin threshold. “It is possible that the best is in between,” he said.
Dr. Mazer also noted that MINT may have achieved significance if it was designed with a larger enrollment and a higher power (for example, 90% instead of 80%) to detect between-group difference for the primary outcome.
Study rationale, design, and findings
Anemia, or low RBC count, is common in patients with MI, Dr. Carson noted. A normal hemoglobin is 13 g/dL in men and 12 g/dL in women. Administering a packed RBC transfusion only when a patient’s hemoglobin falls below 7 or 8 g/dL has been widely adopted, but it is unclear if patients with acute MI may benefit from a higher hemoglobin level.
“Blood transfusion may decrease ischemic injury by improving oxygen delivery to myocardial tissues and reduce the risk of reinfarction or death,” the researchers wrote. “Alternatively, administering more blood could result in more frequent heart failure from fluid overload, infection from immunosuppression, thrombosis from higher viscosity, and inflammation.”
From 2017 to 2023, investigators enrolled 3,504 adults aged 18 and older at 144 sites in the United States (2,157 patients), Canada (885), France (323), Brazil (105), New Zealand (25), and Australia (9).
The participants had ST-elevation or non–ST-elevation MI and hemoglobin less than 10 g/dL within 24 hours. Patients with type 1 (atherosclerotic plaque disruption), type 2 (supply-demand mismatch without atherothrombotic plaque disruption), type 4b, or type 4c MI were eligible.
They were randomly assigned to receive:
- A ‘restrictive’ transfusion strategy (1,749 patients): Transfusion was permitted but not required when a patient’s hemoglobin was less than 8 g/dL and was strongly recommended when it was less than 7 g/dL or when anginal symptoms were not controlled with medications.
- A ‘liberal’ transfusion strategy (1,755 patients): One unit of RBCs was administered after randomization, and RBCs were transfused to maintain hemoglobin 10 g/dL or higher until hospital discharge or 30 days.
The patients had a mean age of 72 years and 46% were women. More than three-quarters (78%) were White and 14% were Black. They had frequent coexisting illnesses, about a third had a history of MI, percutaneous coronary intervention, or heart failure; 14% were on a ventilator and 12% had renal dialysis. The median duration of hospitalization was 5 days in the two groups.
At baseline, the mean hemoglobin was 8.6 g/dL in both groups. At days 1, 2, and 3, the mean hemoglobin was 8.8, 8.9, and 8.9 g/dL, respectively, in the restrictive transfusion group, and 10.1, 10.4, and 10.5 g/dL, respectively, in the liberal transfusion group.
The mean number of transfused blood units was 0.7 units in the restrictive strategy group and 2.5 units in the liberal strategy group, roughly a 3.5-fold difference.
After adjustment for site and incomplete follow-up in 57 patients (20 with the restrictive strategy and 37 with the liberal strategy), the estimated RR for the primary outcome in the restrictive group versus the liberal group was 1.15 (P = .07).
“We observed that the 95% confidence interval contains values that suggest a clinical benefit for the liberal transfusion strategy and does not include values that suggest a benefit for the more restrictive transfusion strategy,” the researchers wrote. Heart failure and other safety outcomes were comparable in the two groups.
The trial was supported by grants from the National Heart, Lung, and Blood Institute and by the Canadian Blood Services and Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health. Dr. Carson, Dr. Leon, Dr. Gibson, and Dr. Mazer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In patients with myocardial infarction and anemia, a “liberal” red blood cell transfusion strategy did not significantly reduce the risk of recurrent MI or death within 30 days, compared with a “restrictive” transfusion strategy, in the 3,500-patient MINT trial.
Jeffrey L. Carson, MD, from Robert Wood Johnson Medical School, New Brunswick, N.J., said in a press briefing.
He presented the study in a late-breaking trial session at the annual scientific sessions of the American Heart Association, and it was simultaneously published online in the New England Journal of Medicine.
“Whether to transfuse is an everyday decision faced by clinicians caring for patients with acute MI,” Dr. Carson said.
“We cannot claim that a liberal transfusion strategy is definitively superior based on our primary outcome,” he said, but “the 95% confidence interval is consistent with treatment effects corresponding to no difference between the two transfusion strategies and to a clinically relevant benefit with the liberal strategy.”
“In contrast to other trials in other settings,” such as anemia and cardiac surgery, Dr. Carson said, “the results suggest that a liberal transfusion strategy has the potential for clinical benefit with an acceptable risk of harm.”
“A liberal transfusion strategy may be the most prudent approach to transfusion in anemic patients with MI,” he added.
Not a home run
Others agreed with this interpretation. Martin B. Leon, MD, from Columbia University, New York, the study discussant in the press briefing, said the study “addresses a question that is common” in clinical practice. It was well conducted, and international (although most patients were in the United States and Canada), in a very broad group of patients, designed to make the results more generalizable. The 98% follow-up was extremely good, Dr. Leon added, and the trialists achieved their goal in that they did show a difference between the two transfusion strategies.
The number needed to treat was 40 to see a benefit in the combined outcome of death or recurrent MI at 30 days, Dr. Leon said. The P value for this was .07, “right on the edge” of statistical significance.
This study is “not a home run,” for the primary outcome, he noted; however, many of the outcomes tended to be in favor of a liberal transfusion strategy. Notably, cardiovascular death, which was not a specified outcome, was significantly lower in the group who received a liberal transfusion strategy.
Although a liberal transfusion strategy was “not definitely superior” in these patients with MI and anemia, Dr. Carson said, he thinks the trial will be interpreted as favoring a liberal transfusion strategy.
C. Michael Gibson, MD, professor of medicine at Harvard Medical School, Boston, and CEO of Harvard’s Baim and PERFUSE institutes for clinical research, voiced similar views.
“Given the lack of acute harm associated with liberal transfusion and the preponderance of evidence favoring liberal transfusion in the largest trial to date,” concluded Dr. Gibson, the assigned discussant at the session, “liberal transfusion appears to be a viable management strategy, particularly among patients with non-STEMI type 1 MI and as clinical judgment dictates.”
Only three small randomized controlled trials have compared transfusion thresholds in a total of 820 patients with MI and anemia, Dr. Gibson said, a point that the trial investigators also made. The results were inconsistent between trials: the CRIT trial (n = 45) favored a restrictive strategy, the MINT pilot study (n = 110) favored a liberal one, and the REALITY trial (n = 668) showed noninferiority of a restrictive strategy, compared with a liberal strategy in 30-day MACE.
The MINT trial was four times larger than all prior studies combined. However, most outcomes were negative or of borderline significance for benefit.
Cardiac death was more common in the restrictive group at 5.5% than the liberal group at 3.2% (risk ratio, 1.74, 95% CI, 1.26-2.40), but this was nonadjudicated, and not designated as a primary, secondary, or tertiary outcome – which the researchers also noted. Fewer than half of the deaths were classified as cardiac, which was “odd,” Dr. Gibson observed.
A restrictive transfusion strategy was associated with increased events among participants with type 1 MI (RR, 1.32, 95% CI, 1.04-1.67), he noted.
Study strengths included that 45.5% of participants were women, Dr. Gibson said. Limitations included that the trial was “somewhat underpowered.” Also, even in the restrictive group, participants received a mean of 0.7 units of packed red blood cells.
Adherence to the 10 g/dL threshold in the liberal transfusion group was moderate (86.3% at hospital discharge), which the researchers acknowledged. They noted that this was frequently caused by clinical discretion, such as concern about fluid overload, and to the timing of hospital discharge. In addition, long-term potential for harm (microchimerism) is not known.
“There was a consistent nonsignificant acute benefit for liberal transfusion and a nominal reduction in CV mortality and improved outcomes in patients with type 1 MI in exploratory analyses, in a trial that ended up underpowered,” Dr. Gibson summarized. “Long-term follow up would be helpful to evaluate chronic outcomes.”
This is a very well-conducted, high-quality, important study that will be considered a landmark trial, C. David Mazer, MD, University of Toronto and St. Michael’s Hospital, also in Toronto, said in an interview.
Unfortunately, “it was not as definitive as hoped for,” Dr. Mazer lamented. Nevertheless, “I think people may interpret it as providing support for a liberal transfusion strategy” in patients with anemia and MI, he said.
Dr. Mazer, who was not involved with this research, was a principal investigator on the TRICS-3 trial, which disputed a liberal RBC transfusion strategy in patients with anemia undergoing cardiac surgery, as previously reported.
The “Red Blood Cell Transfusion: 2023 AABB International Guidelines,” led by Dr. Carson and published in JAMA, recommend a restrictive strategy in stable patients, although these guidelines did not include the current study, Dr. Mazer observed.
In the REALITY trial, there were fewer major adverse cardiac events (MACE) events in the restrictive strategy, he noted.
MINT can be viewed as comparing a high versus low hemoglobin threshold. “It is possible that the best is in between,” he said.
Dr. Mazer also noted that MINT may have achieved significance if it was designed with a larger enrollment and a higher power (for example, 90% instead of 80%) to detect between-group difference for the primary outcome.
Study rationale, design, and findings
Anemia, or low RBC count, is common in patients with MI, Dr. Carson noted. A normal hemoglobin is 13 g/dL in men and 12 g/dL in women. Administering a packed RBC transfusion only when a patient’s hemoglobin falls below 7 or 8 g/dL has been widely adopted, but it is unclear if patients with acute MI may benefit from a higher hemoglobin level.
“Blood transfusion may decrease ischemic injury by improving oxygen delivery to myocardial tissues and reduce the risk of reinfarction or death,” the researchers wrote. “Alternatively, administering more blood could result in more frequent heart failure from fluid overload, infection from immunosuppression, thrombosis from higher viscosity, and inflammation.”
From 2017 to 2023, investigators enrolled 3,504 adults aged 18 and older at 144 sites in the United States (2,157 patients), Canada (885), France (323), Brazil (105), New Zealand (25), and Australia (9).
The participants had ST-elevation or non–ST-elevation MI and hemoglobin less than 10 g/dL within 24 hours. Patients with type 1 (atherosclerotic plaque disruption), type 2 (supply-demand mismatch without atherothrombotic plaque disruption), type 4b, or type 4c MI were eligible.
They were randomly assigned to receive:
- A ‘restrictive’ transfusion strategy (1,749 patients): Transfusion was permitted but not required when a patient’s hemoglobin was less than 8 g/dL and was strongly recommended when it was less than 7 g/dL or when anginal symptoms were not controlled with medications.
- A ‘liberal’ transfusion strategy (1,755 patients): One unit of RBCs was administered after randomization, and RBCs were transfused to maintain hemoglobin 10 g/dL or higher until hospital discharge or 30 days.
The patients had a mean age of 72 years and 46% were women. More than three-quarters (78%) were White and 14% were Black. They had frequent coexisting illnesses, about a third had a history of MI, percutaneous coronary intervention, or heart failure; 14% were on a ventilator and 12% had renal dialysis. The median duration of hospitalization was 5 days in the two groups.
At baseline, the mean hemoglobin was 8.6 g/dL in both groups. At days 1, 2, and 3, the mean hemoglobin was 8.8, 8.9, and 8.9 g/dL, respectively, in the restrictive transfusion group, and 10.1, 10.4, and 10.5 g/dL, respectively, in the liberal transfusion group.
The mean number of transfused blood units was 0.7 units in the restrictive strategy group and 2.5 units in the liberal strategy group, roughly a 3.5-fold difference.
After adjustment for site and incomplete follow-up in 57 patients (20 with the restrictive strategy and 37 with the liberal strategy), the estimated RR for the primary outcome in the restrictive group versus the liberal group was 1.15 (P = .07).
“We observed that the 95% confidence interval contains values that suggest a clinical benefit for the liberal transfusion strategy and does not include values that suggest a benefit for the more restrictive transfusion strategy,” the researchers wrote. Heart failure and other safety outcomes were comparable in the two groups.
The trial was supported by grants from the National Heart, Lung, and Blood Institute and by the Canadian Blood Services and Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health. Dr. Carson, Dr. Leon, Dr. Gibson, and Dr. Mazer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AHA 2023