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Patients find CAC more persuasive than ASCVD risk score for statin decisions
Patients who received a protocol-driven recommendation to initiate statin therapy for primary prevention of cardiovascular disease based upon their CT angiography coronary artery calcium score were twice as likely to actually start on the drug than those whose recommendation was guided by the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Calculator, according to the results of the randomized CorCal Vanguard study.
These results suggest that patients – and their primary care physicians – find the conventional method of screening for cardiovascular risk using the Pooled Cohort Equations to estimate the 10-year risk of MI or stroke, as recommended in ACC/AHA guidelines, to be less persuasive than screening for the presence or absence of actual disease as captured by CT angiography images and the associated coronary artery calcium (CAC) score, Joseph B. Muhlestein, MD, said at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
The CorCal Vanguard study included 601 patients with an average baseline LDL cholesterol of 120 mg/dL, an average age of 60 years, and no history of cardiovascular disease, diabetes, or prior statin therapy. They were randomized to decision-making regarding statin therapy based on either the ACC/AHA guideline–endorsed Pooled Cohort Equations, which use an estimated 10-year risk of 7.5% or more as the threshold for statin initiation, or their CAC score.
If a patient’s CAC score was 0, the recommendation was against starting a statin. Everyone with a CAC greater than 100 received a recommendation for high-intensity statin therapy. And for those with a CAC of 1-100, the decision defaulted to the results of the Pooled Cohort Equations. The screening results were provided to a patient’s primary physician so they could engage in joint decision-making regarding initiation of statin therapy. Adherence to a screening-based recommendation to start on a statin was assessed at 3 and 12 months of follow-up, explained Dr. Muhlestein, a cardiologist at the Intermountain Medical Center Heart Institute in Salt Lake City.
He noted that CorCal Vanguard was merely a feasibility study. Based on the study results he presented at ACC 2020, the full 9,000-patient CorCal primary prevention trial is now enrolling participants. CorCal is the first randomized trial to pit the Pooled Cohort Equations against the CAC score in a large study looking for differences in downstream clinical outcomes.
The rationale for this line of clinical research lies in the known limitations of the ACC/AHA risk calculator. “It may overestimate risk in some populations, patients aren’t always adherent to Pooled Cohort Equations Risk Calculator recommendations, and it doesn’t include novel risk markers such as C-reactive protein that some consider important for risk assessment. And the big question: Should we continue risk screening to determine potential benefit from drug therapy, or should we switch to disease screening?” the cardiologist commented.
The CorCal Vanguard results
A recommendation to start statin therapy was made in 48% of patients in the Pooled Cohort Equations group, versus 36% of the group randomized to CAC. However, only 17% of patients in the Pooled Cohort Equations group actually initiated a statin, a significantly lower rate than the 26% figure in the CAC arm. Fully 70% of patients who received a recommendation to start taking a statin on the basis of their CAC score actually did so, compared to just 36% of those whose recommendation was based upon their Pooled Cohort Equations Risk Calculator.
At 3 months of follow-up, 61% of patients who received an initial recommendation to start statin therapy based upon their CAC screening were actually taking a statin, compared with 41% of those whose recommendation was based upon the Pooled Cohort Equations. At 12 months, the figures were 64% and 49%.
In both groups, at 12 months of follow-up, the No. 1 reason patients weren’t taking a statin as recommended was that their personal physician had advised against it or never prescribed it. That accounted for roughly half of the nonadherence. Another quarter was because of a preference to try lifestyle change first. Fear of drug side effects was a less common reason.
Putting the CorCal Vanguard study results in perspective, Dr. Muhlestein observed that, prior to the screening study, none of the participants had ever been on a statin, yet 37% of them were found by one screening method or the other to be at high cardiovascular risk. Of those high-risk patients, 51% actually initiated statin therapy and the majority of them were still taking their medication 12 months later.
“That has to be a good thing. It emphasizes what can be done when proactive primary prevention is practiced,” the cardiologist said.
He reported having no financial conflicts regarding the CorCal study, which was funded by a grant from the Dell Loy Hansen Cardiovascular Research Fund.
SOURCE: Muhlestein JB et al. ACC 2020, Abstract 909-12.
Patients who received a protocol-driven recommendation to initiate statin therapy for primary prevention of cardiovascular disease based upon their CT angiography coronary artery calcium score were twice as likely to actually start on the drug than those whose recommendation was guided by the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Calculator, according to the results of the randomized CorCal Vanguard study.
These results suggest that patients – and their primary care physicians – find the conventional method of screening for cardiovascular risk using the Pooled Cohort Equations to estimate the 10-year risk of MI or stroke, as recommended in ACC/AHA guidelines, to be less persuasive than screening for the presence or absence of actual disease as captured by CT angiography images and the associated coronary artery calcium (CAC) score, Joseph B. Muhlestein, MD, said at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
The CorCal Vanguard study included 601 patients with an average baseline LDL cholesterol of 120 mg/dL, an average age of 60 years, and no history of cardiovascular disease, diabetes, or prior statin therapy. They were randomized to decision-making regarding statin therapy based on either the ACC/AHA guideline–endorsed Pooled Cohort Equations, which use an estimated 10-year risk of 7.5% or more as the threshold for statin initiation, or their CAC score.
If a patient’s CAC score was 0, the recommendation was against starting a statin. Everyone with a CAC greater than 100 received a recommendation for high-intensity statin therapy. And for those with a CAC of 1-100, the decision defaulted to the results of the Pooled Cohort Equations. The screening results were provided to a patient’s primary physician so they could engage in joint decision-making regarding initiation of statin therapy. Adherence to a screening-based recommendation to start on a statin was assessed at 3 and 12 months of follow-up, explained Dr. Muhlestein, a cardiologist at the Intermountain Medical Center Heart Institute in Salt Lake City.
He noted that CorCal Vanguard was merely a feasibility study. Based on the study results he presented at ACC 2020, the full 9,000-patient CorCal primary prevention trial is now enrolling participants. CorCal is the first randomized trial to pit the Pooled Cohort Equations against the CAC score in a large study looking for differences in downstream clinical outcomes.
The rationale for this line of clinical research lies in the known limitations of the ACC/AHA risk calculator. “It may overestimate risk in some populations, patients aren’t always adherent to Pooled Cohort Equations Risk Calculator recommendations, and it doesn’t include novel risk markers such as C-reactive protein that some consider important for risk assessment. And the big question: Should we continue risk screening to determine potential benefit from drug therapy, or should we switch to disease screening?” the cardiologist commented.
The CorCal Vanguard results
A recommendation to start statin therapy was made in 48% of patients in the Pooled Cohort Equations group, versus 36% of the group randomized to CAC. However, only 17% of patients in the Pooled Cohort Equations group actually initiated a statin, a significantly lower rate than the 26% figure in the CAC arm. Fully 70% of patients who received a recommendation to start taking a statin on the basis of their CAC score actually did so, compared to just 36% of those whose recommendation was based upon their Pooled Cohort Equations Risk Calculator.
At 3 months of follow-up, 61% of patients who received an initial recommendation to start statin therapy based upon their CAC screening were actually taking a statin, compared with 41% of those whose recommendation was based upon the Pooled Cohort Equations. At 12 months, the figures were 64% and 49%.
In both groups, at 12 months of follow-up, the No. 1 reason patients weren’t taking a statin as recommended was that their personal physician had advised against it or never prescribed it. That accounted for roughly half of the nonadherence. Another quarter was because of a preference to try lifestyle change first. Fear of drug side effects was a less common reason.
Putting the CorCal Vanguard study results in perspective, Dr. Muhlestein observed that, prior to the screening study, none of the participants had ever been on a statin, yet 37% of them were found by one screening method or the other to be at high cardiovascular risk. Of those high-risk patients, 51% actually initiated statin therapy and the majority of them were still taking their medication 12 months later.
“That has to be a good thing. It emphasizes what can be done when proactive primary prevention is practiced,” the cardiologist said.
He reported having no financial conflicts regarding the CorCal study, which was funded by a grant from the Dell Loy Hansen Cardiovascular Research Fund.
SOURCE: Muhlestein JB et al. ACC 2020, Abstract 909-12.
Patients who received a protocol-driven recommendation to initiate statin therapy for primary prevention of cardiovascular disease based upon their CT angiography coronary artery calcium score were twice as likely to actually start on the drug than those whose recommendation was guided by the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Calculator, according to the results of the randomized CorCal Vanguard study.
These results suggest that patients – and their primary care physicians – find the conventional method of screening for cardiovascular risk using the Pooled Cohort Equations to estimate the 10-year risk of MI or stroke, as recommended in ACC/AHA guidelines, to be less persuasive than screening for the presence or absence of actual disease as captured by CT angiography images and the associated coronary artery calcium (CAC) score, Joseph B. Muhlestein, MD, said at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
The CorCal Vanguard study included 601 patients with an average baseline LDL cholesterol of 120 mg/dL, an average age of 60 years, and no history of cardiovascular disease, diabetes, or prior statin therapy. They were randomized to decision-making regarding statin therapy based on either the ACC/AHA guideline–endorsed Pooled Cohort Equations, which use an estimated 10-year risk of 7.5% or more as the threshold for statin initiation, or their CAC score.
If a patient’s CAC score was 0, the recommendation was against starting a statin. Everyone with a CAC greater than 100 received a recommendation for high-intensity statin therapy. And for those with a CAC of 1-100, the decision defaulted to the results of the Pooled Cohort Equations. The screening results were provided to a patient’s primary physician so they could engage in joint decision-making regarding initiation of statin therapy. Adherence to a screening-based recommendation to start on a statin was assessed at 3 and 12 months of follow-up, explained Dr. Muhlestein, a cardiologist at the Intermountain Medical Center Heart Institute in Salt Lake City.
He noted that CorCal Vanguard was merely a feasibility study. Based on the study results he presented at ACC 2020, the full 9,000-patient CorCal primary prevention trial is now enrolling participants. CorCal is the first randomized trial to pit the Pooled Cohort Equations against the CAC score in a large study looking for differences in downstream clinical outcomes.
The rationale for this line of clinical research lies in the known limitations of the ACC/AHA risk calculator. “It may overestimate risk in some populations, patients aren’t always adherent to Pooled Cohort Equations Risk Calculator recommendations, and it doesn’t include novel risk markers such as C-reactive protein that some consider important for risk assessment. And the big question: Should we continue risk screening to determine potential benefit from drug therapy, or should we switch to disease screening?” the cardiologist commented.
The CorCal Vanguard results
A recommendation to start statin therapy was made in 48% of patients in the Pooled Cohort Equations group, versus 36% of the group randomized to CAC. However, only 17% of patients in the Pooled Cohort Equations group actually initiated a statin, a significantly lower rate than the 26% figure in the CAC arm. Fully 70% of patients who received a recommendation to start taking a statin on the basis of their CAC score actually did so, compared to just 36% of those whose recommendation was based upon their Pooled Cohort Equations Risk Calculator.
At 3 months of follow-up, 61% of patients who received an initial recommendation to start statin therapy based upon their CAC screening were actually taking a statin, compared with 41% of those whose recommendation was based upon the Pooled Cohort Equations. At 12 months, the figures were 64% and 49%.
In both groups, at 12 months of follow-up, the No. 1 reason patients weren’t taking a statin as recommended was that their personal physician had advised against it or never prescribed it. That accounted for roughly half of the nonadherence. Another quarter was because of a preference to try lifestyle change first. Fear of drug side effects was a less common reason.
Putting the CorCal Vanguard study results in perspective, Dr. Muhlestein observed that, prior to the screening study, none of the participants had ever been on a statin, yet 37% of them were found by one screening method or the other to be at high cardiovascular risk. Of those high-risk patients, 51% actually initiated statin therapy and the majority of them were still taking their medication 12 months later.
“That has to be a good thing. It emphasizes what can be done when proactive primary prevention is practiced,” the cardiologist said.
He reported having no financial conflicts regarding the CorCal study, which was funded by a grant from the Dell Loy Hansen Cardiovascular Research Fund.
SOURCE: Muhlestein JB et al. ACC 2020, Abstract 909-12.
FROM ACC 2020
More from REDUCE-IT: Icosapent ethyl cuts revascularization by a third
A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.
The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.
REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.
The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.
This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.
“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.
“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.
Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).
Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).
The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”
Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.
REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.
“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.
“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.
Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”
Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”
Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”
REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.
A version of this article originally appeared on Medscape.com.
A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.
The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.
REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.
The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.
This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.
“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.
“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.
Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).
Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).
The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”
Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.
REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.
“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.
“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.
Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”
Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”
Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”
REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.
A version of this article originally appeared on Medscape.com.
A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.
The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.
REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.
The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.
This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.
“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.
“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.
Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).
Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).
The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”
Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.
REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.
“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.
“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.
Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”
Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”
Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”
REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.
A version of this article originally appeared on Medscape.com.
Adolescent obesity, diabetes linked to atherosclerotic signs
significantly greater than their normal-weight peers, according to a longitudinal study published online in the Journal of the American Heart Association.
The study evaluated 448 adolescents over 5 years for changes in a variety of metrics to determine changes in arterial structure, including carotid intima media thickness (cIMT), carotid-femoral pulse-wave velocity (PWV), and augmentation index (Aix). The average age of the study group was 17.6 years. The three study groups broke down accordingly: 141 with normal weight, 156 with obesity, and 151 with type 2 diabetes. Patients were evaluated at baseline and 5 years later.
“The presence of obesity and especially type 2 diabetes in adolescents accelerates the early vascular aging process associated with several key risk factors,” wrote Justin R. Ryder, PhD, an assistant professor of pediatrics at the University of Minnesota, Minneapolis, and colleagues.
The researchers also noted that systolic hypertension was associated with changes in cIMT and arterial stiffness comparable to obesity and diabetes. “These data add further evidence underscoring the importance of efforts targeting prevention and treatment of obesity, type 2 diabetes, and elevated blood pressure among youth, with a goal of delaying and/or preventing the progression of early vascular aging,” Dr. Ryder and colleagues wrote.
Obese patients, when compared with normal-weight participants, had the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.02 mm, internal cIMT by 0.03 mm, and PWV carotid-femoral by 0.38 m/sec, all statistically significant differences. Patients with diabetes, compared with normal-weight participants, registered the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.06 mm, internal cIMT by 0.04 mm, Aix by 4.67%, and PWV carotid-femoral by 0.74 m/sec. All differences were highly significant at P less than .001.
The results also showed that higher baseline systolic blood pressure was associated with significantly greater average increases in the following factors: common cIMT by 0.007 mm, bulb cIMT by 0.009 mm, internal cIMT by 0.008 mm, and PWV carotid-femoral by 0.66 m/sec.
Drilling down into the data, the study reported that males had greater increases in bulb cIMT and incremental elastic modulus as well as reduced Aix, compared with females. Nonwhites also had greater increases in bulb cIMT than did whites. Age was associated with greater increases in bulb and internal cIMT and Aix.
“Our data support the concept that male sex is an independent and primary risk factor for accelerated early vascular aging,” Dr. Ryder and colleagues wrote. The study also determined that type 2 diabetes is a more prominent risk factor than obesity for early vascular aging.
The size of the study population, specifically adolescents with diabetes, is a study strength, Dr. Ryder and colleagues noted. Other strengths they pointed to are the 5-year duration and the robust panel of noninvasive measures, although not using hard cardiovascular outcomes is an acknowledged limitation.
“It should also be noted that many of the youth with type 2 diabetes were on medications for glycemic control, lipids, and/or blood pressure regulation,” Dr. Ryder and colleagues wrote. “Despite this, the vascular profiles worsened over time.”
The study showed “a really significant change” in the carotid anatomy in adolescents with obesity and type 2 diabetes over 5 years, Robert Eckel, MD, professor at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Notably, the PWV is not just anatomy; now we’re talking about function. In other words, the augmentation index and PWV will assess the compliance of the artery.”
The findings suggest that atherosclerosis begins with thickening of the arterial walls. “The question is, is thickness reversible?” Dr. Eckel said. “It’s probably not very reversible, so these are early changes that ultimately in the middle years or latter years are associated with major cardiovascular disease.”
They key lesson from the study, Dr. Eckel noted, is to “prevent obesity. If you prevent obesity in the teenage years, you basically prevent diabetes.”
Dr. Ryder disclosed receiving support from Boehringer Ingelheim in the form of drug/placebo. The National Institutes of Health provided funding. Dr. Eckel has no relevant relationships to disclose.
SOURCE: Ryder JR et al. J Am Heart Assoc. 2020 May 6:e014891. doi: 10.1161/JAHA.119.014891.
significantly greater than their normal-weight peers, according to a longitudinal study published online in the Journal of the American Heart Association.
The study evaluated 448 adolescents over 5 years for changes in a variety of metrics to determine changes in arterial structure, including carotid intima media thickness (cIMT), carotid-femoral pulse-wave velocity (PWV), and augmentation index (Aix). The average age of the study group was 17.6 years. The three study groups broke down accordingly: 141 with normal weight, 156 with obesity, and 151 with type 2 diabetes. Patients were evaluated at baseline and 5 years later.
“The presence of obesity and especially type 2 diabetes in adolescents accelerates the early vascular aging process associated with several key risk factors,” wrote Justin R. Ryder, PhD, an assistant professor of pediatrics at the University of Minnesota, Minneapolis, and colleagues.
The researchers also noted that systolic hypertension was associated with changes in cIMT and arterial stiffness comparable to obesity and diabetes. “These data add further evidence underscoring the importance of efforts targeting prevention and treatment of obesity, type 2 diabetes, and elevated blood pressure among youth, with a goal of delaying and/or preventing the progression of early vascular aging,” Dr. Ryder and colleagues wrote.
Obese patients, when compared with normal-weight participants, had the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.02 mm, internal cIMT by 0.03 mm, and PWV carotid-femoral by 0.38 m/sec, all statistically significant differences. Patients with diabetes, compared with normal-weight participants, registered the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.06 mm, internal cIMT by 0.04 mm, Aix by 4.67%, and PWV carotid-femoral by 0.74 m/sec. All differences were highly significant at P less than .001.
The results also showed that higher baseline systolic blood pressure was associated with significantly greater average increases in the following factors: common cIMT by 0.007 mm, bulb cIMT by 0.009 mm, internal cIMT by 0.008 mm, and PWV carotid-femoral by 0.66 m/sec.
Drilling down into the data, the study reported that males had greater increases in bulb cIMT and incremental elastic modulus as well as reduced Aix, compared with females. Nonwhites also had greater increases in bulb cIMT than did whites. Age was associated with greater increases in bulb and internal cIMT and Aix.
“Our data support the concept that male sex is an independent and primary risk factor for accelerated early vascular aging,” Dr. Ryder and colleagues wrote. The study also determined that type 2 diabetes is a more prominent risk factor than obesity for early vascular aging.
The size of the study population, specifically adolescents with diabetes, is a study strength, Dr. Ryder and colleagues noted. Other strengths they pointed to are the 5-year duration and the robust panel of noninvasive measures, although not using hard cardiovascular outcomes is an acknowledged limitation.
“It should also be noted that many of the youth with type 2 diabetes were on medications for glycemic control, lipids, and/or blood pressure regulation,” Dr. Ryder and colleagues wrote. “Despite this, the vascular profiles worsened over time.”
The study showed “a really significant change” in the carotid anatomy in adolescents with obesity and type 2 diabetes over 5 years, Robert Eckel, MD, professor at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Notably, the PWV is not just anatomy; now we’re talking about function. In other words, the augmentation index and PWV will assess the compliance of the artery.”
The findings suggest that atherosclerosis begins with thickening of the arterial walls. “The question is, is thickness reversible?” Dr. Eckel said. “It’s probably not very reversible, so these are early changes that ultimately in the middle years or latter years are associated with major cardiovascular disease.”
They key lesson from the study, Dr. Eckel noted, is to “prevent obesity. If you prevent obesity in the teenage years, you basically prevent diabetes.”
Dr. Ryder disclosed receiving support from Boehringer Ingelheim in the form of drug/placebo. The National Institutes of Health provided funding. Dr. Eckel has no relevant relationships to disclose.
SOURCE: Ryder JR et al. J Am Heart Assoc. 2020 May 6:e014891. doi: 10.1161/JAHA.119.014891.
significantly greater than their normal-weight peers, according to a longitudinal study published online in the Journal of the American Heart Association.
The study evaluated 448 adolescents over 5 years for changes in a variety of metrics to determine changes in arterial structure, including carotid intima media thickness (cIMT), carotid-femoral pulse-wave velocity (PWV), and augmentation index (Aix). The average age of the study group was 17.6 years. The three study groups broke down accordingly: 141 with normal weight, 156 with obesity, and 151 with type 2 diabetes. Patients were evaluated at baseline and 5 years later.
“The presence of obesity and especially type 2 diabetes in adolescents accelerates the early vascular aging process associated with several key risk factors,” wrote Justin R. Ryder, PhD, an assistant professor of pediatrics at the University of Minnesota, Minneapolis, and colleagues.
The researchers also noted that systolic hypertension was associated with changes in cIMT and arterial stiffness comparable to obesity and diabetes. “These data add further evidence underscoring the importance of efforts targeting prevention and treatment of obesity, type 2 diabetes, and elevated blood pressure among youth, with a goal of delaying and/or preventing the progression of early vascular aging,” Dr. Ryder and colleagues wrote.
Obese patients, when compared with normal-weight participants, had the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.02 mm, internal cIMT by 0.03 mm, and PWV carotid-femoral by 0.38 m/sec, all statistically significant differences. Patients with diabetes, compared with normal-weight participants, registered the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.06 mm, internal cIMT by 0.04 mm, Aix by 4.67%, and PWV carotid-femoral by 0.74 m/sec. All differences were highly significant at P less than .001.
The results also showed that higher baseline systolic blood pressure was associated with significantly greater average increases in the following factors: common cIMT by 0.007 mm, bulb cIMT by 0.009 mm, internal cIMT by 0.008 mm, and PWV carotid-femoral by 0.66 m/sec.
Drilling down into the data, the study reported that males had greater increases in bulb cIMT and incremental elastic modulus as well as reduced Aix, compared with females. Nonwhites also had greater increases in bulb cIMT than did whites. Age was associated with greater increases in bulb and internal cIMT and Aix.
“Our data support the concept that male sex is an independent and primary risk factor for accelerated early vascular aging,” Dr. Ryder and colleagues wrote. The study also determined that type 2 diabetes is a more prominent risk factor than obesity for early vascular aging.
The size of the study population, specifically adolescents with diabetes, is a study strength, Dr. Ryder and colleagues noted. Other strengths they pointed to are the 5-year duration and the robust panel of noninvasive measures, although not using hard cardiovascular outcomes is an acknowledged limitation.
“It should also be noted that many of the youth with type 2 diabetes were on medications for glycemic control, lipids, and/or blood pressure regulation,” Dr. Ryder and colleagues wrote. “Despite this, the vascular profiles worsened over time.”
The study showed “a really significant change” in the carotid anatomy in adolescents with obesity and type 2 diabetes over 5 years, Robert Eckel, MD, professor at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Notably, the PWV is not just anatomy; now we’re talking about function. In other words, the augmentation index and PWV will assess the compliance of the artery.”
The findings suggest that atherosclerosis begins with thickening of the arterial walls. “The question is, is thickness reversible?” Dr. Eckel said. “It’s probably not very reversible, so these are early changes that ultimately in the middle years or latter years are associated with major cardiovascular disease.”
They key lesson from the study, Dr. Eckel noted, is to “prevent obesity. If you prevent obesity in the teenage years, you basically prevent diabetes.”
Dr. Ryder disclosed receiving support from Boehringer Ingelheim in the form of drug/placebo. The National Institutes of Health provided funding. Dr. Eckel has no relevant relationships to disclose.
SOURCE: Ryder JR et al. J Am Heart Assoc. 2020 May 6:e014891. doi: 10.1161/JAHA.119.014891.
FROM JOURNAL OF THE AMERICAN HEART ASSOCIATION
FOURIER: Evolocumab follow-up shows no cognitive adverse effects
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
FROM JACC
Key clinical point: A cognition survey of a large number of trial participants showed no signal of adverse effects from evolocumab treatment.
Major finding: Survey results showed cognitive compromise in 3.7% of patients on evolocumab and in 3.6% control patients on placebo.
Study details:
Disclosures: FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Guigliano has received personal fees and research support from Amgen and from several other companies.
Source: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Substantial very late MACE risk after PCI for SIHD
Patients with stable ischemic heart disease remain at substantial risk for major adverse cardiovascular events 1-5 years after percutaneous coronary intervention, even with contemporary second-generation drug-eluting stents, according to a pooled analysis of long-term follow-up data on 10,987 patients in 19 prospective, randomized, head-to-head metallic stent trials.
The analysis showed that, although most major adverse cardiovascular events (MACE) occurred during the first year after stenting, no plateau in MACE was reached between years 1 and 5, Mahesh V. Madhavan, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“Further studies are required to understand the mechanisms of late events and whether improvements in stent technology, revascularization technique, and adjunctive therapies may improve outcomes in patients with SIHD [stable ischemic heart disease],” said Dr. Madhavan, a cardiology fellow at Columbia University Irving Medical Center and New York–Presbyterian Hospital.
This post hoc analysis of pooled individual patient-level data from 19 randomized trials included 10,987 metallic stent recipients with SIHD. Sixty-one percent got second-generation drug-eluting stents (DES), 25% received first-generation DES, and 15% got bare metal stents (BMS). The largest prospective head-to-head RCT was SPIRIT IV, with 2,130 patients. All five TAXUS trials were also included.
The 5-year rate of the primary composite MACE endpoint composed of cardiac death, MI, or ischemia-driven target lesion revascularization was 24.1% in patients with BMS stents, 17.9% with first-gen DES, and 13.4% with second-gen DES, reflecting the advances in stent technology over time. Most of these MACE events occurred during the first year after PCI, with rates of 18%, 8.6%, and 5.3%, respectively, in the three groups. However, the MACE rate beyond the first year out through year 5 remained substantial: 10.2% with first-gen DES, 8.5% with second-gen DES, and 7.4% in the BMS group.
The cardiac death rate from PCI through year 5 was 3.8% with second-gen DES, 3.6% with first-gen DES, and 3.3% with BMS. The MI rate was 7.7% with first-gen DES, 6.1% with BMS, and 5% with second-gen DES.
Stent thrombosis occurred during the first year in 0.9% of first-gen DES and BMS recipients and in 0.7% of patients with second-gen DES. During years 1-5, the rates were 1.6% with first-gen DES, 0.9% with second-gen devices, and 0.2% with BMS.
Second-gen DES provided a big advantage in terms of lessened need for ischemia-driven target lesion revascularization through the first 5 years, with a rate of 7.3%, compared to 18.7% in patients with first-gen DES and 10.5% with BMS.
In a multivariate regression analysis, independent predictors of MACE in the first 5 years post PCI included indicators of greater lesion and/or procedural complexity, such as left main or left anterior descending disease, greater lesion length, and more than one treated lesion, as well as standard cardiovascular risk factors, including recent smoking, hypertension, and diabetes.
In contrast, hyperlipidemia was associated with a significant 15% reduction in MACE risk, which in an interview Dr. Madhavan said may have been due to aggressive lipid-lowering therapy, although he added that this is conjecture because he and his coinvestigators didn’t have access to data on the use of guideline-directed medical therapy or antiplatelet regimens.
Asked about future prospects for reducing the substantial very late risk of MACE highlighted in his study, Dr. Madhavan cited the use of adjunctive imaging during PCI as promising.
“The currently enrolling ILUMEN IV trial, among other studies, will help determine whether imaging-guided intervention can help improve intermediate and long-term rates of MACE,” he observed.
Promising medical therapies that could potentially confer benefit in terms of reducing long-term MACE in patients who’ve undergone PCI for SIHD include novel lipid-lowering drugs, tailored antithrombotic strategies, new anti-inflammatory agents, and the SGLT2 inhibitors, Dr. Madhavan continued.
In terms of advances in stent design, he cited recent evidence that ultrathin-strut stents featuring bioresorbable polymer, such as the Orsiro stent, may reduce late stent-related MACE through 3 years.
“We’ll have to see if these benefits extend to longer-term follow-up up to 5 years,” he said.
He deemed his study results “fairly consistent” with those of the ISCHEMIA trial, where ischemic events in the patients with SIHD assigned to an initial invasive strategy continued to occur in the latter years of follow-up without any clear plateau effect (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Dr. Madhavan reported no financial conflicts regarding his study, funded by an institutional research grant from the National Heart, Lung, and Blood Institute.
Shortly following Dr. Madhavan’s presentation at ACC 2020, the study results were published online (Circ Cardiovasc Interv. 2020 Apr;13[4[:e008565. doi: 10.1161/CIRCINTERVENTIONS.119.008565).
SOURCE: Madhavan MV. ACC 2020, Abstract 909-10.
Patients with stable ischemic heart disease remain at substantial risk for major adverse cardiovascular events 1-5 years after percutaneous coronary intervention, even with contemporary second-generation drug-eluting stents, according to a pooled analysis of long-term follow-up data on 10,987 patients in 19 prospective, randomized, head-to-head metallic stent trials.
The analysis showed that, although most major adverse cardiovascular events (MACE) occurred during the first year after stenting, no plateau in MACE was reached between years 1 and 5, Mahesh V. Madhavan, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“Further studies are required to understand the mechanisms of late events and whether improvements in stent technology, revascularization technique, and adjunctive therapies may improve outcomes in patients with SIHD [stable ischemic heart disease],” said Dr. Madhavan, a cardiology fellow at Columbia University Irving Medical Center and New York–Presbyterian Hospital.
This post hoc analysis of pooled individual patient-level data from 19 randomized trials included 10,987 metallic stent recipients with SIHD. Sixty-one percent got second-generation drug-eluting stents (DES), 25% received first-generation DES, and 15% got bare metal stents (BMS). The largest prospective head-to-head RCT was SPIRIT IV, with 2,130 patients. All five TAXUS trials were also included.
The 5-year rate of the primary composite MACE endpoint composed of cardiac death, MI, or ischemia-driven target lesion revascularization was 24.1% in patients with BMS stents, 17.9% with first-gen DES, and 13.4% with second-gen DES, reflecting the advances in stent technology over time. Most of these MACE events occurred during the first year after PCI, with rates of 18%, 8.6%, and 5.3%, respectively, in the three groups. However, the MACE rate beyond the first year out through year 5 remained substantial: 10.2% with first-gen DES, 8.5% with second-gen DES, and 7.4% in the BMS group.
The cardiac death rate from PCI through year 5 was 3.8% with second-gen DES, 3.6% with first-gen DES, and 3.3% with BMS. The MI rate was 7.7% with first-gen DES, 6.1% with BMS, and 5% with second-gen DES.
Stent thrombosis occurred during the first year in 0.9% of first-gen DES and BMS recipients and in 0.7% of patients with second-gen DES. During years 1-5, the rates were 1.6% with first-gen DES, 0.9% with second-gen devices, and 0.2% with BMS.
Second-gen DES provided a big advantage in terms of lessened need for ischemia-driven target lesion revascularization through the first 5 years, with a rate of 7.3%, compared to 18.7% in patients with first-gen DES and 10.5% with BMS.
In a multivariate regression analysis, independent predictors of MACE in the first 5 years post PCI included indicators of greater lesion and/or procedural complexity, such as left main or left anterior descending disease, greater lesion length, and more than one treated lesion, as well as standard cardiovascular risk factors, including recent smoking, hypertension, and diabetes.
In contrast, hyperlipidemia was associated with a significant 15% reduction in MACE risk, which in an interview Dr. Madhavan said may have been due to aggressive lipid-lowering therapy, although he added that this is conjecture because he and his coinvestigators didn’t have access to data on the use of guideline-directed medical therapy or antiplatelet regimens.
Asked about future prospects for reducing the substantial very late risk of MACE highlighted in his study, Dr. Madhavan cited the use of adjunctive imaging during PCI as promising.
“The currently enrolling ILUMEN IV trial, among other studies, will help determine whether imaging-guided intervention can help improve intermediate and long-term rates of MACE,” he observed.
Promising medical therapies that could potentially confer benefit in terms of reducing long-term MACE in patients who’ve undergone PCI for SIHD include novel lipid-lowering drugs, tailored antithrombotic strategies, new anti-inflammatory agents, and the SGLT2 inhibitors, Dr. Madhavan continued.
In terms of advances in stent design, he cited recent evidence that ultrathin-strut stents featuring bioresorbable polymer, such as the Orsiro stent, may reduce late stent-related MACE through 3 years.
“We’ll have to see if these benefits extend to longer-term follow-up up to 5 years,” he said.
He deemed his study results “fairly consistent” with those of the ISCHEMIA trial, where ischemic events in the patients with SIHD assigned to an initial invasive strategy continued to occur in the latter years of follow-up without any clear plateau effect (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Dr. Madhavan reported no financial conflicts regarding his study, funded by an institutional research grant from the National Heart, Lung, and Blood Institute.
Shortly following Dr. Madhavan’s presentation at ACC 2020, the study results were published online (Circ Cardiovasc Interv. 2020 Apr;13[4[:e008565. doi: 10.1161/CIRCINTERVENTIONS.119.008565).
SOURCE: Madhavan MV. ACC 2020, Abstract 909-10.
Patients with stable ischemic heart disease remain at substantial risk for major adverse cardiovascular events 1-5 years after percutaneous coronary intervention, even with contemporary second-generation drug-eluting stents, according to a pooled analysis of long-term follow-up data on 10,987 patients in 19 prospective, randomized, head-to-head metallic stent trials.
The analysis showed that, although most major adverse cardiovascular events (MACE) occurred during the first year after stenting, no plateau in MACE was reached between years 1 and 5, Mahesh V. Madhavan, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“Further studies are required to understand the mechanisms of late events and whether improvements in stent technology, revascularization technique, and adjunctive therapies may improve outcomes in patients with SIHD [stable ischemic heart disease],” said Dr. Madhavan, a cardiology fellow at Columbia University Irving Medical Center and New York–Presbyterian Hospital.
This post hoc analysis of pooled individual patient-level data from 19 randomized trials included 10,987 metallic stent recipients with SIHD. Sixty-one percent got second-generation drug-eluting stents (DES), 25% received first-generation DES, and 15% got bare metal stents (BMS). The largest prospective head-to-head RCT was SPIRIT IV, with 2,130 patients. All five TAXUS trials were also included.
The 5-year rate of the primary composite MACE endpoint composed of cardiac death, MI, or ischemia-driven target lesion revascularization was 24.1% in patients with BMS stents, 17.9% with first-gen DES, and 13.4% with second-gen DES, reflecting the advances in stent technology over time. Most of these MACE events occurred during the first year after PCI, with rates of 18%, 8.6%, and 5.3%, respectively, in the three groups. However, the MACE rate beyond the first year out through year 5 remained substantial: 10.2% with first-gen DES, 8.5% with second-gen DES, and 7.4% in the BMS group.
The cardiac death rate from PCI through year 5 was 3.8% with second-gen DES, 3.6% with first-gen DES, and 3.3% with BMS. The MI rate was 7.7% with first-gen DES, 6.1% with BMS, and 5% with second-gen DES.
Stent thrombosis occurred during the first year in 0.9% of first-gen DES and BMS recipients and in 0.7% of patients with second-gen DES. During years 1-5, the rates were 1.6% with first-gen DES, 0.9% with second-gen devices, and 0.2% with BMS.
Second-gen DES provided a big advantage in terms of lessened need for ischemia-driven target lesion revascularization through the first 5 years, with a rate of 7.3%, compared to 18.7% in patients with first-gen DES and 10.5% with BMS.
In a multivariate regression analysis, independent predictors of MACE in the first 5 years post PCI included indicators of greater lesion and/or procedural complexity, such as left main or left anterior descending disease, greater lesion length, and more than one treated lesion, as well as standard cardiovascular risk factors, including recent smoking, hypertension, and diabetes.
In contrast, hyperlipidemia was associated with a significant 15% reduction in MACE risk, which in an interview Dr. Madhavan said may have been due to aggressive lipid-lowering therapy, although he added that this is conjecture because he and his coinvestigators didn’t have access to data on the use of guideline-directed medical therapy or antiplatelet regimens.
Asked about future prospects for reducing the substantial very late risk of MACE highlighted in his study, Dr. Madhavan cited the use of adjunctive imaging during PCI as promising.
“The currently enrolling ILUMEN IV trial, among other studies, will help determine whether imaging-guided intervention can help improve intermediate and long-term rates of MACE,” he observed.
Promising medical therapies that could potentially confer benefit in terms of reducing long-term MACE in patients who’ve undergone PCI for SIHD include novel lipid-lowering drugs, tailored antithrombotic strategies, new anti-inflammatory agents, and the SGLT2 inhibitors, Dr. Madhavan continued.
In terms of advances in stent design, he cited recent evidence that ultrathin-strut stents featuring bioresorbable polymer, such as the Orsiro stent, may reduce late stent-related MACE through 3 years.
“We’ll have to see if these benefits extend to longer-term follow-up up to 5 years,” he said.
He deemed his study results “fairly consistent” with those of the ISCHEMIA trial, where ischemic events in the patients with SIHD assigned to an initial invasive strategy continued to occur in the latter years of follow-up without any clear plateau effect (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Dr. Madhavan reported no financial conflicts regarding his study, funded by an institutional research grant from the National Heart, Lung, and Blood Institute.
Shortly following Dr. Madhavan’s presentation at ACC 2020, the study results were published online (Circ Cardiovasc Interv. 2020 Apr;13[4[:e008565. doi: 10.1161/CIRCINTERVENTIONS.119.008565).
SOURCE: Madhavan MV. ACC 2020, Abstract 909-10.
FROM ACC 20
PCSK9 inhibitors unexpectedly link with lower VTE, aortic stenosis
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
REPORTING FROM ACC 20
COVID-19 cases highlight longstanding racial disparities in health care
African Americans are overrepresented among patients who have died as a result of the COVID-19 pandemic, but the current crisis puts a spotlight on long-standing racial disparities in health care and health access in the United States, according to David R. Williams, PhD, a professor of public health at the Harvard T.H. Chan School of Public Health in Boston.
Dr. Williams, a social scientist specializing in the link between race and health, is a professor of African and African American Studies and of Sociology at Harvard. He spoke on the topic of racial disparities amid the COVID-19 pandemic in a teleconference sponsored by the Robert Wood Johnson Foundation.
“Many Americans are shocked” by the higher mortality rates among African American COVID-19 patients, said Dr. Williams. However, data from decades of research show that “black people in America live sicker and shorter lives,” he said.
Keys to the increased mortality among African Americans include an increased prevalence of risk factors, increased risk for exposure to the virus because of socioeconomic factors, and less access to health care if they do become ill, he said.
Many minority individuals work outside the home in areas deemed essential during the pandemic, such as transit, delivery, maintenance, cleaning, and in businesses such as grocery stores, although in general “race continues to matter for health at every level of income and education,” Dr. Williams said.
In addition, social distance guidelines are not realistic for many people in high-density, low-income areas, who often live in shared, multigenerational housing, he said.
Data show that individuals with chronic conditions such as diabetes and cardiovascular disease are more likely to die as a result of COVID-19, and minority populations are more likely to develop these conditions at younger ages, Dr. Williams noted. Access to health care also plays a role. Many minority individuals of lower socioeconomic status are less likely to have health insurance, or if they do, may have Medicaid, which is not consistently accepted, he said. Also, some low-income neighborhoods lack convenient access to primary care and thus to screening services, he noted.
Dr. Williams said the COVID-19 pandemic could serve as an opportunity to examine and improve health care services for underserved communities. In the short term, “we need to collect data so we can see patterns” and address pressing needs, he said, but long-term goals should “prioritize investments that would create healthy homes and communities,” he emphasized.
A recent study from the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report cited COVID-NET (the COVID-19 Associated Hospitalization Surveillance Network) as showing that, in their catchment population, “approximately 59% of residents are white, 18% are black, and 14% are Hispanic; however, among 580 hospitalized COVID-19 patients with race/ethnicity data, approximately 45% were white, 33% were black, and 8% were Hispanic, suggesting that black populations might be disproportionately affected by COVID-19,” the researchers said.
“These findings, including the potential impact of both sex and race on COVID-19–associated hospitalization rates, need to be confirmed with additional data,” according to the report.
Collecting racial/ethnic information is not always feasible on the front lines, and many areas still face shortages of ventilators and protective equipment, said Dr. Williams.
“I want to salute the providers on the front lines of this pandemic, many putting their own lives at risk, I want to acknowledge the good that they are doing,” Dr. Williams emphasized. He noted that all of us, himself included, may have conscious or unconscious stereotypes, but the key is to acknowledge the potential for these thoughts and feelings and continue to provide the best care.
Clyde W. Yancy, MD, of Northwestern University in Chicago, expressed similar concerns about disparity in COVID-19 cases in an editorial published on April 15 in JAMA.
“Researchers have emphasized older age, male sex, hypertension, diabetes, obesity, concomitant cardiovascular diseases (including coronary artery disease and heart failure), and myocardial injury as important risk factors associated with worse outcomes,” wrote Dr. Yancy. However, evidence also suggests that “persons who are African American or black are contracting SARS-CoV-2 at higher rates and are more likely to die,” he said.
“Why is this uniquely important to me? I am an academic cardiologist; I study health care disparities; and I am a black man,” he wrote.
“Even though these data are preliminary and further study is warranted, the pattern is irrefutable: Underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately,” said Dr. Yancy.
Dr. Williams’ and Dr. Yancy’s comments were supported by an analysis of COVID-19 patient data from several areas of the country conducted by the Washington Post. In that analysis, data showed that several counties with a majority black population showed three times the rate of COVID-19 infections and approximately six times as many deaths compared with counties with a majority of white residents.
“The U.S. has needed a trigger to fully address health care disparities; COVID-19 may be that bellwether event,” said Dr. Yancy. “Certainly, within the broad and powerful economic and legislative engines of the US, there is room to definitively address a scourge even worse than COVID-19: health care disparities. It only takes will. It is time to end the refrain,” he said.
Dr. Williams had no financial conflicts to disclose. Dr. Yancy had no financial conflicts to disclose.
SOURCES: Yancy CW. JAMA 2020 Apr 15. doi: 10.1001/jama.2020.6548Garg S et al. MMWR Morb Mortal Wkly Rep 2020 Apr 8;69:458-64.
Thebault R et al. The coronavirus is infecting and killing black Americans at an alarmingly high rate. Washington Post. 2020 Apr 7.
African Americans are overrepresented among patients who have died as a result of the COVID-19 pandemic, but the current crisis puts a spotlight on long-standing racial disparities in health care and health access in the United States, according to David R. Williams, PhD, a professor of public health at the Harvard T.H. Chan School of Public Health in Boston.
Dr. Williams, a social scientist specializing in the link between race and health, is a professor of African and African American Studies and of Sociology at Harvard. He spoke on the topic of racial disparities amid the COVID-19 pandemic in a teleconference sponsored by the Robert Wood Johnson Foundation.
“Many Americans are shocked” by the higher mortality rates among African American COVID-19 patients, said Dr. Williams. However, data from decades of research show that “black people in America live sicker and shorter lives,” he said.
Keys to the increased mortality among African Americans include an increased prevalence of risk factors, increased risk for exposure to the virus because of socioeconomic factors, and less access to health care if they do become ill, he said.
Many minority individuals work outside the home in areas deemed essential during the pandemic, such as transit, delivery, maintenance, cleaning, and in businesses such as grocery stores, although in general “race continues to matter for health at every level of income and education,” Dr. Williams said.
In addition, social distance guidelines are not realistic for many people in high-density, low-income areas, who often live in shared, multigenerational housing, he said.
Data show that individuals with chronic conditions such as diabetes and cardiovascular disease are more likely to die as a result of COVID-19, and minority populations are more likely to develop these conditions at younger ages, Dr. Williams noted. Access to health care also plays a role. Many minority individuals of lower socioeconomic status are less likely to have health insurance, or if they do, may have Medicaid, which is not consistently accepted, he said. Also, some low-income neighborhoods lack convenient access to primary care and thus to screening services, he noted.
Dr. Williams said the COVID-19 pandemic could serve as an opportunity to examine and improve health care services for underserved communities. In the short term, “we need to collect data so we can see patterns” and address pressing needs, he said, but long-term goals should “prioritize investments that would create healthy homes and communities,” he emphasized.
A recent study from the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report cited COVID-NET (the COVID-19 Associated Hospitalization Surveillance Network) as showing that, in their catchment population, “approximately 59% of residents are white, 18% are black, and 14% are Hispanic; however, among 580 hospitalized COVID-19 patients with race/ethnicity data, approximately 45% were white, 33% were black, and 8% were Hispanic, suggesting that black populations might be disproportionately affected by COVID-19,” the researchers said.
“These findings, including the potential impact of both sex and race on COVID-19–associated hospitalization rates, need to be confirmed with additional data,” according to the report.
Collecting racial/ethnic information is not always feasible on the front lines, and many areas still face shortages of ventilators and protective equipment, said Dr. Williams.
“I want to salute the providers on the front lines of this pandemic, many putting their own lives at risk, I want to acknowledge the good that they are doing,” Dr. Williams emphasized. He noted that all of us, himself included, may have conscious or unconscious stereotypes, but the key is to acknowledge the potential for these thoughts and feelings and continue to provide the best care.
Clyde W. Yancy, MD, of Northwestern University in Chicago, expressed similar concerns about disparity in COVID-19 cases in an editorial published on April 15 in JAMA.
“Researchers have emphasized older age, male sex, hypertension, diabetes, obesity, concomitant cardiovascular diseases (including coronary artery disease and heart failure), and myocardial injury as important risk factors associated with worse outcomes,” wrote Dr. Yancy. However, evidence also suggests that “persons who are African American or black are contracting SARS-CoV-2 at higher rates and are more likely to die,” he said.
“Why is this uniquely important to me? I am an academic cardiologist; I study health care disparities; and I am a black man,” he wrote.
“Even though these data are preliminary and further study is warranted, the pattern is irrefutable: Underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately,” said Dr. Yancy.
Dr. Williams’ and Dr. Yancy’s comments were supported by an analysis of COVID-19 patient data from several areas of the country conducted by the Washington Post. In that analysis, data showed that several counties with a majority black population showed three times the rate of COVID-19 infections and approximately six times as many deaths compared with counties with a majority of white residents.
“The U.S. has needed a trigger to fully address health care disparities; COVID-19 may be that bellwether event,” said Dr. Yancy. “Certainly, within the broad and powerful economic and legislative engines of the US, there is room to definitively address a scourge even worse than COVID-19: health care disparities. It only takes will. It is time to end the refrain,” he said.
Dr. Williams had no financial conflicts to disclose. Dr. Yancy had no financial conflicts to disclose.
SOURCES: Yancy CW. JAMA 2020 Apr 15. doi: 10.1001/jama.2020.6548Garg S et al. MMWR Morb Mortal Wkly Rep 2020 Apr 8;69:458-64.
Thebault R et al. The coronavirus is infecting and killing black Americans at an alarmingly high rate. Washington Post. 2020 Apr 7.
African Americans are overrepresented among patients who have died as a result of the COVID-19 pandemic, but the current crisis puts a spotlight on long-standing racial disparities in health care and health access in the United States, according to David R. Williams, PhD, a professor of public health at the Harvard T.H. Chan School of Public Health in Boston.
Dr. Williams, a social scientist specializing in the link between race and health, is a professor of African and African American Studies and of Sociology at Harvard. He spoke on the topic of racial disparities amid the COVID-19 pandemic in a teleconference sponsored by the Robert Wood Johnson Foundation.
“Many Americans are shocked” by the higher mortality rates among African American COVID-19 patients, said Dr. Williams. However, data from decades of research show that “black people in America live sicker and shorter lives,” he said.
Keys to the increased mortality among African Americans include an increased prevalence of risk factors, increased risk for exposure to the virus because of socioeconomic factors, and less access to health care if they do become ill, he said.
Many minority individuals work outside the home in areas deemed essential during the pandemic, such as transit, delivery, maintenance, cleaning, and in businesses such as grocery stores, although in general “race continues to matter for health at every level of income and education,” Dr. Williams said.
In addition, social distance guidelines are not realistic for many people in high-density, low-income areas, who often live in shared, multigenerational housing, he said.
Data show that individuals with chronic conditions such as diabetes and cardiovascular disease are more likely to die as a result of COVID-19, and minority populations are more likely to develop these conditions at younger ages, Dr. Williams noted. Access to health care also plays a role. Many minority individuals of lower socioeconomic status are less likely to have health insurance, or if they do, may have Medicaid, which is not consistently accepted, he said. Also, some low-income neighborhoods lack convenient access to primary care and thus to screening services, he noted.
Dr. Williams said the COVID-19 pandemic could serve as an opportunity to examine and improve health care services for underserved communities. In the short term, “we need to collect data so we can see patterns” and address pressing needs, he said, but long-term goals should “prioritize investments that would create healthy homes and communities,” he emphasized.
A recent study from the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report cited COVID-NET (the COVID-19 Associated Hospitalization Surveillance Network) as showing that, in their catchment population, “approximately 59% of residents are white, 18% are black, and 14% are Hispanic; however, among 580 hospitalized COVID-19 patients with race/ethnicity data, approximately 45% were white, 33% were black, and 8% were Hispanic, suggesting that black populations might be disproportionately affected by COVID-19,” the researchers said.
“These findings, including the potential impact of both sex and race on COVID-19–associated hospitalization rates, need to be confirmed with additional data,” according to the report.
Collecting racial/ethnic information is not always feasible on the front lines, and many areas still face shortages of ventilators and protective equipment, said Dr. Williams.
“I want to salute the providers on the front lines of this pandemic, many putting their own lives at risk, I want to acknowledge the good that they are doing,” Dr. Williams emphasized. He noted that all of us, himself included, may have conscious or unconscious stereotypes, but the key is to acknowledge the potential for these thoughts and feelings and continue to provide the best care.
Clyde W. Yancy, MD, of Northwestern University in Chicago, expressed similar concerns about disparity in COVID-19 cases in an editorial published on April 15 in JAMA.
“Researchers have emphasized older age, male sex, hypertension, diabetes, obesity, concomitant cardiovascular diseases (including coronary artery disease and heart failure), and myocardial injury as important risk factors associated with worse outcomes,” wrote Dr. Yancy. However, evidence also suggests that “persons who are African American or black are contracting SARS-CoV-2 at higher rates and are more likely to die,” he said.
“Why is this uniquely important to me? I am an academic cardiologist; I study health care disparities; and I am a black man,” he wrote.
“Even though these data are preliminary and further study is warranted, the pattern is irrefutable: Underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately,” said Dr. Yancy.
Dr. Williams’ and Dr. Yancy’s comments were supported by an analysis of COVID-19 patient data from several areas of the country conducted by the Washington Post. In that analysis, data showed that several counties with a majority black population showed three times the rate of COVID-19 infections and approximately six times as many deaths compared with counties with a majority of white residents.
“The U.S. has needed a trigger to fully address health care disparities; COVID-19 may be that bellwether event,” said Dr. Yancy. “Certainly, within the broad and powerful economic and legislative engines of the US, there is room to definitively address a scourge even worse than COVID-19: health care disparities. It only takes will. It is time to end the refrain,” he said.
Dr. Williams had no financial conflicts to disclose. Dr. Yancy had no financial conflicts to disclose.
SOURCES: Yancy CW. JAMA 2020 Apr 15. doi: 10.1001/jama.2020.6548Garg S et al. MMWR Morb Mortal Wkly Rep 2020 Apr 8;69:458-64.
Thebault R et al. The coronavirus is infecting and killing black Americans at an alarmingly high rate. Washington Post. 2020 Apr 7.
FROM A TELECONFERENCE SPONSORED BY THE ROBERT WOOD JOHNSON FOUNDATION
Troponins touted as ‘ally’ in COVID-19 triage, but message is nuanced
, cardiologists in the United Kingdom advise in a recently published viewpoint.
The tests can be used to “inform the triage of patients to critical care, guide the use of supportive treatments, and facilitate targeted cardiac investigations in those most likely to benefit,” Nicholas Mills, MD, PhD, University of Edinburgh, United Kingdom, told theheart.org | Medscape Cardiology. He is senior author on the viewpoint published online April 6 in the journal Circulation.
Older adults and those with a history of underlying cardiovascular disease appear to be at greatest risk of dying from COVID-19. “From early reports it is clear that elevated cardiac troponin concentrations predict in-hospital mortality,” said Mills.
In a recent report on hospitalized patients with COVID-19 in Wuhan, China, for example, cardiac injury (hs-cTn above the 99th-percentile upper reference limit) was seen in 1 in 5 patients and was an independent predictor of dying in the hospital. Mortality was 10-fold higher in those with cardiac injury on presentation.
Elevated cardiac troponin in the setting of COVID-19, Mills said, “may reflect illness severity with myocardial injury arising due to myocardial oxygen supply–demand imbalance. Or it may be due to direct cardiac involvement through viral myocarditis or stress cardiomyopathy, or where the prothrombotic and proinflammatory state is precipitating acute coronary syndromes.”
In their viewpoint, the authors note that circulating cTn is a marker of myocardial injury, “including but not limited to myocardial infarction or myocarditis, and the clinical relevance of this distinction has never been so clear.”
Therefore, the consequence of not measuring cardiac troponin may be to “ignore the plethora of ischemic and nonischemic causes” of myocardial injury related to COVID-19. “Clinicians who have used troponin measurement as a binary test for myocardial infarction independent of clinical context and those who consider an elevated cardiac troponin concentration to be a mandate for invasive coronary angiography must recalibrate,” they write.
“Rather than encouraging avoidance of troponin testing, we must harness the unheralded engagement from the cardiovascular community due to COVID-19 to better understand the utility of this essential biomarker and to educate clinicians on its interpretation and implications for prognosis and clinical decision making.”
Based on “same logic” as recent ACC guidance
The viewpoint was to some extent a response to a recent informal guidance from the American College of Cardiology (ACC) that advised caution in use of troponin and natriuretic peptide tests in patients with COVID-19.
Even so, that ACC guidance and the new viewpoint in Circulation are based on the “same logic,” James Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. Both documents:
- Point out that troponins are frequently abnormal in patients with severe cases of COVID-19
- Caution that clinicians should not equate an abnormal hs-cTn with acute myocardial infarction
- Note that, in most cases, hs-cTn elevations are a result of noncoronary mechanisms
- Recognize the potential risk to caregivers and the continued unchecked spread of SARS-CoV-2 related to downstream testing that might not be needed
“The Circulation opinion piece states that clinicians often use troponin as a binary test for myocardial infarction and a mandate for downstream testing, suggesting clinicians will need to recalibrate that approach, something I agree with and which is the central message of the ACC position,” Januzzi said.
Probably the biggest difference between the two documents, he said, is in the Circulation authors’ apparent enthusiasm to use hs-cTn as a tool to judge disease severity in patients with COVID-19.
It’s been known for more than a decade that myocardial injury is “an important risk predictor” in critical illness, Januzzi explained. “So the link between cardiac injury and outcomes in critical illness is nothing new. The difference is the fact we are seeing so many patients with COVID-19 all at once, and the authors suggest that using troponin might help in triage decision making.”
“There may be [such] a role here, but the data have not been systematically collected, and whether troponin truly adds something beyond information already available at the bedside — for example, does it add anything not already obvious at the bedside? — has not yet been conclusively proven,” Januzzi cautioned.
“As well, there are no prospective data supporting troponin as a trigger for ICU triage or for deciding on specific treatments.”
Positive cTn status “common” in COVID-19 patients
In his experience, Barry Cohen, MD, Morristown Medical Center, New Jersey, told theheart.org | Medscape Cardiology, that positive cTn status is “common in COVID-19 patients and appears to have prognostic value, not only in type 1 MI due to atherothrombotic disease (related to a proinflammatory and prothrombotic state), but more frequently type 2 MI (supply–demand mismatch), viral myocarditis, coronary microvascular ischemia, stress cardiomyopathy or tachyarrhythmias.”
Moreover, Cohen said, hs-cTn “has identified patients at increased risk for ventilation support (invasive and noninvasive), acute respiratory distress syndrome, acute kidney injury, and mortality.”
Echoing both the ACC document and the Circulation report, Cohen also said hs-cTn measurements “appear to help risk stratify COVID-19 patients, but clearly do not mean that a troponin-positive patient needs to go to the cath lab and be treated as having acute coronary syndrome. Only a minority of these patients require this intervention.”
Mills discloses receiving honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. Januzzi has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Cohen has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
, cardiologists in the United Kingdom advise in a recently published viewpoint.
The tests can be used to “inform the triage of patients to critical care, guide the use of supportive treatments, and facilitate targeted cardiac investigations in those most likely to benefit,” Nicholas Mills, MD, PhD, University of Edinburgh, United Kingdom, told theheart.org | Medscape Cardiology. He is senior author on the viewpoint published online April 6 in the journal Circulation.
Older adults and those with a history of underlying cardiovascular disease appear to be at greatest risk of dying from COVID-19. “From early reports it is clear that elevated cardiac troponin concentrations predict in-hospital mortality,” said Mills.
In a recent report on hospitalized patients with COVID-19 in Wuhan, China, for example, cardiac injury (hs-cTn above the 99th-percentile upper reference limit) was seen in 1 in 5 patients and was an independent predictor of dying in the hospital. Mortality was 10-fold higher in those with cardiac injury on presentation.
Elevated cardiac troponin in the setting of COVID-19, Mills said, “may reflect illness severity with myocardial injury arising due to myocardial oxygen supply–demand imbalance. Or it may be due to direct cardiac involvement through viral myocarditis or stress cardiomyopathy, or where the prothrombotic and proinflammatory state is precipitating acute coronary syndromes.”
In their viewpoint, the authors note that circulating cTn is a marker of myocardial injury, “including but not limited to myocardial infarction or myocarditis, and the clinical relevance of this distinction has never been so clear.”
Therefore, the consequence of not measuring cardiac troponin may be to “ignore the plethora of ischemic and nonischemic causes” of myocardial injury related to COVID-19. “Clinicians who have used troponin measurement as a binary test for myocardial infarction independent of clinical context and those who consider an elevated cardiac troponin concentration to be a mandate for invasive coronary angiography must recalibrate,” they write.
“Rather than encouraging avoidance of troponin testing, we must harness the unheralded engagement from the cardiovascular community due to COVID-19 to better understand the utility of this essential biomarker and to educate clinicians on its interpretation and implications for prognosis and clinical decision making.”
Based on “same logic” as recent ACC guidance
The viewpoint was to some extent a response to a recent informal guidance from the American College of Cardiology (ACC) that advised caution in use of troponin and natriuretic peptide tests in patients with COVID-19.
Even so, that ACC guidance and the new viewpoint in Circulation are based on the “same logic,” James Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. Both documents:
- Point out that troponins are frequently abnormal in patients with severe cases of COVID-19
- Caution that clinicians should not equate an abnormal hs-cTn with acute myocardial infarction
- Note that, in most cases, hs-cTn elevations are a result of noncoronary mechanisms
- Recognize the potential risk to caregivers and the continued unchecked spread of SARS-CoV-2 related to downstream testing that might not be needed
“The Circulation opinion piece states that clinicians often use troponin as a binary test for myocardial infarction and a mandate for downstream testing, suggesting clinicians will need to recalibrate that approach, something I agree with and which is the central message of the ACC position,” Januzzi said.
Probably the biggest difference between the two documents, he said, is in the Circulation authors’ apparent enthusiasm to use hs-cTn as a tool to judge disease severity in patients with COVID-19.
It’s been known for more than a decade that myocardial injury is “an important risk predictor” in critical illness, Januzzi explained. “So the link between cardiac injury and outcomes in critical illness is nothing new. The difference is the fact we are seeing so many patients with COVID-19 all at once, and the authors suggest that using troponin might help in triage decision making.”
“There may be [such] a role here, but the data have not been systematically collected, and whether troponin truly adds something beyond information already available at the bedside — for example, does it add anything not already obvious at the bedside? — has not yet been conclusively proven,” Januzzi cautioned.
“As well, there are no prospective data supporting troponin as a trigger for ICU triage or for deciding on specific treatments.”
Positive cTn status “common” in COVID-19 patients
In his experience, Barry Cohen, MD, Morristown Medical Center, New Jersey, told theheart.org | Medscape Cardiology, that positive cTn status is “common in COVID-19 patients and appears to have prognostic value, not only in type 1 MI due to atherothrombotic disease (related to a proinflammatory and prothrombotic state), but more frequently type 2 MI (supply–demand mismatch), viral myocarditis, coronary microvascular ischemia, stress cardiomyopathy or tachyarrhythmias.”
Moreover, Cohen said, hs-cTn “has identified patients at increased risk for ventilation support (invasive and noninvasive), acute respiratory distress syndrome, acute kidney injury, and mortality.”
Echoing both the ACC document and the Circulation report, Cohen also said hs-cTn measurements “appear to help risk stratify COVID-19 patients, but clearly do not mean that a troponin-positive patient needs to go to the cath lab and be treated as having acute coronary syndrome. Only a minority of these patients require this intervention.”
Mills discloses receiving honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. Januzzi has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Cohen has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
, cardiologists in the United Kingdom advise in a recently published viewpoint.
The tests can be used to “inform the triage of patients to critical care, guide the use of supportive treatments, and facilitate targeted cardiac investigations in those most likely to benefit,” Nicholas Mills, MD, PhD, University of Edinburgh, United Kingdom, told theheart.org | Medscape Cardiology. He is senior author on the viewpoint published online April 6 in the journal Circulation.
Older adults and those with a history of underlying cardiovascular disease appear to be at greatest risk of dying from COVID-19. “From early reports it is clear that elevated cardiac troponin concentrations predict in-hospital mortality,” said Mills.
In a recent report on hospitalized patients with COVID-19 in Wuhan, China, for example, cardiac injury (hs-cTn above the 99th-percentile upper reference limit) was seen in 1 in 5 patients and was an independent predictor of dying in the hospital. Mortality was 10-fold higher in those with cardiac injury on presentation.
Elevated cardiac troponin in the setting of COVID-19, Mills said, “may reflect illness severity with myocardial injury arising due to myocardial oxygen supply–demand imbalance. Or it may be due to direct cardiac involvement through viral myocarditis or stress cardiomyopathy, or where the prothrombotic and proinflammatory state is precipitating acute coronary syndromes.”
In their viewpoint, the authors note that circulating cTn is a marker of myocardial injury, “including but not limited to myocardial infarction or myocarditis, and the clinical relevance of this distinction has never been so clear.”
Therefore, the consequence of not measuring cardiac troponin may be to “ignore the plethora of ischemic and nonischemic causes” of myocardial injury related to COVID-19. “Clinicians who have used troponin measurement as a binary test for myocardial infarction independent of clinical context and those who consider an elevated cardiac troponin concentration to be a mandate for invasive coronary angiography must recalibrate,” they write.
“Rather than encouraging avoidance of troponin testing, we must harness the unheralded engagement from the cardiovascular community due to COVID-19 to better understand the utility of this essential biomarker and to educate clinicians on its interpretation and implications for prognosis and clinical decision making.”
Based on “same logic” as recent ACC guidance
The viewpoint was to some extent a response to a recent informal guidance from the American College of Cardiology (ACC) that advised caution in use of troponin and natriuretic peptide tests in patients with COVID-19.
Even so, that ACC guidance and the new viewpoint in Circulation are based on the “same logic,” James Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. Both documents:
- Point out that troponins are frequently abnormal in patients with severe cases of COVID-19
- Caution that clinicians should not equate an abnormal hs-cTn with acute myocardial infarction
- Note that, in most cases, hs-cTn elevations are a result of noncoronary mechanisms
- Recognize the potential risk to caregivers and the continued unchecked spread of SARS-CoV-2 related to downstream testing that might not be needed
“The Circulation opinion piece states that clinicians often use troponin as a binary test for myocardial infarction and a mandate for downstream testing, suggesting clinicians will need to recalibrate that approach, something I agree with and which is the central message of the ACC position,” Januzzi said.
Probably the biggest difference between the two documents, he said, is in the Circulation authors’ apparent enthusiasm to use hs-cTn as a tool to judge disease severity in patients with COVID-19.
It’s been known for more than a decade that myocardial injury is “an important risk predictor” in critical illness, Januzzi explained. “So the link between cardiac injury and outcomes in critical illness is nothing new. The difference is the fact we are seeing so many patients with COVID-19 all at once, and the authors suggest that using troponin might help in triage decision making.”
“There may be [such] a role here, but the data have not been systematically collected, and whether troponin truly adds something beyond information already available at the bedside — for example, does it add anything not already obvious at the bedside? — has not yet been conclusively proven,” Januzzi cautioned.
“As well, there are no prospective data supporting troponin as a trigger for ICU triage or for deciding on specific treatments.”
Positive cTn status “common” in COVID-19 patients
In his experience, Barry Cohen, MD, Morristown Medical Center, New Jersey, told theheart.org | Medscape Cardiology, that positive cTn status is “common in COVID-19 patients and appears to have prognostic value, not only in type 1 MI due to atherothrombotic disease (related to a proinflammatory and prothrombotic state), but more frequently type 2 MI (supply–demand mismatch), viral myocarditis, coronary microvascular ischemia, stress cardiomyopathy or tachyarrhythmias.”
Moreover, Cohen said, hs-cTn “has identified patients at increased risk for ventilation support (invasive and noninvasive), acute respiratory distress syndrome, acute kidney injury, and mortality.”
Echoing both the ACC document and the Circulation report, Cohen also said hs-cTn measurements “appear to help risk stratify COVID-19 patients, but clearly do not mean that a troponin-positive patient needs to go to the cath lab and be treated as having acute coronary syndrome. Only a minority of these patients require this intervention.”
Mills discloses receiving honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. Januzzi has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Cohen has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
AHA updates management when CAD and T2DM coincide
Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.
“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.
The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.
The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.
“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .
The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.
“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”
“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).
Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m2.
“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.
Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.
The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.
Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”
Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.
Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.
“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.
The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.
The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.
“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .
The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.
“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”
“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).
Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m2.
“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.
Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.
The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.
Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”
Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.
Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.
“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.
The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.
The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.
“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .
The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.
“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”
“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).
Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m2.
“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.
Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.
The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.
Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”
Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.
FROM CIRCULATION
Radial arteries show CABG survival advantage over saphenous veins
Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.
“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.
The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.
“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.
The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.
Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.
“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.
The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.
“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.
Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”
The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.
SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.
Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.
“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.
The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.
“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.
The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.
Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.
“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.
The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.
“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.
Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”
The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.
SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.
Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.
“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.
The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.
“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.
The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.
Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.
“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.
The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.
“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.
Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”
The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.
SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.
FROM ACC 2020