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Moment of truth approaches for low-risk TAVR
SNOWMASS, COLO. – There are now more transcatheter aortic valve replacements performed each year than surgical ones in the United States, a disparity that may grow vastly larger.
That’s if the results of the two pivotal randomized trials comparing transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in low-surgical-risk patients scheduled for presentation at the annual scientific session of the American College of Cardiology in March turn out to show TAVR outcomes are equivalent or superior to SAVR.
And that just might be the scenario, provided the eye-popping results already reported from another, much smaller study – the Low Risk TAVR study, a 200-patient, prospective, nonrandomized, observational study – are at all reflective of what’s to come when the pivotal PARTNER 3 and EVOLUT R trials are released at the ACC meeting in New Orleans, Michael J. Mack, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“The TAVR train has left the station on the way to low risk, and I don’t really see it coming back,” said Dr. Mack, medical director for cardiothoracic surgery at Baylor Scott & White Health in Dallas.
He wasn’t part of the Low Risk TAVR study, in which 200 low-surgical-risk patients with symptomatic severe aortic stenosis underwent TAVR with contemporary devices at 11 centers and were matched to 719 historical control SAVR patients at the same centers. But he called the study results “pretty spectacular”: zero 30-day all cause mortality in the TAVR group versus 1.7% with SAVR, no in-hospital strokes with TAVR versus a 0.6% rate with SAVR, and similar permanent pacemaker implantation rates of 5.0% with TAVR and 4.5% with SAVR.
Also, the TAVR group had a mere 3.0% rate of new-onset atrial fibrillation, a 2-day hospital length of stay, and a 0.5% incidence of greater-than-mild paravalvular leak at 30 days (J Am Coll Cardiol. 2018 Oct 30;72[18]:2095-105).
The two major trials due to report 1-year outcomes at the ACC meeting in March are similarly designed. The PARTNER 3 trial includes 1,000 low-surgical-risk patients with a mean age of 73 years and a predicted 30-day surgical mortality risk of 1.9%. Seventy-one percent of them were New York Heart Association (NYHA) Class II at enrollment. Participants were randomized to TAVR with the Edwards Lifesciences Sapien 3 valve or to SAVR, with the primary outcome being a composite of all-cause mortality, stroke, and rehospitalization 1 year post procedure. The EVOLUT R trial is similar, except the TAVR valve is the Medtronic CoreValve.
Both trials will continue to follow patients annually for 10 years in order to address the still-open issue of TAVR and SAVR valve durability. Also, the Food and Drug Administration has mandated that 4D CT imaging substudies be conducted in 800 of the combined 2,000 participants in the two trials in order to provide new insight into the issue of subclinical valve leaflet thrombosis, which was detected in 14% of participants in the Low Risk TAVR study 30 days post procedure.
“The clinical impact and need for anticoagulant therapy are currently unknown. However, clot anywhere else in the body doesn’t do good things, so it’s hard to imagine it’s helping here. Pretending it doesn’t exist isn’t going to make the problem go away,” Dr. Mack said.
The 4D CT imaging substudy results are expected to be presented later this year at the Transcatheter Cardiovascular Therapeutics conference in San Francisco.
In 2017, 51,064 TAVR procedures for symptomatic severe aortic stenosis were done in the United States, compared with 41,490 SAVRs. The past several years have seen a decreasing proportion of TAVRs being done in high-surgical-risk patients and a growing proportion in intermediate-risk patients.
Even if PARTNER 3 and EVOLUT R prove to be resoundingly positive for TAVR in low-risk patients, however, SAVR is not going to vanish, according to Dr. Mack. He cited four factors working against universal adoption of TAVR: the uncertainty surrounding valve durability, which will take years to resolve; the issue of TAVR valve leaflet thrombosis and the for-now theoretic possibility that all TAVR patients might need to receive postprocedure oral anticoagulation; the high rate of new permanent pacemaker implantation associated with TAVR, which Dr. Mack called the procedure’s Achilles heel; and the total absence of high-quality data on TAVR in patients with bicuspid aortic stenosis.
Even though TAVR for diseased bicuspid valves is not off-label therapy – the FDA’s indication for TAVR is for native valve aortic stenosis – patients with bicuspid valves weren’t included in any of the randomized trials, he explained.
Younger patients are likely to stick with SAVR for the foreseeable future, regardless of the outcomes of PARTNER 3 and EVOLUT R, according to the surgeon, because of the unresolved issue of valve durability, as well as TAVR’s greater associated need for a permanent pacemaker, both significant considerations in individuals with a life expectancy of another 20-30 years.
There are now roughly 600 TAVR centers and 1,150 SAVR centers nationally. One of the hot topics in the field stems from the fact that half of these TAVR centers do only one TAVR per week or less. That’s concerning in light of a recent New York State study showing a clear association between operator volume and outcomes.
“The more you do, the better your outcomes are, similar to many other procedures in medicine,” Dr. Mack commented.
On the other hand, it’s unlikely that patients who present to one of the roughly 550 SAVR-only centers are truly getting informed consent as to their options, he added.
TAVR timeline for 2019
March
PARTNER 3 and EVOLUT R primary outcomes to be presented at the American College of Cardiology annual scientific session.
Centers for Medicare & Medicaid Services to issue proposal for a revised National Coverage Determination for TAVR reimbursement.
June
Following a public comment period, CMS will release final revised criteria for TAVR reimbursement.
September
Results of the PARTNER 3 and EVOLUT R 4D CT imaging substudies will probably be presented late in the month at the annual Transcatheter Cardiovascular Therapeutics conference in San Francisco.
Late 2019
If PARTNER 3 and EVOLUT R trials are positive, FDA approval of the TAVR valves in low-surgical-risk patients is expected.
Dr. Mack is coprincipal investigator of PARTNER 3, which was sponsored by Edwards Lifesciences, and of Abbott Vascular’s COAPT trial. He’s also on the executive committee of the INTREPID trial, sponsored by Medtronic.
SNOWMASS, COLO. – There are now more transcatheter aortic valve replacements performed each year than surgical ones in the United States, a disparity that may grow vastly larger.
That’s if the results of the two pivotal randomized trials comparing transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in low-surgical-risk patients scheduled for presentation at the annual scientific session of the American College of Cardiology in March turn out to show TAVR outcomes are equivalent or superior to SAVR.
And that just might be the scenario, provided the eye-popping results already reported from another, much smaller study – the Low Risk TAVR study, a 200-patient, prospective, nonrandomized, observational study – are at all reflective of what’s to come when the pivotal PARTNER 3 and EVOLUT R trials are released at the ACC meeting in New Orleans, Michael J. Mack, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“The TAVR train has left the station on the way to low risk, and I don’t really see it coming back,” said Dr. Mack, medical director for cardiothoracic surgery at Baylor Scott & White Health in Dallas.
He wasn’t part of the Low Risk TAVR study, in which 200 low-surgical-risk patients with symptomatic severe aortic stenosis underwent TAVR with contemporary devices at 11 centers and were matched to 719 historical control SAVR patients at the same centers. But he called the study results “pretty spectacular”: zero 30-day all cause mortality in the TAVR group versus 1.7% with SAVR, no in-hospital strokes with TAVR versus a 0.6% rate with SAVR, and similar permanent pacemaker implantation rates of 5.0% with TAVR and 4.5% with SAVR.
Also, the TAVR group had a mere 3.0% rate of new-onset atrial fibrillation, a 2-day hospital length of stay, and a 0.5% incidence of greater-than-mild paravalvular leak at 30 days (J Am Coll Cardiol. 2018 Oct 30;72[18]:2095-105).
The two major trials due to report 1-year outcomes at the ACC meeting in March are similarly designed. The PARTNER 3 trial includes 1,000 low-surgical-risk patients with a mean age of 73 years and a predicted 30-day surgical mortality risk of 1.9%. Seventy-one percent of them were New York Heart Association (NYHA) Class II at enrollment. Participants were randomized to TAVR with the Edwards Lifesciences Sapien 3 valve or to SAVR, with the primary outcome being a composite of all-cause mortality, stroke, and rehospitalization 1 year post procedure. The EVOLUT R trial is similar, except the TAVR valve is the Medtronic CoreValve.
Both trials will continue to follow patients annually for 10 years in order to address the still-open issue of TAVR and SAVR valve durability. Also, the Food and Drug Administration has mandated that 4D CT imaging substudies be conducted in 800 of the combined 2,000 participants in the two trials in order to provide new insight into the issue of subclinical valve leaflet thrombosis, which was detected in 14% of participants in the Low Risk TAVR study 30 days post procedure.
“The clinical impact and need for anticoagulant therapy are currently unknown. However, clot anywhere else in the body doesn’t do good things, so it’s hard to imagine it’s helping here. Pretending it doesn’t exist isn’t going to make the problem go away,” Dr. Mack said.
The 4D CT imaging substudy results are expected to be presented later this year at the Transcatheter Cardiovascular Therapeutics conference in San Francisco.
In 2017, 51,064 TAVR procedures for symptomatic severe aortic stenosis were done in the United States, compared with 41,490 SAVRs. The past several years have seen a decreasing proportion of TAVRs being done in high-surgical-risk patients and a growing proportion in intermediate-risk patients.
Even if PARTNER 3 and EVOLUT R prove to be resoundingly positive for TAVR in low-risk patients, however, SAVR is not going to vanish, according to Dr. Mack. He cited four factors working against universal adoption of TAVR: the uncertainty surrounding valve durability, which will take years to resolve; the issue of TAVR valve leaflet thrombosis and the for-now theoretic possibility that all TAVR patients might need to receive postprocedure oral anticoagulation; the high rate of new permanent pacemaker implantation associated with TAVR, which Dr. Mack called the procedure’s Achilles heel; and the total absence of high-quality data on TAVR in patients with bicuspid aortic stenosis.
Even though TAVR for diseased bicuspid valves is not off-label therapy – the FDA’s indication for TAVR is for native valve aortic stenosis – patients with bicuspid valves weren’t included in any of the randomized trials, he explained.
Younger patients are likely to stick with SAVR for the foreseeable future, regardless of the outcomes of PARTNER 3 and EVOLUT R, according to the surgeon, because of the unresolved issue of valve durability, as well as TAVR’s greater associated need for a permanent pacemaker, both significant considerations in individuals with a life expectancy of another 20-30 years.
There are now roughly 600 TAVR centers and 1,150 SAVR centers nationally. One of the hot topics in the field stems from the fact that half of these TAVR centers do only one TAVR per week or less. That’s concerning in light of a recent New York State study showing a clear association between operator volume and outcomes.
“The more you do, the better your outcomes are, similar to many other procedures in medicine,” Dr. Mack commented.
On the other hand, it’s unlikely that patients who present to one of the roughly 550 SAVR-only centers are truly getting informed consent as to their options, he added.
TAVR timeline for 2019
March
PARTNER 3 and EVOLUT R primary outcomes to be presented at the American College of Cardiology annual scientific session.
Centers for Medicare & Medicaid Services to issue proposal for a revised National Coverage Determination for TAVR reimbursement.
June
Following a public comment period, CMS will release final revised criteria for TAVR reimbursement.
September
Results of the PARTNER 3 and EVOLUT R 4D CT imaging substudies will probably be presented late in the month at the annual Transcatheter Cardiovascular Therapeutics conference in San Francisco.
Late 2019
If PARTNER 3 and EVOLUT R trials are positive, FDA approval of the TAVR valves in low-surgical-risk patients is expected.
Dr. Mack is coprincipal investigator of PARTNER 3, which was sponsored by Edwards Lifesciences, and of Abbott Vascular’s COAPT trial. He’s also on the executive committee of the INTREPID trial, sponsored by Medtronic.
SNOWMASS, COLO. – There are now more transcatheter aortic valve replacements performed each year than surgical ones in the United States, a disparity that may grow vastly larger.
That’s if the results of the two pivotal randomized trials comparing transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in low-surgical-risk patients scheduled for presentation at the annual scientific session of the American College of Cardiology in March turn out to show TAVR outcomes are equivalent or superior to SAVR.
And that just might be the scenario, provided the eye-popping results already reported from another, much smaller study – the Low Risk TAVR study, a 200-patient, prospective, nonrandomized, observational study – are at all reflective of what’s to come when the pivotal PARTNER 3 and EVOLUT R trials are released at the ACC meeting in New Orleans, Michael J. Mack, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“The TAVR train has left the station on the way to low risk, and I don’t really see it coming back,” said Dr. Mack, medical director for cardiothoracic surgery at Baylor Scott & White Health in Dallas.
He wasn’t part of the Low Risk TAVR study, in which 200 low-surgical-risk patients with symptomatic severe aortic stenosis underwent TAVR with contemporary devices at 11 centers and were matched to 719 historical control SAVR patients at the same centers. But he called the study results “pretty spectacular”: zero 30-day all cause mortality in the TAVR group versus 1.7% with SAVR, no in-hospital strokes with TAVR versus a 0.6% rate with SAVR, and similar permanent pacemaker implantation rates of 5.0% with TAVR and 4.5% with SAVR.
Also, the TAVR group had a mere 3.0% rate of new-onset atrial fibrillation, a 2-day hospital length of stay, and a 0.5% incidence of greater-than-mild paravalvular leak at 30 days (J Am Coll Cardiol. 2018 Oct 30;72[18]:2095-105).
The two major trials due to report 1-year outcomes at the ACC meeting in March are similarly designed. The PARTNER 3 trial includes 1,000 low-surgical-risk patients with a mean age of 73 years and a predicted 30-day surgical mortality risk of 1.9%. Seventy-one percent of them were New York Heart Association (NYHA) Class II at enrollment. Participants were randomized to TAVR with the Edwards Lifesciences Sapien 3 valve or to SAVR, with the primary outcome being a composite of all-cause mortality, stroke, and rehospitalization 1 year post procedure. The EVOLUT R trial is similar, except the TAVR valve is the Medtronic CoreValve.
Both trials will continue to follow patients annually for 10 years in order to address the still-open issue of TAVR and SAVR valve durability. Also, the Food and Drug Administration has mandated that 4D CT imaging substudies be conducted in 800 of the combined 2,000 participants in the two trials in order to provide new insight into the issue of subclinical valve leaflet thrombosis, which was detected in 14% of participants in the Low Risk TAVR study 30 days post procedure.
“The clinical impact and need for anticoagulant therapy are currently unknown. However, clot anywhere else in the body doesn’t do good things, so it’s hard to imagine it’s helping here. Pretending it doesn’t exist isn’t going to make the problem go away,” Dr. Mack said.
The 4D CT imaging substudy results are expected to be presented later this year at the Transcatheter Cardiovascular Therapeutics conference in San Francisco.
In 2017, 51,064 TAVR procedures for symptomatic severe aortic stenosis were done in the United States, compared with 41,490 SAVRs. The past several years have seen a decreasing proportion of TAVRs being done in high-surgical-risk patients and a growing proportion in intermediate-risk patients.
Even if PARTNER 3 and EVOLUT R prove to be resoundingly positive for TAVR in low-risk patients, however, SAVR is not going to vanish, according to Dr. Mack. He cited four factors working against universal adoption of TAVR: the uncertainty surrounding valve durability, which will take years to resolve; the issue of TAVR valve leaflet thrombosis and the for-now theoretic possibility that all TAVR patients might need to receive postprocedure oral anticoagulation; the high rate of new permanent pacemaker implantation associated with TAVR, which Dr. Mack called the procedure’s Achilles heel; and the total absence of high-quality data on TAVR in patients with bicuspid aortic stenosis.
Even though TAVR for diseased bicuspid valves is not off-label therapy – the FDA’s indication for TAVR is for native valve aortic stenosis – patients with bicuspid valves weren’t included in any of the randomized trials, he explained.
Younger patients are likely to stick with SAVR for the foreseeable future, regardless of the outcomes of PARTNER 3 and EVOLUT R, according to the surgeon, because of the unresolved issue of valve durability, as well as TAVR’s greater associated need for a permanent pacemaker, both significant considerations in individuals with a life expectancy of another 20-30 years.
There are now roughly 600 TAVR centers and 1,150 SAVR centers nationally. One of the hot topics in the field stems from the fact that half of these TAVR centers do only one TAVR per week or less. That’s concerning in light of a recent New York State study showing a clear association between operator volume and outcomes.
“The more you do, the better your outcomes are, similar to many other procedures in medicine,” Dr. Mack commented.
On the other hand, it’s unlikely that patients who present to one of the roughly 550 SAVR-only centers are truly getting informed consent as to their options, he added.
TAVR timeline for 2019
March
PARTNER 3 and EVOLUT R primary outcomes to be presented at the American College of Cardiology annual scientific session.
Centers for Medicare & Medicaid Services to issue proposal for a revised National Coverage Determination for TAVR reimbursement.
June
Following a public comment period, CMS will release final revised criteria for TAVR reimbursement.
September
Results of the PARTNER 3 and EVOLUT R 4D CT imaging substudies will probably be presented late in the month at the annual Transcatheter Cardiovascular Therapeutics conference in San Francisco.
Late 2019
If PARTNER 3 and EVOLUT R trials are positive, FDA approval of the TAVR valves in low-surgical-risk patients is expected.
Dr. Mack is coprincipal investigator of PARTNER 3, which was sponsored by Edwards Lifesciences, and of Abbott Vascular’s COAPT trial. He’s also on the executive committee of the INTREPID trial, sponsored by Medtronic.
EXPERT ANALYSIS FROM ACC SNOWMASS 2019
Biomarkers predict VTE risk with menopausal oral hormone therapy
CHICAGO – An elevated baseline D-dimer level is helpful to women and their physicians in clarifying decision making about oral hormone therapy for troublesome menopausal symptoms, Mary Cushman, MD, said at the American Heart Association scientific sessions.
She was lead investigator in a nested case-control study embedded in the landmark Women’s Health Initiative (WHI), which showed that participants who had a baseline D-dimer greater than 0.54 mg/L – putting them in the top 25% – and were randomized to oral menopausal hormone therapy had a 5-year incidence of venous thromboembolism (VTE) of 6%. That’s 500% higher than in women with a lower D-dimer randomized to placebo.
“The number needed to test for D-dimer in advance of prescribing in order to prevent one VTE over 5 years of hormone therapy was only 33. So this is potentially something in the toolbox you can use in counseling women about oral hormone therapy,” said Dr. Cushman, professor of medicine and pathology and medical director of the thrombosis and hemostasis program at the University of Vermont, Burlington.
The biomarker study included 1,082 WHI participants aged 50-79 years randomized to oral conjugated equine estrogen with or without medroxyprogesterone acetate or to placebo, 215 of whom experienced VTE during a mean 4.1 years of follow-up. Levels of a variety of biomarkers obtained at baseline were assessed in terms of their associated risk of future VTE. The biomarkers included C-reactive protein and procoagulant, anticoagulant, and fibrinolytic factors.
In a logistic regression analysis adjusted for age, race, body mass index, and hysterectomy, the strongest association with VTE was a high D-dimer. That 500% increased risk of VTE with hormone therapy in women with a D-dimer greater than 0.54 mg/L was comparable in magnitude with the risk Dr. Cushman and her coinvestigators previously reported for the combination of factor V Leiden and hormone therapy.
Dr. Cushman and her associates also took a first step towards developing a multibiomarker risk score. They found that WHI participants randomized to hormone therapy who had abnormal baseline values for any three or more of eight biomarkers had a 1,450% greater risk of future VTE than women with zero or one abnormal biomarker who were assigned to placebo. The eight-biomarker panel described in the recently published study comprised D-dimer, factor V Leiden, protein C, total protein S, free protein S, antithrombin, plasmin-antiplasmin complex, and fragment 1.2. However, the investigators indicated the risk score needs further study before it’s ready for adoption in clinical practice (Res Pract Thromb Haemost. 2018 Apr 17;2[2]:310-9).
Dr. Cushman noted that, although the main findings of the WHI have largely resulted in abandonment of menopausal hormone therapy for disease prevention, many women still want to take oral hormone therapy for relief of bothersome menopausal symptoms. She tries to steer them instead to safer nonoral formulations. Transdermal estrogen replacement has no associated risk of VTE and doesn’t activate anticoagulation. Neither does vaginal estradiol.
In offering what she called “the 30,000-foot view of the impact of venous thrombosis on women’s health,” Dr. Cushman noted that VTE is the third-most common vascular disease in the United States, with up to 900,000 cases per year. The lifetime risk in women after age 45 is 8.4%. Half of VTEs are provoked and therefore potentially preventable, with common triggers being surgery, cancer, pregnancy, trauma, and immobilization, especially during travel.
In addition, a retrospective study conducted in the Worcester, Mass., area showed that 1-month mortality after VTE remained static in the 5%-10% range during 1999-2009.
“This is a fatal disease, even though we treat it as an outpatient quite a lot,” Dr. Cushman observed.
Common nonfatal complications of VTE include major bleeding in 5%-10% of cases, a recurrence rate of 5%-10% annually, a 20%-40% of the burdensome and not infrequently disabling condition known as postthrombotic syndrome, and a 3%-4% incidence of chronic thromboembolic pulmonary hypertension. Yet despite the seriousness of VTE, awareness about VTE is poor among both patients and physicians, and appropriate prophylaxis is underutilized, she said.
The key to improved primary prevention of VTE, Dr. Cushman continued, is greater attention to modifiable behavioral risk factors, along with more use of prophylactic medication when needed.
The traditional cardiovascular risk factors, like hypertension, smoking, and hyperlipidemia, aren’t relevant to VTE risk. But obesity and sedentary lifestyle have come to be recognized as important modifiable risk factors. In one study of more than 30,000 Americans, the risk of VTE was shown to be reduced by 40% in individuals who exercised at least four times per week, compared with the physically inactive.
And in an analysis led by Dr. Cushman of nearly 21,000 participants over age 45 years with 12.6 years of follow-up in the Longitudinal Investigation of Thromboembolism Etiology (LITE), the investigators found that greater levels of all body size measures – not just body mass index, but calf circumference, waist-hip ratio, hip circumference, and others – were associated with increased VTE risk. These associations weren’t affected by levels of circulating biomarkers for inflammation or hypercoagulability, suggesting that it’s obesity per se, with its associated adverse impact on blood flow caused by physical factors, that explains the mechanism underlying obesity as a risk factor for VTE (Thromb Res. 2016 Aug;144:127-32).
At the meeting’s opening ceremonies, AHA President Ivor Benjamin, MD, of the Medical College of Wisconsin, Milwaukee, presented Dr. Cushman with the AHA Population Research Prize. She was honored for her “critically acclaimed research utilizing biomarker assessments in population studies to elucidate pathways of disease etiology for the three most common vascular diseases – coronary heart disease, stroke, and venous thromboembolism – as well as their risk factors,” said Dr. Benjamin.
Dr. Cushman reported having no financial conflicts regarding her D-dimer study, which was funded by the National Institutes of Health.
CHICAGO – An elevated baseline D-dimer level is helpful to women and their physicians in clarifying decision making about oral hormone therapy for troublesome menopausal symptoms, Mary Cushman, MD, said at the American Heart Association scientific sessions.
She was lead investigator in a nested case-control study embedded in the landmark Women’s Health Initiative (WHI), which showed that participants who had a baseline D-dimer greater than 0.54 mg/L – putting them in the top 25% – and were randomized to oral menopausal hormone therapy had a 5-year incidence of venous thromboembolism (VTE) of 6%. That’s 500% higher than in women with a lower D-dimer randomized to placebo.
“The number needed to test for D-dimer in advance of prescribing in order to prevent one VTE over 5 years of hormone therapy was only 33. So this is potentially something in the toolbox you can use in counseling women about oral hormone therapy,” said Dr. Cushman, professor of medicine and pathology and medical director of the thrombosis and hemostasis program at the University of Vermont, Burlington.
The biomarker study included 1,082 WHI participants aged 50-79 years randomized to oral conjugated equine estrogen with or without medroxyprogesterone acetate or to placebo, 215 of whom experienced VTE during a mean 4.1 years of follow-up. Levels of a variety of biomarkers obtained at baseline were assessed in terms of their associated risk of future VTE. The biomarkers included C-reactive protein and procoagulant, anticoagulant, and fibrinolytic factors.
In a logistic regression analysis adjusted for age, race, body mass index, and hysterectomy, the strongest association with VTE was a high D-dimer. That 500% increased risk of VTE with hormone therapy in women with a D-dimer greater than 0.54 mg/L was comparable in magnitude with the risk Dr. Cushman and her coinvestigators previously reported for the combination of factor V Leiden and hormone therapy.
Dr. Cushman and her associates also took a first step towards developing a multibiomarker risk score. They found that WHI participants randomized to hormone therapy who had abnormal baseline values for any three or more of eight biomarkers had a 1,450% greater risk of future VTE than women with zero or one abnormal biomarker who were assigned to placebo. The eight-biomarker panel described in the recently published study comprised D-dimer, factor V Leiden, protein C, total protein S, free protein S, antithrombin, plasmin-antiplasmin complex, and fragment 1.2. However, the investigators indicated the risk score needs further study before it’s ready for adoption in clinical practice (Res Pract Thromb Haemost. 2018 Apr 17;2[2]:310-9).
Dr. Cushman noted that, although the main findings of the WHI have largely resulted in abandonment of menopausal hormone therapy for disease prevention, many women still want to take oral hormone therapy for relief of bothersome menopausal symptoms. She tries to steer them instead to safer nonoral formulations. Transdermal estrogen replacement has no associated risk of VTE and doesn’t activate anticoagulation. Neither does vaginal estradiol.
In offering what she called “the 30,000-foot view of the impact of venous thrombosis on women’s health,” Dr. Cushman noted that VTE is the third-most common vascular disease in the United States, with up to 900,000 cases per year. The lifetime risk in women after age 45 is 8.4%. Half of VTEs are provoked and therefore potentially preventable, with common triggers being surgery, cancer, pregnancy, trauma, and immobilization, especially during travel.
In addition, a retrospective study conducted in the Worcester, Mass., area showed that 1-month mortality after VTE remained static in the 5%-10% range during 1999-2009.
“This is a fatal disease, even though we treat it as an outpatient quite a lot,” Dr. Cushman observed.
Common nonfatal complications of VTE include major bleeding in 5%-10% of cases, a recurrence rate of 5%-10% annually, a 20%-40% of the burdensome and not infrequently disabling condition known as postthrombotic syndrome, and a 3%-4% incidence of chronic thromboembolic pulmonary hypertension. Yet despite the seriousness of VTE, awareness about VTE is poor among both patients and physicians, and appropriate prophylaxis is underutilized, she said.
The key to improved primary prevention of VTE, Dr. Cushman continued, is greater attention to modifiable behavioral risk factors, along with more use of prophylactic medication when needed.
The traditional cardiovascular risk factors, like hypertension, smoking, and hyperlipidemia, aren’t relevant to VTE risk. But obesity and sedentary lifestyle have come to be recognized as important modifiable risk factors. In one study of more than 30,000 Americans, the risk of VTE was shown to be reduced by 40% in individuals who exercised at least four times per week, compared with the physically inactive.
And in an analysis led by Dr. Cushman of nearly 21,000 participants over age 45 years with 12.6 years of follow-up in the Longitudinal Investigation of Thromboembolism Etiology (LITE), the investigators found that greater levels of all body size measures – not just body mass index, but calf circumference, waist-hip ratio, hip circumference, and others – were associated with increased VTE risk. These associations weren’t affected by levels of circulating biomarkers for inflammation or hypercoagulability, suggesting that it’s obesity per se, with its associated adverse impact on blood flow caused by physical factors, that explains the mechanism underlying obesity as a risk factor for VTE (Thromb Res. 2016 Aug;144:127-32).
At the meeting’s opening ceremonies, AHA President Ivor Benjamin, MD, of the Medical College of Wisconsin, Milwaukee, presented Dr. Cushman with the AHA Population Research Prize. She was honored for her “critically acclaimed research utilizing biomarker assessments in population studies to elucidate pathways of disease etiology for the three most common vascular diseases – coronary heart disease, stroke, and venous thromboembolism – as well as their risk factors,” said Dr. Benjamin.
Dr. Cushman reported having no financial conflicts regarding her D-dimer study, which was funded by the National Institutes of Health.
CHICAGO – An elevated baseline D-dimer level is helpful to women and their physicians in clarifying decision making about oral hormone therapy for troublesome menopausal symptoms, Mary Cushman, MD, said at the American Heart Association scientific sessions.
She was lead investigator in a nested case-control study embedded in the landmark Women’s Health Initiative (WHI), which showed that participants who had a baseline D-dimer greater than 0.54 mg/L – putting them in the top 25% – and were randomized to oral menopausal hormone therapy had a 5-year incidence of venous thromboembolism (VTE) of 6%. That’s 500% higher than in women with a lower D-dimer randomized to placebo.
“The number needed to test for D-dimer in advance of prescribing in order to prevent one VTE over 5 years of hormone therapy was only 33. So this is potentially something in the toolbox you can use in counseling women about oral hormone therapy,” said Dr. Cushman, professor of medicine and pathology and medical director of the thrombosis and hemostasis program at the University of Vermont, Burlington.
The biomarker study included 1,082 WHI participants aged 50-79 years randomized to oral conjugated equine estrogen with or without medroxyprogesterone acetate or to placebo, 215 of whom experienced VTE during a mean 4.1 years of follow-up. Levels of a variety of biomarkers obtained at baseline were assessed in terms of their associated risk of future VTE. The biomarkers included C-reactive protein and procoagulant, anticoagulant, and fibrinolytic factors.
In a logistic regression analysis adjusted for age, race, body mass index, and hysterectomy, the strongest association with VTE was a high D-dimer. That 500% increased risk of VTE with hormone therapy in women with a D-dimer greater than 0.54 mg/L was comparable in magnitude with the risk Dr. Cushman and her coinvestigators previously reported for the combination of factor V Leiden and hormone therapy.
Dr. Cushman and her associates also took a first step towards developing a multibiomarker risk score. They found that WHI participants randomized to hormone therapy who had abnormal baseline values for any three or more of eight biomarkers had a 1,450% greater risk of future VTE than women with zero or one abnormal biomarker who were assigned to placebo. The eight-biomarker panel described in the recently published study comprised D-dimer, factor V Leiden, protein C, total protein S, free protein S, antithrombin, plasmin-antiplasmin complex, and fragment 1.2. However, the investigators indicated the risk score needs further study before it’s ready for adoption in clinical practice (Res Pract Thromb Haemost. 2018 Apr 17;2[2]:310-9).
Dr. Cushman noted that, although the main findings of the WHI have largely resulted in abandonment of menopausal hormone therapy for disease prevention, many women still want to take oral hormone therapy for relief of bothersome menopausal symptoms. She tries to steer them instead to safer nonoral formulations. Transdermal estrogen replacement has no associated risk of VTE and doesn’t activate anticoagulation. Neither does vaginal estradiol.
In offering what she called “the 30,000-foot view of the impact of venous thrombosis on women’s health,” Dr. Cushman noted that VTE is the third-most common vascular disease in the United States, with up to 900,000 cases per year. The lifetime risk in women after age 45 is 8.4%. Half of VTEs are provoked and therefore potentially preventable, with common triggers being surgery, cancer, pregnancy, trauma, and immobilization, especially during travel.
In addition, a retrospective study conducted in the Worcester, Mass., area showed that 1-month mortality after VTE remained static in the 5%-10% range during 1999-2009.
“This is a fatal disease, even though we treat it as an outpatient quite a lot,” Dr. Cushman observed.
Common nonfatal complications of VTE include major bleeding in 5%-10% of cases, a recurrence rate of 5%-10% annually, a 20%-40% of the burdensome and not infrequently disabling condition known as postthrombotic syndrome, and a 3%-4% incidence of chronic thromboembolic pulmonary hypertension. Yet despite the seriousness of VTE, awareness about VTE is poor among both patients and physicians, and appropriate prophylaxis is underutilized, she said.
The key to improved primary prevention of VTE, Dr. Cushman continued, is greater attention to modifiable behavioral risk factors, along with more use of prophylactic medication when needed.
The traditional cardiovascular risk factors, like hypertension, smoking, and hyperlipidemia, aren’t relevant to VTE risk. But obesity and sedentary lifestyle have come to be recognized as important modifiable risk factors. In one study of more than 30,000 Americans, the risk of VTE was shown to be reduced by 40% in individuals who exercised at least four times per week, compared with the physically inactive.
And in an analysis led by Dr. Cushman of nearly 21,000 participants over age 45 years with 12.6 years of follow-up in the Longitudinal Investigation of Thromboembolism Etiology (LITE), the investigators found that greater levels of all body size measures – not just body mass index, but calf circumference, waist-hip ratio, hip circumference, and others – were associated with increased VTE risk. These associations weren’t affected by levels of circulating biomarkers for inflammation or hypercoagulability, suggesting that it’s obesity per se, with its associated adverse impact on blood flow caused by physical factors, that explains the mechanism underlying obesity as a risk factor for VTE (Thromb Res. 2016 Aug;144:127-32).
At the meeting’s opening ceremonies, AHA President Ivor Benjamin, MD, of the Medical College of Wisconsin, Milwaukee, presented Dr. Cushman with the AHA Population Research Prize. She was honored for her “critically acclaimed research utilizing biomarker assessments in population studies to elucidate pathways of disease etiology for the three most common vascular diseases – coronary heart disease, stroke, and venous thromboembolism – as well as their risk factors,” said Dr. Benjamin.
Dr. Cushman reported having no financial conflicts regarding her D-dimer study, which was funded by the National Institutes of Health.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Women in the top 25% for D-dimer level before going on menopausal hormone therapy had a 6% incidence of venous thromboembolism over 5 years.
Study details: This was a nested case-control study focused on identifying biomarkers for venous thromboembolism risk which included 1,082 participants in the Women’s Health Initiative randomized to menopausal hormone therapy or placebo.
Disclosures: The presenter reported having no financial conflicts regarding the study, which was funded by the National Institutes of Health.
EVAR insights from the GREAT registry
CHICAGO – The Global Registry for Endovascular Aortic Treatment is a unique resource that, although still early in its planned 10-year follow-up period, has already yielded important insights into one of the hottest topics in endovascular repair of abdominal aortic aneurysms: that is, the impact of the proximal aortic neck, Clayton J. Brinster, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
The Global Registry for Endovascular Aortic Treatment (GREAT) is a prospective, observational, real-world registry that enrolled more than 5,000 consecutive patients undergoing endovascular aortic repair (EVAR) in the United States, Europe, Australia, New Zealand, and Brazil before enrollment closed in October 2016.
GREAT is the largest stent graft registry in the world. One of its special features is that it has essentially no exclusion criteria. This enables researchers to compare outcomes in patients undergoing on-label EVAR using devices deployed within the official instructions for use (IFU) to results in real-world practice, which not infrequently entails treatment for nonstandard indications using devices outside the narrowly defined IFU generated via pivotal clinical trials, explained Dr. Brinster, a vascular surgeon at the Ochsner Clinic Foundation in New Orleans.
The biggest limitation of GREAT is that it’s sponsored by Gore and restricted to recipients of GORE thoracic and abdominal stent grafts. However, the registry has an oversight and safety monitoring board that is independent of the company, Dr. Brinster continued.
He highlighted three recently published studies that have utilized early GREAT data to examine the impact on EVAR outcomes of various features of the proximal aortic neck.
Noncylindrical neck anatomy
An international team of investigators analyzed the incidence and impact of noncylindrical neck anatomy, defined as a 2-mm or greater change in diameter over the first 15 mm of proximal aortic neck length. Of 3,077 GREAT participants treated with the Gore Excluder endograft, 1,312, or 43%, had an hourglass, tapered, or conical neck shape that qualified as noncylindrical. Noncylindrical necks were more common in women. Fifteen percent of patients with a noncylindrical neck received the device outside the Excluder IFU, as did 11% with a cylindrical neck.
After an average follow-up of about 20 months, the noncylindrical neck group had a 3.1% rate of device-related intervention, significantly better than the 4.9% rate in patients with a cylindrical neck. In a multivariate regression analysis, female gender and maximum abdominal aortic aneurysm diameter were significant risk factors for device-related or endoleak-specific reintervention; noncylindrical neck morphology was not. Indeed, women were 2.2-fold more likely to require device-related reintervention than men (J Vasc Surg. 2018; 68[6]:1714-24).
Large proximal aortic neck
Of 3,166 consecutive patients in GREAT, 37.6% had a large aortic neck diameter, defined as 25 mm or wider. The rate of 5-year freedom from type Ia endoleak was 96.8% in the large-neck group, significantly less than the 98.6% rate in patients with a normal aortic neck diameter. Of note, rates didn’t diverge until after 2 years of follow-up, emphasizing the need for careful long-term surveillance despite initial technical success.
The 5-year rate of freedom from the primary composite endpoint of type Ia endoleak, reintervention, aortic rupture, or isolated aortic-related mortality was also significantly worse in the large-neck group: 81.3% versus 87%. Moreover, the 5-year survival rate was only 64.6% in the large–aortic neck group, compared with 76.5% in the comparator arm, even though aortic-related mortality didn’t differ between the two groups. “The findings raise the question of whether young patients, with predicted life expectancies exceeding 10 years, should receive standard endovascular intervention if they have large aortic neck diameters at baseline (Eur J Vasc Endovasc Surg. 2018;56[2]:189-99).
Severe neck angulation
Australian investigators wondered if the IFU for the Gore C3 Excluder was overly restrictive in defining abdominal aortic aneurysms with necks greater than 60 degrees as off-label for the device. In the first 1,394 patients enrolled in GREAT, the researchers identified 127 (9.2%) who exhibited more than 60 and less than 140 degrees of neck angulation and didn’t require endoanchors for proximal fixation. Their mean neck angle was 78 degrees, with a mean neck length of 29 mm. Mean graft oversizing was 23.5%, which was also outside the Excluder IFU.
During a median follow-up of 236 days there were 7 type Ia endoleaks, for an incidence of 5.6%. The degree of neck angulation, neck length, and the amount of oversizing were not associated with endoleak (Ann Vasc Surg. 2018;49:152-57). However, Dr. Brinster wants to see longer follow-up data before he is prepared to accept that a mean 23.5% graft oversizing is a benign intervention.
“One must remember that, with that percentage of oversizing in an already abnormal neck, aortic neck dilation could be a significant problem longer term,” the vascular surgeon said.
Dr. Brinster reported having no conflicts regarding his presentation.
bjancin@mdedge.com
CHICAGO – The Global Registry for Endovascular Aortic Treatment is a unique resource that, although still early in its planned 10-year follow-up period, has already yielded important insights into one of the hottest topics in endovascular repair of abdominal aortic aneurysms: that is, the impact of the proximal aortic neck, Clayton J. Brinster, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
The Global Registry for Endovascular Aortic Treatment (GREAT) is a prospective, observational, real-world registry that enrolled more than 5,000 consecutive patients undergoing endovascular aortic repair (EVAR) in the United States, Europe, Australia, New Zealand, and Brazil before enrollment closed in October 2016.
GREAT is the largest stent graft registry in the world. One of its special features is that it has essentially no exclusion criteria. This enables researchers to compare outcomes in patients undergoing on-label EVAR using devices deployed within the official instructions for use (IFU) to results in real-world practice, which not infrequently entails treatment for nonstandard indications using devices outside the narrowly defined IFU generated via pivotal clinical trials, explained Dr. Brinster, a vascular surgeon at the Ochsner Clinic Foundation in New Orleans.
The biggest limitation of GREAT is that it’s sponsored by Gore and restricted to recipients of GORE thoracic and abdominal stent grafts. However, the registry has an oversight and safety monitoring board that is independent of the company, Dr. Brinster continued.
He highlighted three recently published studies that have utilized early GREAT data to examine the impact on EVAR outcomes of various features of the proximal aortic neck.
Noncylindrical neck anatomy
An international team of investigators analyzed the incidence and impact of noncylindrical neck anatomy, defined as a 2-mm or greater change in diameter over the first 15 mm of proximal aortic neck length. Of 3,077 GREAT participants treated with the Gore Excluder endograft, 1,312, or 43%, had an hourglass, tapered, or conical neck shape that qualified as noncylindrical. Noncylindrical necks were more common in women. Fifteen percent of patients with a noncylindrical neck received the device outside the Excluder IFU, as did 11% with a cylindrical neck.
After an average follow-up of about 20 months, the noncylindrical neck group had a 3.1% rate of device-related intervention, significantly better than the 4.9% rate in patients with a cylindrical neck. In a multivariate regression analysis, female gender and maximum abdominal aortic aneurysm diameter were significant risk factors for device-related or endoleak-specific reintervention; noncylindrical neck morphology was not. Indeed, women were 2.2-fold more likely to require device-related reintervention than men (J Vasc Surg. 2018; 68[6]:1714-24).
Large proximal aortic neck
Of 3,166 consecutive patients in GREAT, 37.6% had a large aortic neck diameter, defined as 25 mm or wider. The rate of 5-year freedom from type Ia endoleak was 96.8% in the large-neck group, significantly less than the 98.6% rate in patients with a normal aortic neck diameter. Of note, rates didn’t diverge until after 2 years of follow-up, emphasizing the need for careful long-term surveillance despite initial technical success.
The 5-year rate of freedom from the primary composite endpoint of type Ia endoleak, reintervention, aortic rupture, or isolated aortic-related mortality was also significantly worse in the large-neck group: 81.3% versus 87%. Moreover, the 5-year survival rate was only 64.6% in the large–aortic neck group, compared with 76.5% in the comparator arm, even though aortic-related mortality didn’t differ between the two groups. “The findings raise the question of whether young patients, with predicted life expectancies exceeding 10 years, should receive standard endovascular intervention if they have large aortic neck diameters at baseline (Eur J Vasc Endovasc Surg. 2018;56[2]:189-99).
Severe neck angulation
Australian investigators wondered if the IFU for the Gore C3 Excluder was overly restrictive in defining abdominal aortic aneurysms with necks greater than 60 degrees as off-label for the device. In the first 1,394 patients enrolled in GREAT, the researchers identified 127 (9.2%) who exhibited more than 60 and less than 140 degrees of neck angulation and didn’t require endoanchors for proximal fixation. Their mean neck angle was 78 degrees, with a mean neck length of 29 mm. Mean graft oversizing was 23.5%, which was also outside the Excluder IFU.
During a median follow-up of 236 days there were 7 type Ia endoleaks, for an incidence of 5.6%. The degree of neck angulation, neck length, and the amount of oversizing were not associated with endoleak (Ann Vasc Surg. 2018;49:152-57). However, Dr. Brinster wants to see longer follow-up data before he is prepared to accept that a mean 23.5% graft oversizing is a benign intervention.
“One must remember that, with that percentage of oversizing in an already abnormal neck, aortic neck dilation could be a significant problem longer term,” the vascular surgeon said.
Dr. Brinster reported having no conflicts regarding his presentation.
bjancin@mdedge.com
CHICAGO – The Global Registry for Endovascular Aortic Treatment is a unique resource that, although still early in its planned 10-year follow-up period, has already yielded important insights into one of the hottest topics in endovascular repair of abdominal aortic aneurysms: that is, the impact of the proximal aortic neck, Clayton J. Brinster, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
The Global Registry for Endovascular Aortic Treatment (GREAT) is a prospective, observational, real-world registry that enrolled more than 5,000 consecutive patients undergoing endovascular aortic repair (EVAR) in the United States, Europe, Australia, New Zealand, and Brazil before enrollment closed in October 2016.
GREAT is the largest stent graft registry in the world. One of its special features is that it has essentially no exclusion criteria. This enables researchers to compare outcomes in patients undergoing on-label EVAR using devices deployed within the official instructions for use (IFU) to results in real-world practice, which not infrequently entails treatment for nonstandard indications using devices outside the narrowly defined IFU generated via pivotal clinical trials, explained Dr. Brinster, a vascular surgeon at the Ochsner Clinic Foundation in New Orleans.
The biggest limitation of GREAT is that it’s sponsored by Gore and restricted to recipients of GORE thoracic and abdominal stent grafts. However, the registry has an oversight and safety monitoring board that is independent of the company, Dr. Brinster continued.
He highlighted three recently published studies that have utilized early GREAT data to examine the impact on EVAR outcomes of various features of the proximal aortic neck.
Noncylindrical neck anatomy
An international team of investigators analyzed the incidence and impact of noncylindrical neck anatomy, defined as a 2-mm or greater change in diameter over the first 15 mm of proximal aortic neck length. Of 3,077 GREAT participants treated with the Gore Excluder endograft, 1,312, or 43%, had an hourglass, tapered, or conical neck shape that qualified as noncylindrical. Noncylindrical necks were more common in women. Fifteen percent of patients with a noncylindrical neck received the device outside the Excluder IFU, as did 11% with a cylindrical neck.
After an average follow-up of about 20 months, the noncylindrical neck group had a 3.1% rate of device-related intervention, significantly better than the 4.9% rate in patients with a cylindrical neck. In a multivariate regression analysis, female gender and maximum abdominal aortic aneurysm diameter were significant risk factors for device-related or endoleak-specific reintervention; noncylindrical neck morphology was not. Indeed, women were 2.2-fold more likely to require device-related reintervention than men (J Vasc Surg. 2018; 68[6]:1714-24).
Large proximal aortic neck
Of 3,166 consecutive patients in GREAT, 37.6% had a large aortic neck diameter, defined as 25 mm or wider. The rate of 5-year freedom from type Ia endoleak was 96.8% in the large-neck group, significantly less than the 98.6% rate in patients with a normal aortic neck diameter. Of note, rates didn’t diverge until after 2 years of follow-up, emphasizing the need for careful long-term surveillance despite initial technical success.
The 5-year rate of freedom from the primary composite endpoint of type Ia endoleak, reintervention, aortic rupture, or isolated aortic-related mortality was also significantly worse in the large-neck group: 81.3% versus 87%. Moreover, the 5-year survival rate was only 64.6% in the large–aortic neck group, compared with 76.5% in the comparator arm, even though aortic-related mortality didn’t differ between the two groups. “The findings raise the question of whether young patients, with predicted life expectancies exceeding 10 years, should receive standard endovascular intervention if they have large aortic neck diameters at baseline (Eur J Vasc Endovasc Surg. 2018;56[2]:189-99).
Severe neck angulation
Australian investigators wondered if the IFU for the Gore C3 Excluder was overly restrictive in defining abdominal aortic aneurysms with necks greater than 60 degrees as off-label for the device. In the first 1,394 patients enrolled in GREAT, the researchers identified 127 (9.2%) who exhibited more than 60 and less than 140 degrees of neck angulation and didn’t require endoanchors for proximal fixation. Their mean neck angle was 78 degrees, with a mean neck length of 29 mm. Mean graft oversizing was 23.5%, which was also outside the Excluder IFU.
During a median follow-up of 236 days there were 7 type Ia endoleaks, for an incidence of 5.6%. The degree of neck angulation, neck length, and the amount of oversizing were not associated with endoleak (Ann Vasc Surg. 2018;49:152-57). However, Dr. Brinster wants to see longer follow-up data before he is prepared to accept that a mean 23.5% graft oversizing is a benign intervention.
“One must remember that, with that percentage of oversizing in an already abnormal neck, aortic neck dilation could be a significant problem longer term,” the vascular surgeon said.
Dr. Brinster reported having no conflicts regarding his presentation.
bjancin@mdedge.com
EXPERT ANALYSIS FROM THE NORTHWESTERN VASCULAR SYMPOSIUM
New twists in medical management of PAD
SNOWMASS, COLO. – Be leery of lowering high blood pressure too much in patients with lower extremity peripheral artery disease, Robert A. Vogel, MD, cautioned the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology
“We used to worry about lowering blood pressure too much in [coronary artery disease]. I need to rekindle that thought, because you want to be very careful about lowering blood pressure too much in PAD,” said Dr. Vogel, a preventive cardiology specialist at the University of Colorado, Denver.
He cited a recent reanalysis of data from the landmark ALLHAT (Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial) conducted by investigators at Stanford (Calif.) University. During a median 4.3 years of prospective follow-up of 33,357 participants with a median baseline blood pressure of 146/84 mm Hg, the risk of the composite endpoint of lower extremity PAD events – defined as PAD-related hospitalization, revascularization procedures, medical treatment, or PAD-related death – was increased by 26% in patients with a systolic blood pressure below 120 mm Hg, compared with an SBP of 120-129 mm Hg.
In a similar Cox regression analysis, the risk of PAD events was increased by 72% in patients with a diastolic blood pressure below 60 mm Hg, compared with that of patients with a DBP of 70-79 mm Hg, and to a lesser, albeit still statistically significant and clinically meaningful, extent in those with a DBP of 60-69 mm Hg (Circulation. 2018;138:1805-14).
Dr. Vogel’s cautionary note about overzealous blood pressure–lowering was one of several developments he highlighted since publication of the 2016 American Heart Association/American College of Cardiology guidelines on the medical management of lower extremity PAD (J Am Coll Cardiol. 2017;69:1465-508). Others include new data demonstrating that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy shows particularly strong benefit in the patient subgroup with PAD, as did rivaroxaban (Xarelto) at 2.5 mg b.i.d. plus aspirin 100 mg/day in the COMPASS trial.
Also, the final week of 2018 saw publication of the ACC Expert Consensus Decision Pathway on Tobacco Cessation (J Am Coll Cardiol. 2018 Dec 25;72[25]:3332-65), which Dr. Vogel considers an exemplary document every physician who cares for patients with PAD ought to read.
The Class I recommendations in the ACC/AHA guidelines for medical management of PAD include introducing a supervised exercise program before resorting to a revascularization procedure, providing advice on smoking cessation at every visit, antiplatelet therapy, a high-intensity statin, cilostazol for claudication, and coordination of the patient’s diabetes care with an endocrinologist or primary care physician.
Numerous studies have documented that physicians by and large aren’t doing so well in bringing these evidence-based therapies to bear. For example, a recent study of 155,647 Veterans Affairs patients with new-onset PAD found that 28% weren’t on a statin. Only 18.4% with PAD and comorbid coronary or carotid disease were on a high-intensity statin, as were just 6.4% with PAD only. In a multivariate adjusted analysis, high-intensity statin users had a 33% lower risk of amputation and a 26% lower risk of mortality, compared with statin nonusers (Circulation. 2018;137:1435-46).
It’s as if there’s a widespread failure to appreciate the substantial morbidity and mortality conferred by PAD, so Dr. Vogel put it into perspective: “In broad strokes, atherosclerosis starts in the aorta, moves to the coronaries, goes to the carotids, and ends up in the legs. By the time you have lower-extremity atherosclerosis, you are a vasculopath,” he explained.
Smoking cessation
“Lower-extremity PAD is a disease of smoking. Cholesterol goes to the heart, blood pressure goes to the head, and smoking goes to the legs, in broad strokes. Current smokers are 12 times more likely to have PAD than never smokers. And if you stop smoking, you reduce death by more than 50%,” the cardiologist said.
“You’ve got to get these folks to stop smoking, a difficult task. I do my clinical work at a VA hospital, and I can tell you this is a challenge,” he continued.
The new ACC Expert Consensus report is a boon in this regard.
“It’s not that long, and it’s very, very good. Very helpful. It’s not theoretical, it’s very practical,” according to Dr. Vogel. But he didn’t sugar coat what’s involved in getting PAD patients to quit smoking.
“At best, per round of smoking cessation, with pharmacology as well as multiple-session counseling, you can get 15%-20% abstinence per cycle. And it often takes many cycles of counseling to get people to stop smoking,” he added.
Low-dose rivaroxaban plus aspirin
Dr. Vogel believes the combination of low-dose rivaroxaban plus aspirin is worthy of serious consideration in patients with PAD on the strength of the COMPASS trial, a randomized, double-blind study of more than 27,000 patients with stable CAD, 27% of whom also had PAD. The PAD group on rivaroxaban 2.5 mg b.i.d. plus aspirin had a 28% relative risk reduction in the composite endpoint of cardiovascular death, stroke, or MI, compared with those on aspirin plus placebo. This benefit came at a cost of a 51% increase in the risk of major bleeding, but not fatal bleeding or bleeding causing critical damage to the brain or other organs.
Taking into account both the primary efficacy and severe bleeding rates, the net clinical benefit of low-dose rivaroxaban was 20%. The absolute risk reduction was larger in the PAD subgroup than in those with CAD-only because of their greater baseline risk (N Engl J Med. 2017;377:1319-30).
At present a 2.5-mg dose of rivaroxaban isn’t commercially available, so patients have to cut higher-dose tablets, but on the strength of the COMPASS results, a 2.5-mg tablet is in the works, Dr. Vogel said.
PCSK9 inhibitors
In the FOURIER trial of evolocumab (Praluent) versus placebo on top of maximally tolerated statin therapy in more than 27,000 patients with atherosclerotic disease, including 3,642 with PAD, the rate of MALE (major adverse limb events) was reduced by 42% in the evolocumab group, with a number-needed-to-treat in order to prevent one additional MALE event of only 16 (Circulation. 2018;137:338-50).
“This is a subgroup that really benefits from PCSK9 inhibition. It’s something to think about,” Dr. Vogel said.
Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center, receiving research grants from Sanofi, and serving on speakers bureaus for Regeneron and Sanofi.
SNOWMASS, COLO. – Be leery of lowering high blood pressure too much in patients with lower extremity peripheral artery disease, Robert A. Vogel, MD, cautioned the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology
“We used to worry about lowering blood pressure too much in [coronary artery disease]. I need to rekindle that thought, because you want to be very careful about lowering blood pressure too much in PAD,” said Dr. Vogel, a preventive cardiology specialist at the University of Colorado, Denver.
He cited a recent reanalysis of data from the landmark ALLHAT (Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial) conducted by investigators at Stanford (Calif.) University. During a median 4.3 years of prospective follow-up of 33,357 participants with a median baseline blood pressure of 146/84 mm Hg, the risk of the composite endpoint of lower extremity PAD events – defined as PAD-related hospitalization, revascularization procedures, medical treatment, or PAD-related death – was increased by 26% in patients with a systolic blood pressure below 120 mm Hg, compared with an SBP of 120-129 mm Hg.
In a similar Cox regression analysis, the risk of PAD events was increased by 72% in patients with a diastolic blood pressure below 60 mm Hg, compared with that of patients with a DBP of 70-79 mm Hg, and to a lesser, albeit still statistically significant and clinically meaningful, extent in those with a DBP of 60-69 mm Hg (Circulation. 2018;138:1805-14).
Dr. Vogel’s cautionary note about overzealous blood pressure–lowering was one of several developments he highlighted since publication of the 2016 American Heart Association/American College of Cardiology guidelines on the medical management of lower extremity PAD (J Am Coll Cardiol. 2017;69:1465-508). Others include new data demonstrating that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy shows particularly strong benefit in the patient subgroup with PAD, as did rivaroxaban (Xarelto) at 2.5 mg b.i.d. plus aspirin 100 mg/day in the COMPASS trial.
Also, the final week of 2018 saw publication of the ACC Expert Consensus Decision Pathway on Tobacco Cessation (J Am Coll Cardiol. 2018 Dec 25;72[25]:3332-65), which Dr. Vogel considers an exemplary document every physician who cares for patients with PAD ought to read.
The Class I recommendations in the ACC/AHA guidelines for medical management of PAD include introducing a supervised exercise program before resorting to a revascularization procedure, providing advice on smoking cessation at every visit, antiplatelet therapy, a high-intensity statin, cilostazol for claudication, and coordination of the patient’s diabetes care with an endocrinologist or primary care physician.
Numerous studies have documented that physicians by and large aren’t doing so well in bringing these evidence-based therapies to bear. For example, a recent study of 155,647 Veterans Affairs patients with new-onset PAD found that 28% weren’t on a statin. Only 18.4% with PAD and comorbid coronary or carotid disease were on a high-intensity statin, as were just 6.4% with PAD only. In a multivariate adjusted analysis, high-intensity statin users had a 33% lower risk of amputation and a 26% lower risk of mortality, compared with statin nonusers (Circulation. 2018;137:1435-46).
It’s as if there’s a widespread failure to appreciate the substantial morbidity and mortality conferred by PAD, so Dr. Vogel put it into perspective: “In broad strokes, atherosclerosis starts in the aorta, moves to the coronaries, goes to the carotids, and ends up in the legs. By the time you have lower-extremity atherosclerosis, you are a vasculopath,” he explained.
Smoking cessation
“Lower-extremity PAD is a disease of smoking. Cholesterol goes to the heart, blood pressure goes to the head, and smoking goes to the legs, in broad strokes. Current smokers are 12 times more likely to have PAD than never smokers. And if you stop smoking, you reduce death by more than 50%,” the cardiologist said.
“You’ve got to get these folks to stop smoking, a difficult task. I do my clinical work at a VA hospital, and I can tell you this is a challenge,” he continued.
The new ACC Expert Consensus report is a boon in this regard.
“It’s not that long, and it’s very, very good. Very helpful. It’s not theoretical, it’s very practical,” according to Dr. Vogel. But he didn’t sugar coat what’s involved in getting PAD patients to quit smoking.
“At best, per round of smoking cessation, with pharmacology as well as multiple-session counseling, you can get 15%-20% abstinence per cycle. And it often takes many cycles of counseling to get people to stop smoking,” he added.
Low-dose rivaroxaban plus aspirin
Dr. Vogel believes the combination of low-dose rivaroxaban plus aspirin is worthy of serious consideration in patients with PAD on the strength of the COMPASS trial, a randomized, double-blind study of more than 27,000 patients with stable CAD, 27% of whom also had PAD. The PAD group on rivaroxaban 2.5 mg b.i.d. plus aspirin had a 28% relative risk reduction in the composite endpoint of cardiovascular death, stroke, or MI, compared with those on aspirin plus placebo. This benefit came at a cost of a 51% increase in the risk of major bleeding, but not fatal bleeding or bleeding causing critical damage to the brain or other organs.
Taking into account both the primary efficacy and severe bleeding rates, the net clinical benefit of low-dose rivaroxaban was 20%. The absolute risk reduction was larger in the PAD subgroup than in those with CAD-only because of their greater baseline risk (N Engl J Med. 2017;377:1319-30).
At present a 2.5-mg dose of rivaroxaban isn’t commercially available, so patients have to cut higher-dose tablets, but on the strength of the COMPASS results, a 2.5-mg tablet is in the works, Dr. Vogel said.
PCSK9 inhibitors
In the FOURIER trial of evolocumab (Praluent) versus placebo on top of maximally tolerated statin therapy in more than 27,000 patients with atherosclerotic disease, including 3,642 with PAD, the rate of MALE (major adverse limb events) was reduced by 42% in the evolocumab group, with a number-needed-to-treat in order to prevent one additional MALE event of only 16 (Circulation. 2018;137:338-50).
“This is a subgroup that really benefits from PCSK9 inhibition. It’s something to think about,” Dr. Vogel said.
Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center, receiving research grants from Sanofi, and serving on speakers bureaus for Regeneron and Sanofi.
SNOWMASS, COLO. – Be leery of lowering high blood pressure too much in patients with lower extremity peripheral artery disease, Robert A. Vogel, MD, cautioned the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology
“We used to worry about lowering blood pressure too much in [coronary artery disease]. I need to rekindle that thought, because you want to be very careful about lowering blood pressure too much in PAD,” said Dr. Vogel, a preventive cardiology specialist at the University of Colorado, Denver.
He cited a recent reanalysis of data from the landmark ALLHAT (Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial) conducted by investigators at Stanford (Calif.) University. During a median 4.3 years of prospective follow-up of 33,357 participants with a median baseline blood pressure of 146/84 mm Hg, the risk of the composite endpoint of lower extremity PAD events – defined as PAD-related hospitalization, revascularization procedures, medical treatment, or PAD-related death – was increased by 26% in patients with a systolic blood pressure below 120 mm Hg, compared with an SBP of 120-129 mm Hg.
In a similar Cox regression analysis, the risk of PAD events was increased by 72% in patients with a diastolic blood pressure below 60 mm Hg, compared with that of patients with a DBP of 70-79 mm Hg, and to a lesser, albeit still statistically significant and clinically meaningful, extent in those with a DBP of 60-69 mm Hg (Circulation. 2018;138:1805-14).
Dr. Vogel’s cautionary note about overzealous blood pressure–lowering was one of several developments he highlighted since publication of the 2016 American Heart Association/American College of Cardiology guidelines on the medical management of lower extremity PAD (J Am Coll Cardiol. 2017;69:1465-508). Others include new data demonstrating that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy shows particularly strong benefit in the patient subgroup with PAD, as did rivaroxaban (Xarelto) at 2.5 mg b.i.d. plus aspirin 100 mg/day in the COMPASS trial.
Also, the final week of 2018 saw publication of the ACC Expert Consensus Decision Pathway on Tobacco Cessation (J Am Coll Cardiol. 2018 Dec 25;72[25]:3332-65), which Dr. Vogel considers an exemplary document every physician who cares for patients with PAD ought to read.
The Class I recommendations in the ACC/AHA guidelines for medical management of PAD include introducing a supervised exercise program before resorting to a revascularization procedure, providing advice on smoking cessation at every visit, antiplatelet therapy, a high-intensity statin, cilostazol for claudication, and coordination of the patient’s diabetes care with an endocrinologist or primary care physician.
Numerous studies have documented that physicians by and large aren’t doing so well in bringing these evidence-based therapies to bear. For example, a recent study of 155,647 Veterans Affairs patients with new-onset PAD found that 28% weren’t on a statin. Only 18.4% with PAD and comorbid coronary or carotid disease were on a high-intensity statin, as were just 6.4% with PAD only. In a multivariate adjusted analysis, high-intensity statin users had a 33% lower risk of amputation and a 26% lower risk of mortality, compared with statin nonusers (Circulation. 2018;137:1435-46).
It’s as if there’s a widespread failure to appreciate the substantial morbidity and mortality conferred by PAD, so Dr. Vogel put it into perspective: “In broad strokes, atherosclerosis starts in the aorta, moves to the coronaries, goes to the carotids, and ends up in the legs. By the time you have lower-extremity atherosclerosis, you are a vasculopath,” he explained.
Smoking cessation
“Lower-extremity PAD is a disease of smoking. Cholesterol goes to the heart, blood pressure goes to the head, and smoking goes to the legs, in broad strokes. Current smokers are 12 times more likely to have PAD than never smokers. And if you stop smoking, you reduce death by more than 50%,” the cardiologist said.
“You’ve got to get these folks to stop smoking, a difficult task. I do my clinical work at a VA hospital, and I can tell you this is a challenge,” he continued.
The new ACC Expert Consensus report is a boon in this regard.
“It’s not that long, and it’s very, very good. Very helpful. It’s not theoretical, it’s very practical,” according to Dr. Vogel. But he didn’t sugar coat what’s involved in getting PAD patients to quit smoking.
“At best, per round of smoking cessation, with pharmacology as well as multiple-session counseling, you can get 15%-20% abstinence per cycle. And it often takes many cycles of counseling to get people to stop smoking,” he added.
Low-dose rivaroxaban plus aspirin
Dr. Vogel believes the combination of low-dose rivaroxaban plus aspirin is worthy of serious consideration in patients with PAD on the strength of the COMPASS trial, a randomized, double-blind study of more than 27,000 patients with stable CAD, 27% of whom also had PAD. The PAD group on rivaroxaban 2.5 mg b.i.d. plus aspirin had a 28% relative risk reduction in the composite endpoint of cardiovascular death, stroke, or MI, compared with those on aspirin plus placebo. This benefit came at a cost of a 51% increase in the risk of major bleeding, but not fatal bleeding or bleeding causing critical damage to the brain or other organs.
Taking into account both the primary efficacy and severe bleeding rates, the net clinical benefit of low-dose rivaroxaban was 20%. The absolute risk reduction was larger in the PAD subgroup than in those with CAD-only because of their greater baseline risk (N Engl J Med. 2017;377:1319-30).
At present a 2.5-mg dose of rivaroxaban isn’t commercially available, so patients have to cut higher-dose tablets, but on the strength of the COMPASS results, a 2.5-mg tablet is in the works, Dr. Vogel said.
PCSK9 inhibitors
In the FOURIER trial of evolocumab (Praluent) versus placebo on top of maximally tolerated statin therapy in more than 27,000 patients with atherosclerotic disease, including 3,642 with PAD, the rate of MALE (major adverse limb events) was reduced by 42% in the evolocumab group, with a number-needed-to-treat in order to prevent one additional MALE event of only 16 (Circulation. 2018;137:338-50).
“This is a subgroup that really benefits from PCSK9 inhibition. It’s something to think about,” Dr. Vogel said.
Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center, receiving research grants from Sanofi, and serving on speakers bureaus for Regeneron and Sanofi.
EXPERT ANALYSIS FROM ACC SNOWMASS 2019
Pregnancy problems predict cardiovascular future
SNOWMASS, COLO. – Think of pregnancy as a cardiovascular stress test, Carole A. Warnes, MD, urged at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
Pregnancy complications may unmask a predisposition to premature cardiovascular disease. Yet a woman’s reproductive history is often overlooked in this regard, despite the fact that cardiovascular disease is the number-one cause of death in women, observed Dr. Warnes, the Snowmass conference director and professor of medicine at the Mayo Clinic in Rochester, Minn.
“I think reproductive history is often overlooked as a predictor of cardiovascular and even peripheral vascular events. I suspect many of us don’t routinely ask our patients about miscarriages and stillbirths. We might think about preeclampsia, but these are also hallmarks of trouble to come,” the cardiologist said.
Indeed, this point was underscored in a retrospective Danish national population-based cohort registry study of more than 1 million women followed for nearly 16 million person-years after one or more miscarriages, stillbirths, or live singleton births. Women with stillbirths were 2.69-fold more likely to have an MI, 2.42-fold more likely to develop renovascular hypertension, and 1.74-fold more likely to have a stroke during follow-up than those with no stillbirths.
Moreover, women with miscarriages were 1.13-, 1.2-, and 1.16-fold more likely to have an MI, renovascular hypertension, and stroke, respectively, than women with no miscarriages. And the risks were additive: For each additional miscarriage, the risks of MI, renovascular hypertension, and stroke increased by 9%, 19%, and 13%, respectively (Circulation. 2013;127[17]:1775-82).
The concept of maternal placental syndromes encompasses four events believed to originate from diseased placental blood vessels: preeclampsia, gestational hypertension, placental abruption, and placental infarction. In a population-based retrospective study known as CHAMPS (Cardiovascular Health After Maternal Placental Syndromes), conducted in more than 1 million Ontario women who were free from cardiovascular disease prior to their first delivery, 7% were diagnosed with a maternal placental syndrome. Their incidence of a composite endpoint comprised of hospitalization or revascularization for CAD, peripheral artery disease, or cerebrovascular disease at least 90 days after delivery discharge was double that of women without a maternal placental syndrome.
“These women manifested their first cardiovascular event at an average age of 38, not 50 or 60,” Dr. Warnes said.
The risk of premature cardiovascular disease was magnified 4.4-fold in women with a maternal placental syndrome plus an intrauterine fetal death, compared with those with neither, after adjustment for sociodemographic factors and other potential confounders, and by 3.1-fold in women with a maternal placental syndrome and poor fetal growth (Lancet. 2005;366[9499]:1797-803).
These findings were independently confirmed recently in a population-based retrospective study of nearly 303,000 Florida women free of prepregnancy hypertension, diabetes, heart disease, or renal disease who were followed for a median of 4.9 years after their first delivery. During that relative brief follow-up period, the adjusted risk of cardiovascular disease was increased by 19% in those with a maternal placental syndrome, compared with those without. And the risk was additive: women with more than one maternal placental syndrome had a 43% greater short-term risk of developing cardiovascular disease, compared with those with none. And when women with a maternal placental syndrome also had a preterm birth or a small-for-gestational age baby, their risk increased 45% (Am J Obstet Gynecol. 2016;215[4]:484.e1-484.e14).
It’s not just preeclampsia, which affects 3%-5% of all pregnancies, and gestational hypertension – defined as high blood pressure arising only after 20 weeks’ gestation and without proteinuria – that have been linked to future premature cardiovascular disease. In the Northern Finland Birth Cohort 1966, in which investigators have followed 10,314 women born in that year for 39 years, any form of high blood pressure during pregnancy was a harbinger of subsequent cardiovascular disease, diabetes, and chronic kidney disease. That included chronic isolated systolic and isolated diastolic hypertension (Circulation. 2013;127[6]:681-90).
The pathophysiologic processes involved in complicated pregnancies echo those of CAD and stroke: inflammation, altered angiogenesis, vasculopathy, thrombosis, and insulin resistance. Still unsettled, however, is the chicken-versus-egg question of whether preeclampsia and other pregnancy complications represent the initial expression of an adverse phenotype associated with early development of cardiovascular disease or the complications injure the vascular endothelium and thereby trigger accelerated atherosclerosis. In any case, markers of endothelial activation have been documented up to 15 years after an episode of preeclampsia, Dr. Warnes said.
All of these data underscore the importance of identifying at-risk women based upon reproductive history, scheduling additional medical checkups so they don’t drop off the radar for the next 20 years, encouraging lifestyle modification, and giving consideration to early initiation of antihypertensive and lipid-lowering therapies.
“Pregnancy complications give us a glimpse of this awful disease trajectory at a time when women are completely asymptomatic and we could intervene and perhaps change outcomes with targeted therapy when it might be expected to work better and patients might be more receptive to such interventions,” she said.
Dr. Warnes reported having no financial conflicts of interest.
SNOWMASS, COLO. – Think of pregnancy as a cardiovascular stress test, Carole A. Warnes, MD, urged at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
Pregnancy complications may unmask a predisposition to premature cardiovascular disease. Yet a woman’s reproductive history is often overlooked in this regard, despite the fact that cardiovascular disease is the number-one cause of death in women, observed Dr. Warnes, the Snowmass conference director and professor of medicine at the Mayo Clinic in Rochester, Minn.
“I think reproductive history is often overlooked as a predictor of cardiovascular and even peripheral vascular events. I suspect many of us don’t routinely ask our patients about miscarriages and stillbirths. We might think about preeclampsia, but these are also hallmarks of trouble to come,” the cardiologist said.
Indeed, this point was underscored in a retrospective Danish national population-based cohort registry study of more than 1 million women followed for nearly 16 million person-years after one or more miscarriages, stillbirths, or live singleton births. Women with stillbirths were 2.69-fold more likely to have an MI, 2.42-fold more likely to develop renovascular hypertension, and 1.74-fold more likely to have a stroke during follow-up than those with no stillbirths.
Moreover, women with miscarriages were 1.13-, 1.2-, and 1.16-fold more likely to have an MI, renovascular hypertension, and stroke, respectively, than women with no miscarriages. And the risks were additive: For each additional miscarriage, the risks of MI, renovascular hypertension, and stroke increased by 9%, 19%, and 13%, respectively (Circulation. 2013;127[17]:1775-82).
The concept of maternal placental syndromes encompasses four events believed to originate from diseased placental blood vessels: preeclampsia, gestational hypertension, placental abruption, and placental infarction. In a population-based retrospective study known as CHAMPS (Cardiovascular Health After Maternal Placental Syndromes), conducted in more than 1 million Ontario women who were free from cardiovascular disease prior to their first delivery, 7% were diagnosed with a maternal placental syndrome. Their incidence of a composite endpoint comprised of hospitalization or revascularization for CAD, peripheral artery disease, or cerebrovascular disease at least 90 days after delivery discharge was double that of women without a maternal placental syndrome.
“These women manifested their first cardiovascular event at an average age of 38, not 50 or 60,” Dr. Warnes said.
The risk of premature cardiovascular disease was magnified 4.4-fold in women with a maternal placental syndrome plus an intrauterine fetal death, compared with those with neither, after adjustment for sociodemographic factors and other potential confounders, and by 3.1-fold in women with a maternal placental syndrome and poor fetal growth (Lancet. 2005;366[9499]:1797-803).
These findings were independently confirmed recently in a population-based retrospective study of nearly 303,000 Florida women free of prepregnancy hypertension, diabetes, heart disease, or renal disease who were followed for a median of 4.9 years after their first delivery. During that relative brief follow-up period, the adjusted risk of cardiovascular disease was increased by 19% in those with a maternal placental syndrome, compared with those without. And the risk was additive: women with more than one maternal placental syndrome had a 43% greater short-term risk of developing cardiovascular disease, compared with those with none. And when women with a maternal placental syndrome also had a preterm birth or a small-for-gestational age baby, their risk increased 45% (Am J Obstet Gynecol. 2016;215[4]:484.e1-484.e14).
It’s not just preeclampsia, which affects 3%-5% of all pregnancies, and gestational hypertension – defined as high blood pressure arising only after 20 weeks’ gestation and without proteinuria – that have been linked to future premature cardiovascular disease. In the Northern Finland Birth Cohort 1966, in which investigators have followed 10,314 women born in that year for 39 years, any form of high blood pressure during pregnancy was a harbinger of subsequent cardiovascular disease, diabetes, and chronic kidney disease. That included chronic isolated systolic and isolated diastolic hypertension (Circulation. 2013;127[6]:681-90).
The pathophysiologic processes involved in complicated pregnancies echo those of CAD and stroke: inflammation, altered angiogenesis, vasculopathy, thrombosis, and insulin resistance. Still unsettled, however, is the chicken-versus-egg question of whether preeclampsia and other pregnancy complications represent the initial expression of an adverse phenotype associated with early development of cardiovascular disease or the complications injure the vascular endothelium and thereby trigger accelerated atherosclerosis. In any case, markers of endothelial activation have been documented up to 15 years after an episode of preeclampsia, Dr. Warnes said.
All of these data underscore the importance of identifying at-risk women based upon reproductive history, scheduling additional medical checkups so they don’t drop off the radar for the next 20 years, encouraging lifestyle modification, and giving consideration to early initiation of antihypertensive and lipid-lowering therapies.
“Pregnancy complications give us a glimpse of this awful disease trajectory at a time when women are completely asymptomatic and we could intervene and perhaps change outcomes with targeted therapy when it might be expected to work better and patients might be more receptive to such interventions,” she said.
Dr. Warnes reported having no financial conflicts of interest.
SNOWMASS, COLO. – Think of pregnancy as a cardiovascular stress test, Carole A. Warnes, MD, urged at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
Pregnancy complications may unmask a predisposition to premature cardiovascular disease. Yet a woman’s reproductive history is often overlooked in this regard, despite the fact that cardiovascular disease is the number-one cause of death in women, observed Dr. Warnes, the Snowmass conference director and professor of medicine at the Mayo Clinic in Rochester, Minn.
“I think reproductive history is often overlooked as a predictor of cardiovascular and even peripheral vascular events. I suspect many of us don’t routinely ask our patients about miscarriages and stillbirths. We might think about preeclampsia, but these are also hallmarks of trouble to come,” the cardiologist said.
Indeed, this point was underscored in a retrospective Danish national population-based cohort registry study of more than 1 million women followed for nearly 16 million person-years after one or more miscarriages, stillbirths, or live singleton births. Women with stillbirths were 2.69-fold more likely to have an MI, 2.42-fold more likely to develop renovascular hypertension, and 1.74-fold more likely to have a stroke during follow-up than those with no stillbirths.
Moreover, women with miscarriages were 1.13-, 1.2-, and 1.16-fold more likely to have an MI, renovascular hypertension, and stroke, respectively, than women with no miscarriages. And the risks were additive: For each additional miscarriage, the risks of MI, renovascular hypertension, and stroke increased by 9%, 19%, and 13%, respectively (Circulation. 2013;127[17]:1775-82).
The concept of maternal placental syndromes encompasses four events believed to originate from diseased placental blood vessels: preeclampsia, gestational hypertension, placental abruption, and placental infarction. In a population-based retrospective study known as CHAMPS (Cardiovascular Health After Maternal Placental Syndromes), conducted in more than 1 million Ontario women who were free from cardiovascular disease prior to their first delivery, 7% were diagnosed with a maternal placental syndrome. Their incidence of a composite endpoint comprised of hospitalization or revascularization for CAD, peripheral artery disease, or cerebrovascular disease at least 90 days after delivery discharge was double that of women without a maternal placental syndrome.
“These women manifested their first cardiovascular event at an average age of 38, not 50 or 60,” Dr. Warnes said.
The risk of premature cardiovascular disease was magnified 4.4-fold in women with a maternal placental syndrome plus an intrauterine fetal death, compared with those with neither, after adjustment for sociodemographic factors and other potential confounders, and by 3.1-fold in women with a maternal placental syndrome and poor fetal growth (Lancet. 2005;366[9499]:1797-803).
These findings were independently confirmed recently in a population-based retrospective study of nearly 303,000 Florida women free of prepregnancy hypertension, diabetes, heart disease, or renal disease who were followed for a median of 4.9 years after their first delivery. During that relative brief follow-up period, the adjusted risk of cardiovascular disease was increased by 19% in those with a maternal placental syndrome, compared with those without. And the risk was additive: women with more than one maternal placental syndrome had a 43% greater short-term risk of developing cardiovascular disease, compared with those with none. And when women with a maternal placental syndrome also had a preterm birth or a small-for-gestational age baby, their risk increased 45% (Am J Obstet Gynecol. 2016;215[4]:484.e1-484.e14).
It’s not just preeclampsia, which affects 3%-5% of all pregnancies, and gestational hypertension – defined as high blood pressure arising only after 20 weeks’ gestation and without proteinuria – that have been linked to future premature cardiovascular disease. In the Northern Finland Birth Cohort 1966, in which investigators have followed 10,314 women born in that year for 39 years, any form of high blood pressure during pregnancy was a harbinger of subsequent cardiovascular disease, diabetes, and chronic kidney disease. That included chronic isolated systolic and isolated diastolic hypertension (Circulation. 2013;127[6]:681-90).
The pathophysiologic processes involved in complicated pregnancies echo those of CAD and stroke: inflammation, altered angiogenesis, vasculopathy, thrombosis, and insulin resistance. Still unsettled, however, is the chicken-versus-egg question of whether preeclampsia and other pregnancy complications represent the initial expression of an adverse phenotype associated with early development of cardiovascular disease or the complications injure the vascular endothelium and thereby trigger accelerated atherosclerosis. In any case, markers of endothelial activation have been documented up to 15 years after an episode of preeclampsia, Dr. Warnes said.
All of these data underscore the importance of identifying at-risk women based upon reproductive history, scheduling additional medical checkups so they don’t drop off the radar for the next 20 years, encouraging lifestyle modification, and giving consideration to early initiation of antihypertensive and lipid-lowering therapies.
“Pregnancy complications give us a glimpse of this awful disease trajectory at a time when women are completely asymptomatic and we could intervene and perhaps change outcomes with targeted therapy when it might be expected to work better and patients might be more receptive to such interventions,” she said.
Dr. Warnes reported having no financial conflicts of interest.
EXPERT ANALYSIS FROM ACC SNOWMASS 2019
Aspirin for primary cardiovascular prevention, RIP
SNOWMASS, COLO. – during the space of a few short weeks in autumn 2018.
“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.
He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.
• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).
• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).
Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).
“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.
• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).
“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.
How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.
“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.
Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.
During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.
“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”
He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.
This article was updated 1/31/19.
SNOWMASS, COLO. – during the space of a few short weeks in autumn 2018.
“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.
He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.
• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).
• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).
Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).
“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.
• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).
“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.
How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.
“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.
Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.
During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.
“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”
He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.
This article was updated 1/31/19.
SNOWMASS, COLO. – during the space of a few short weeks in autumn 2018.
“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.
He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.
• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).
• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).
Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).
“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.
• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).
“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.
How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.
“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.
Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.
During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.
“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”
He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.
This article was updated 1/31/19.
REPORTING FROM ACC SNOWMASS 2019
Before you refer for AF ablation
SNOWMASS, COLO. – Appropriate in the way of benefit, along with instilling awareness of the warning signals heralding serious late complications, Samuel J. Asirvatham, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Who to steer toward ablation? You have to have a symptomatic patient – that’s a given. For the ones who are paroxysmal, the ones with a relatively normal heart, there’s a much better chance that you’ll help manage their symptoms with ablation than if they have persistent or permanent A-fib. Notice I do not use the word ‘cure’ for A-fib. We talk about controlling symptoms and decreasing frequency, because the longer follow-up you have with intensive monitoring, the more you realize that patients still tend to have some A-fib,” explained Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.
The rationale for early atrial fibrillation (AF) ablation in younger patients with troublesome symptoms of paroxysmal AF despite pharmacologic attempts at rate or rhythm control is that it will arrest the progression from an atrial arrhythmia that has just a few triggers readily neutralized by pulmonary vein isolation to persistent AF with a diseased heart and a multitude of arrhythmia trigger points coming from many directions.
A solid candidate for ablation of paroxysmal AF has about a 75% likelihood of having a successful first ablation procedure, with substantial improvement in symptoms and no need for medication. Another 9%-10% will achieve marked reduction in symptom burden upon addition of antiarrhythmic agents that weren’t effective before ablation.
Late complications can be deceptive
Periprocedural stroke/transient ischemic attack, tamponade, or bleeding on the table are infrequent complications readily recognized by the interventionalist. More problematic are several late complications which are often misinterpreted, with the resultant delay causing major harm.
- Pulmonary vein stenosis. This complication of inadvertent ablation inside the pulmonary vein manifests as shortness of breath, typically beginning about 4 weeks post ablation.
“This is very different from the shortness of breath they had with atrial fibrillation. They almost always have a cough that they didn’t have before, and they may have hemoptysis. It’s very important to recognize this promptly, because before it closes completely we can do an angioplasty and stent the vein with good results. But once it closes completely, it becomes an extremely complicated procedure to try to reopen that vein,” according to Dr. Asirvatham.
Very often the patient’s general cardiologist, chest physician, or primary care physician fails to recognize what’s happening. He cited an example: He recently had a patient with a cough who was first referred to an infectious disease specialist, who ordered a bronchoalveolar lavage. The specimen grew atypical actinomycetes. That prompted a referral to thoracic surgery for an open-lung biopsy. But that procedure required cardiac clearance beforehand. It was a cardiologist who said, ‘Wait – all this started after you had an ablation?’
“That patient had pulmonary vein stenosis. And, unfortunately, that complication has not gone away. Being a referral center for pulmonary vein isolation, we see just as many cases of pulmonary vein stenosis today as we did a few years ago,” he said.
- Atrial esophageal fistula. The hallmark of this complication is onset of a plethora of what Dr. Asirvatham called “funny symptoms” more than a month post ablation. These include fever, transient ischemic attacks (TIAs), sepsislike symptoms, discomfort in swallowing, and in some cases hemoptysis.
“The predominant picture is endocarditis/TIA/stroke. If you see this, and the patient has had ablation, immediately refer to surgery to have the fistula between the esophagus and heart fixed. This is not a patient where you say, ‘Nothing by mouth, give some antibiotics, and see what happens.’ I can tell you what will happen: The patient will die,” the cardiologist said.
- Atrial stiffness. This typically occurs about a month after a second or third ablation procedure, when the patient develops shortness of breath that keeps worsening.
“You think ‘pulmonary vein stenosis,’ but the CT scan shows the veins are wide open. Many of these patients will get misdiagnosed as having heart failure with preserved ejection fraction even though they never had it before. The problem here is the atrium has become too stiff from the ablation, and this stiff atrium causes increased pressure, resulting in the shortness of breath. Sometimes patients feel better over time, but sometimes it’s very difficult to treat. But it’s important to recognize atrial stiffness and exclude other causes like pulmonary vein stenosis,” Dr. Asirvatham continued.
- Gastroparesis. This occurs because of injury to the vagus nerve branches located at the top of the esophagus, with resultant delayed gastric emptying.
“It’s an uncomfortable feeling of fullness all the time. The patient will say, ‘It seems like I just ate, even though I ate 8 hours ago,” the electrophysiologist said. “Most of these patients will recover in about 6 months. They may feel better on a gastric motility agent, like a macrolide antibiotic. I personally have not seen a patient who did not feel better within 6-8 months.”
Novel treatment approaches: “A-fib may be an autonomic epilepsy of the heart”
“Patients sometimes will ask you, ‘What is this ablation? What does that mean?’ You have to be truthful and tell them that it’s just a fancy word for burning,” the electrophysiologist said.
Achievement of AF ablation without radiofrequency or cryoablation, instead utilizing nonthermal direct-current pulsed electrical fields, is “the hottest topic in the field of electrophysiology,” according to Dr. Asirvatham.
These electrical fields result in irreversible electroporation of targeted myocardial cell membranes, leading to cell death. It is a tissue-specific intervention, so it’s much less likely than conventional ablation to cause collateral damage to the esophagus and other structures.
“Direct current electroporation has transitioned from proof-of-concept studies to three relatively large patient trials. This is potentially an important breakthrough because if we don’t heat, a lot of the complications of A-fib ablation will probably decrease,” he explained.
Two other promising outside-the-box approaches to the treatment of AF are autonomic nervous system modulation at sites distant from the heart and particle beam ablation without need for cardiac catheters.
“If you put electrodes everywhere in the body to see where A-fib starts, it’s not in the atrium, not in the pulmonary veins, it’s in the nerves behind the pulmonary veins, and before those nerves it’s in some other area of the autonomic nervous system. This has given rise to the notion that A-fib may be an autonomic epilepsy of the heart,” according to the electrophysiologist.
This concept has given rise to a completely different approach to treatment of AF through neurostimulation. That’s how acupuncture works. Also, headphones have been used successfully to terminate and prevent AF by stimulating autonomic nerve centers near the ears. Low-level electrical stimulation of the vagus nerve in order to reduce stellate ganglion activity is under study. So is the application of botulinum toxin at key points in the autonomic nervous system.
“Catheters, drugs, and devices that target these areas, maybe without any ablation in the heart itself, is an exciting area of future management of A-fib,” he said.
Another promising approach is borrowed from radiation oncology: particulate ablation using beams of carbon atoms, protons, or photons.
“The first patients have now been treated for ventricular tachycardia and A-fib. It really is quite amazing how precise the lesion formation is. And with no catheters in the heart, clot can’t form on catheters,” he observed.
Dr. Asirvatham reported having no financial conflicts regarding his presentation, although he serves as a consultant to a handful of medical startup companies and holds patents on intellectual property, the royalties for which go directly to the Mayo Clinic.
SNOWMASS, COLO. – Appropriate in the way of benefit, along with instilling awareness of the warning signals heralding serious late complications, Samuel J. Asirvatham, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Who to steer toward ablation? You have to have a symptomatic patient – that’s a given. For the ones who are paroxysmal, the ones with a relatively normal heart, there’s a much better chance that you’ll help manage their symptoms with ablation than if they have persistent or permanent A-fib. Notice I do not use the word ‘cure’ for A-fib. We talk about controlling symptoms and decreasing frequency, because the longer follow-up you have with intensive monitoring, the more you realize that patients still tend to have some A-fib,” explained Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.
The rationale for early atrial fibrillation (AF) ablation in younger patients with troublesome symptoms of paroxysmal AF despite pharmacologic attempts at rate or rhythm control is that it will arrest the progression from an atrial arrhythmia that has just a few triggers readily neutralized by pulmonary vein isolation to persistent AF with a diseased heart and a multitude of arrhythmia trigger points coming from many directions.
A solid candidate for ablation of paroxysmal AF has about a 75% likelihood of having a successful first ablation procedure, with substantial improvement in symptoms and no need for medication. Another 9%-10% will achieve marked reduction in symptom burden upon addition of antiarrhythmic agents that weren’t effective before ablation.
Late complications can be deceptive
Periprocedural stroke/transient ischemic attack, tamponade, or bleeding on the table are infrequent complications readily recognized by the interventionalist. More problematic are several late complications which are often misinterpreted, with the resultant delay causing major harm.
- Pulmonary vein stenosis. This complication of inadvertent ablation inside the pulmonary vein manifests as shortness of breath, typically beginning about 4 weeks post ablation.
“This is very different from the shortness of breath they had with atrial fibrillation. They almost always have a cough that they didn’t have before, and they may have hemoptysis. It’s very important to recognize this promptly, because before it closes completely we can do an angioplasty and stent the vein with good results. But once it closes completely, it becomes an extremely complicated procedure to try to reopen that vein,” according to Dr. Asirvatham.
Very often the patient’s general cardiologist, chest physician, or primary care physician fails to recognize what’s happening. He cited an example: He recently had a patient with a cough who was first referred to an infectious disease specialist, who ordered a bronchoalveolar lavage. The specimen grew atypical actinomycetes. That prompted a referral to thoracic surgery for an open-lung biopsy. But that procedure required cardiac clearance beforehand. It was a cardiologist who said, ‘Wait – all this started after you had an ablation?’
“That patient had pulmonary vein stenosis. And, unfortunately, that complication has not gone away. Being a referral center for pulmonary vein isolation, we see just as many cases of pulmonary vein stenosis today as we did a few years ago,” he said.
- Atrial esophageal fistula. The hallmark of this complication is onset of a plethora of what Dr. Asirvatham called “funny symptoms” more than a month post ablation. These include fever, transient ischemic attacks (TIAs), sepsislike symptoms, discomfort in swallowing, and in some cases hemoptysis.
“The predominant picture is endocarditis/TIA/stroke. If you see this, and the patient has had ablation, immediately refer to surgery to have the fistula between the esophagus and heart fixed. This is not a patient where you say, ‘Nothing by mouth, give some antibiotics, and see what happens.’ I can tell you what will happen: The patient will die,” the cardiologist said.
- Atrial stiffness. This typically occurs about a month after a second or third ablation procedure, when the patient develops shortness of breath that keeps worsening.
“You think ‘pulmonary vein stenosis,’ but the CT scan shows the veins are wide open. Many of these patients will get misdiagnosed as having heart failure with preserved ejection fraction even though they never had it before. The problem here is the atrium has become too stiff from the ablation, and this stiff atrium causes increased pressure, resulting in the shortness of breath. Sometimes patients feel better over time, but sometimes it’s very difficult to treat. But it’s important to recognize atrial stiffness and exclude other causes like pulmonary vein stenosis,” Dr. Asirvatham continued.
- Gastroparesis. This occurs because of injury to the vagus nerve branches located at the top of the esophagus, with resultant delayed gastric emptying.
“It’s an uncomfortable feeling of fullness all the time. The patient will say, ‘It seems like I just ate, even though I ate 8 hours ago,” the electrophysiologist said. “Most of these patients will recover in about 6 months. They may feel better on a gastric motility agent, like a macrolide antibiotic. I personally have not seen a patient who did not feel better within 6-8 months.”
Novel treatment approaches: “A-fib may be an autonomic epilepsy of the heart”
“Patients sometimes will ask you, ‘What is this ablation? What does that mean?’ You have to be truthful and tell them that it’s just a fancy word for burning,” the electrophysiologist said.
Achievement of AF ablation without radiofrequency or cryoablation, instead utilizing nonthermal direct-current pulsed electrical fields, is “the hottest topic in the field of electrophysiology,” according to Dr. Asirvatham.
These electrical fields result in irreversible electroporation of targeted myocardial cell membranes, leading to cell death. It is a tissue-specific intervention, so it’s much less likely than conventional ablation to cause collateral damage to the esophagus and other structures.
“Direct current electroporation has transitioned from proof-of-concept studies to three relatively large patient trials. This is potentially an important breakthrough because if we don’t heat, a lot of the complications of A-fib ablation will probably decrease,” he explained.
Two other promising outside-the-box approaches to the treatment of AF are autonomic nervous system modulation at sites distant from the heart and particle beam ablation without need for cardiac catheters.
“If you put electrodes everywhere in the body to see where A-fib starts, it’s not in the atrium, not in the pulmonary veins, it’s in the nerves behind the pulmonary veins, and before those nerves it’s in some other area of the autonomic nervous system. This has given rise to the notion that A-fib may be an autonomic epilepsy of the heart,” according to the electrophysiologist.
This concept has given rise to a completely different approach to treatment of AF through neurostimulation. That’s how acupuncture works. Also, headphones have been used successfully to terminate and prevent AF by stimulating autonomic nerve centers near the ears. Low-level electrical stimulation of the vagus nerve in order to reduce stellate ganglion activity is under study. So is the application of botulinum toxin at key points in the autonomic nervous system.
“Catheters, drugs, and devices that target these areas, maybe without any ablation in the heart itself, is an exciting area of future management of A-fib,” he said.
Another promising approach is borrowed from radiation oncology: particulate ablation using beams of carbon atoms, protons, or photons.
“The first patients have now been treated for ventricular tachycardia and A-fib. It really is quite amazing how precise the lesion formation is. And with no catheters in the heart, clot can’t form on catheters,” he observed.
Dr. Asirvatham reported having no financial conflicts regarding his presentation, although he serves as a consultant to a handful of medical startup companies and holds patents on intellectual property, the royalties for which go directly to the Mayo Clinic.
SNOWMASS, COLO. – Appropriate in the way of benefit, along with instilling awareness of the warning signals heralding serious late complications, Samuel J. Asirvatham, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Who to steer toward ablation? You have to have a symptomatic patient – that’s a given. For the ones who are paroxysmal, the ones with a relatively normal heart, there’s a much better chance that you’ll help manage their symptoms with ablation than if they have persistent or permanent A-fib. Notice I do not use the word ‘cure’ for A-fib. We talk about controlling symptoms and decreasing frequency, because the longer follow-up you have with intensive monitoring, the more you realize that patients still tend to have some A-fib,” explained Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.
The rationale for early atrial fibrillation (AF) ablation in younger patients with troublesome symptoms of paroxysmal AF despite pharmacologic attempts at rate or rhythm control is that it will arrest the progression from an atrial arrhythmia that has just a few triggers readily neutralized by pulmonary vein isolation to persistent AF with a diseased heart and a multitude of arrhythmia trigger points coming from many directions.
A solid candidate for ablation of paroxysmal AF has about a 75% likelihood of having a successful first ablation procedure, with substantial improvement in symptoms and no need for medication. Another 9%-10% will achieve marked reduction in symptom burden upon addition of antiarrhythmic agents that weren’t effective before ablation.
Late complications can be deceptive
Periprocedural stroke/transient ischemic attack, tamponade, or bleeding on the table are infrequent complications readily recognized by the interventionalist. More problematic are several late complications which are often misinterpreted, with the resultant delay causing major harm.
- Pulmonary vein stenosis. This complication of inadvertent ablation inside the pulmonary vein manifests as shortness of breath, typically beginning about 4 weeks post ablation.
“This is very different from the shortness of breath they had with atrial fibrillation. They almost always have a cough that they didn’t have before, and they may have hemoptysis. It’s very important to recognize this promptly, because before it closes completely we can do an angioplasty and stent the vein with good results. But once it closes completely, it becomes an extremely complicated procedure to try to reopen that vein,” according to Dr. Asirvatham.
Very often the patient’s general cardiologist, chest physician, or primary care physician fails to recognize what’s happening. He cited an example: He recently had a patient with a cough who was first referred to an infectious disease specialist, who ordered a bronchoalveolar lavage. The specimen grew atypical actinomycetes. That prompted a referral to thoracic surgery for an open-lung biopsy. But that procedure required cardiac clearance beforehand. It was a cardiologist who said, ‘Wait – all this started after you had an ablation?’
“That patient had pulmonary vein stenosis. And, unfortunately, that complication has not gone away. Being a referral center for pulmonary vein isolation, we see just as many cases of pulmonary vein stenosis today as we did a few years ago,” he said.
- Atrial esophageal fistula. The hallmark of this complication is onset of a plethora of what Dr. Asirvatham called “funny symptoms” more than a month post ablation. These include fever, transient ischemic attacks (TIAs), sepsislike symptoms, discomfort in swallowing, and in some cases hemoptysis.
“The predominant picture is endocarditis/TIA/stroke. If you see this, and the patient has had ablation, immediately refer to surgery to have the fistula between the esophagus and heart fixed. This is not a patient where you say, ‘Nothing by mouth, give some antibiotics, and see what happens.’ I can tell you what will happen: The patient will die,” the cardiologist said.
- Atrial stiffness. This typically occurs about a month after a second or third ablation procedure, when the patient develops shortness of breath that keeps worsening.
“You think ‘pulmonary vein stenosis,’ but the CT scan shows the veins are wide open. Many of these patients will get misdiagnosed as having heart failure with preserved ejection fraction even though they never had it before. The problem here is the atrium has become too stiff from the ablation, and this stiff atrium causes increased pressure, resulting in the shortness of breath. Sometimes patients feel better over time, but sometimes it’s very difficult to treat. But it’s important to recognize atrial stiffness and exclude other causes like pulmonary vein stenosis,” Dr. Asirvatham continued.
- Gastroparesis. This occurs because of injury to the vagus nerve branches located at the top of the esophagus, with resultant delayed gastric emptying.
“It’s an uncomfortable feeling of fullness all the time. The patient will say, ‘It seems like I just ate, even though I ate 8 hours ago,” the electrophysiologist said. “Most of these patients will recover in about 6 months. They may feel better on a gastric motility agent, like a macrolide antibiotic. I personally have not seen a patient who did not feel better within 6-8 months.”
Novel treatment approaches: “A-fib may be an autonomic epilepsy of the heart”
“Patients sometimes will ask you, ‘What is this ablation? What does that mean?’ You have to be truthful and tell them that it’s just a fancy word for burning,” the electrophysiologist said.
Achievement of AF ablation without radiofrequency or cryoablation, instead utilizing nonthermal direct-current pulsed electrical fields, is “the hottest topic in the field of electrophysiology,” according to Dr. Asirvatham.
These electrical fields result in irreversible electroporation of targeted myocardial cell membranes, leading to cell death. It is a tissue-specific intervention, so it’s much less likely than conventional ablation to cause collateral damage to the esophagus and other structures.
“Direct current electroporation has transitioned from proof-of-concept studies to three relatively large patient trials. This is potentially an important breakthrough because if we don’t heat, a lot of the complications of A-fib ablation will probably decrease,” he explained.
Two other promising outside-the-box approaches to the treatment of AF are autonomic nervous system modulation at sites distant from the heart and particle beam ablation without need for cardiac catheters.
“If you put electrodes everywhere in the body to see where A-fib starts, it’s not in the atrium, not in the pulmonary veins, it’s in the nerves behind the pulmonary veins, and before those nerves it’s in some other area of the autonomic nervous system. This has given rise to the notion that A-fib may be an autonomic epilepsy of the heart,” according to the electrophysiologist.
This concept has given rise to a completely different approach to treatment of AF through neurostimulation. That’s how acupuncture works. Also, headphones have been used successfully to terminate and prevent AF by stimulating autonomic nerve centers near the ears. Low-level electrical stimulation of the vagus nerve in order to reduce stellate ganglion activity is under study. So is the application of botulinum toxin at key points in the autonomic nervous system.
“Catheters, drugs, and devices that target these areas, maybe without any ablation in the heart itself, is an exciting area of future management of A-fib,” he said.
Another promising approach is borrowed from radiation oncology: particulate ablation using beams of carbon atoms, protons, or photons.
“The first patients have now been treated for ventricular tachycardia and A-fib. It really is quite amazing how precise the lesion formation is. And with no catheters in the heart, clot can’t form on catheters,” he observed.
Dr. Asirvatham reported having no financial conflicts regarding his presentation, although he serves as a consultant to a handful of medical startup companies and holds patents on intellectual property, the royalties for which go directly to the Mayo Clinic.
REPORTING FROM ACC SNOWMASS 2019
PCSK9 inhibition isn’t the answer for high Lp(a)
CHICAGO – according to the results of the ANITSCHKOW study, Erik S. Stroes, MD, PhD, reported at the American Heart Association scientific sessions.
“The reality is that for now we don’t have any drugs to significantly lower elevated Lp(a),” he said. “We can identify patients with elevated Lp(a), but we don’t have a clue how to treat them.”
Elevated Lp(a) is a highly prevalent lipid abnormality. It induces arterial wall inflammation, a known predictor of future cardiovascular events. The monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9) dramatically reduce LDL cholesterol and also reduce arterial wall inflammation. In the published studies, PCSK9 inhibitors also reduced Lp(a) by an average of 27%; however, most participants in those studies had isolated high LDL with a normal or slightly elevated Lp(a).
ANITSCHKOW was the first double-blind, randomized, placebo-controlled study to look at the effects of a PCSK9 inhibitor – in this case, evolocumab (Repatha) – in patients with severe elevations in both LDL and Lp(a). The results proved disappointing yet informative, according to Dr. Stroes, professor of internal medicine and a vascular medicine specialist at the University of Amsterdam.
The 16-week, 14-site trial included 128 Dutch, American, and Canadian patients with a mean baseline LDL of 146 mg/dL and a median Lp(a) of 202 nmol/L who were randomized to monthly subcutanous injections of evolocumab at 420 mg or placebo. All participants had evidence of significant arterial wall inflammation at baseline as measured by PET-CT. Of the subjects, 54% were on statin therapy.
Evolucumab achieved a placebo-subtracted 61% reduction in LDL to 60 mg/dL but a mere 14% reduction in Lp(a) to 188 nmol/L, still far in excess of the 50 nmol/L cutoff defining elevated Lp(a).
The primary endpoint was change in arterial wall inflammation from baseline to week 16 as measured using PET-CT. Based upon the results of other studies showing a 3.3% drop in arterial wall inflammation for every 10% reduction in LDL, Dr. Stroes and his coinvestigators expected to see a 20% decrease in arterial wall inflammation in the evolocumab group. Instead, they found a mere 8.4% reduction, which wasn’t significantly different than in placebo-treated controls. And there was no difference in arterial wall inflammation between the group on concomitant statin therapy and those who weren’t.
The implication is that the residual Lp(a) elevation despite PCSK9 inhibitor therapy might explain the discrepancy, compared with previous studies in which LDL lowering did reduce arterial wall inflammation, according to Dr. Stroes.
“Persistent arterial wall inflammation on PET-CT after evolocumab, potentially related to persistent Lp(a) elevation, implies the need for additional therapies to decrease the proinflammatory state in Lp(a) elevation,” he observed.
Lp(a) in the spotlight
An elevated Lp(a) of 50 nmol/L or more is present in 20% of the general population, according to a Danish study. More than 70% of a person’s Lp(a) level is genetically driven. And a genetically driven elevated Lp(a) has been shown to be associated with a twofold to fourfold increased risk of cardiovascular events.
Moreover, other investigators have shown that a severely elevated Lp(a) (greater than 180 nmol/L) poses a cardiovascular risk comparable with that of heterozygous familial hypercholesterolemia and is present in 1 in 100 individuals.
“We spend a lot of time on familial hypercholesterolemia, and we should. But mind you, this severe Lp(a) elevation is more frequent than heterozygous FH,” Dr. Stroes said.
Session cochair Robert H. Eckel, MD, asked the audience for a show of hands by those who regularly measure Lp(a) in their patients. Very few hands were raised.
“I measure Lp(a) frequently, and I think it’s a very important risk factor,” declared Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.
The ANITSCHKOW study was sponsored by Amgen. Dr. Stroes reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.
CHICAGO – according to the results of the ANITSCHKOW study, Erik S. Stroes, MD, PhD, reported at the American Heart Association scientific sessions.
“The reality is that for now we don’t have any drugs to significantly lower elevated Lp(a),” he said. “We can identify patients with elevated Lp(a), but we don’t have a clue how to treat them.”
Elevated Lp(a) is a highly prevalent lipid abnormality. It induces arterial wall inflammation, a known predictor of future cardiovascular events. The monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9) dramatically reduce LDL cholesterol and also reduce arterial wall inflammation. In the published studies, PCSK9 inhibitors also reduced Lp(a) by an average of 27%; however, most participants in those studies had isolated high LDL with a normal or slightly elevated Lp(a).
ANITSCHKOW was the first double-blind, randomized, placebo-controlled study to look at the effects of a PCSK9 inhibitor – in this case, evolocumab (Repatha) – in patients with severe elevations in both LDL and Lp(a). The results proved disappointing yet informative, according to Dr. Stroes, professor of internal medicine and a vascular medicine specialist at the University of Amsterdam.
The 16-week, 14-site trial included 128 Dutch, American, and Canadian patients with a mean baseline LDL of 146 mg/dL and a median Lp(a) of 202 nmol/L who were randomized to monthly subcutanous injections of evolocumab at 420 mg or placebo. All participants had evidence of significant arterial wall inflammation at baseline as measured by PET-CT. Of the subjects, 54% were on statin therapy.
Evolucumab achieved a placebo-subtracted 61% reduction in LDL to 60 mg/dL but a mere 14% reduction in Lp(a) to 188 nmol/L, still far in excess of the 50 nmol/L cutoff defining elevated Lp(a).
The primary endpoint was change in arterial wall inflammation from baseline to week 16 as measured using PET-CT. Based upon the results of other studies showing a 3.3% drop in arterial wall inflammation for every 10% reduction in LDL, Dr. Stroes and his coinvestigators expected to see a 20% decrease in arterial wall inflammation in the evolocumab group. Instead, they found a mere 8.4% reduction, which wasn’t significantly different than in placebo-treated controls. And there was no difference in arterial wall inflammation between the group on concomitant statin therapy and those who weren’t.
The implication is that the residual Lp(a) elevation despite PCSK9 inhibitor therapy might explain the discrepancy, compared with previous studies in which LDL lowering did reduce arterial wall inflammation, according to Dr. Stroes.
“Persistent arterial wall inflammation on PET-CT after evolocumab, potentially related to persistent Lp(a) elevation, implies the need for additional therapies to decrease the proinflammatory state in Lp(a) elevation,” he observed.
Lp(a) in the spotlight
An elevated Lp(a) of 50 nmol/L or more is present in 20% of the general population, according to a Danish study. More than 70% of a person’s Lp(a) level is genetically driven. And a genetically driven elevated Lp(a) has been shown to be associated with a twofold to fourfold increased risk of cardiovascular events.
Moreover, other investigators have shown that a severely elevated Lp(a) (greater than 180 nmol/L) poses a cardiovascular risk comparable with that of heterozygous familial hypercholesterolemia and is present in 1 in 100 individuals.
“We spend a lot of time on familial hypercholesterolemia, and we should. But mind you, this severe Lp(a) elevation is more frequent than heterozygous FH,” Dr. Stroes said.
Session cochair Robert H. Eckel, MD, asked the audience for a show of hands by those who regularly measure Lp(a) in their patients. Very few hands were raised.
“I measure Lp(a) frequently, and I think it’s a very important risk factor,” declared Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.
The ANITSCHKOW study was sponsored by Amgen. Dr. Stroes reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.
CHICAGO – according to the results of the ANITSCHKOW study, Erik S. Stroes, MD, PhD, reported at the American Heart Association scientific sessions.
“The reality is that for now we don’t have any drugs to significantly lower elevated Lp(a),” he said. “We can identify patients with elevated Lp(a), but we don’t have a clue how to treat them.”
Elevated Lp(a) is a highly prevalent lipid abnormality. It induces arterial wall inflammation, a known predictor of future cardiovascular events. The monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9) dramatically reduce LDL cholesterol and also reduce arterial wall inflammation. In the published studies, PCSK9 inhibitors also reduced Lp(a) by an average of 27%; however, most participants in those studies had isolated high LDL with a normal or slightly elevated Lp(a).
ANITSCHKOW was the first double-blind, randomized, placebo-controlled study to look at the effects of a PCSK9 inhibitor – in this case, evolocumab (Repatha) – in patients with severe elevations in both LDL and Lp(a). The results proved disappointing yet informative, according to Dr. Stroes, professor of internal medicine and a vascular medicine specialist at the University of Amsterdam.
The 16-week, 14-site trial included 128 Dutch, American, and Canadian patients with a mean baseline LDL of 146 mg/dL and a median Lp(a) of 202 nmol/L who were randomized to monthly subcutanous injections of evolocumab at 420 mg or placebo. All participants had evidence of significant arterial wall inflammation at baseline as measured by PET-CT. Of the subjects, 54% were on statin therapy.
Evolucumab achieved a placebo-subtracted 61% reduction in LDL to 60 mg/dL but a mere 14% reduction in Lp(a) to 188 nmol/L, still far in excess of the 50 nmol/L cutoff defining elevated Lp(a).
The primary endpoint was change in arterial wall inflammation from baseline to week 16 as measured using PET-CT. Based upon the results of other studies showing a 3.3% drop in arterial wall inflammation for every 10% reduction in LDL, Dr. Stroes and his coinvestigators expected to see a 20% decrease in arterial wall inflammation in the evolocumab group. Instead, they found a mere 8.4% reduction, which wasn’t significantly different than in placebo-treated controls. And there was no difference in arterial wall inflammation between the group on concomitant statin therapy and those who weren’t.
The implication is that the residual Lp(a) elevation despite PCSK9 inhibitor therapy might explain the discrepancy, compared with previous studies in which LDL lowering did reduce arterial wall inflammation, according to Dr. Stroes.
“Persistent arterial wall inflammation on PET-CT after evolocumab, potentially related to persistent Lp(a) elevation, implies the need for additional therapies to decrease the proinflammatory state in Lp(a) elevation,” he observed.
Lp(a) in the spotlight
An elevated Lp(a) of 50 nmol/L or more is present in 20% of the general population, according to a Danish study. More than 70% of a person’s Lp(a) level is genetically driven. And a genetically driven elevated Lp(a) has been shown to be associated with a twofold to fourfold increased risk of cardiovascular events.
Moreover, other investigators have shown that a severely elevated Lp(a) (greater than 180 nmol/L) poses a cardiovascular risk comparable with that of heterozygous familial hypercholesterolemia and is present in 1 in 100 individuals.
“We spend a lot of time on familial hypercholesterolemia, and we should. But mind you, this severe Lp(a) elevation is more frequent than heterozygous FH,” Dr. Stroes said.
Session cochair Robert H. Eckel, MD, asked the audience for a show of hands by those who regularly measure Lp(a) in their patients. Very few hands were raised.
“I measure Lp(a) frequently, and I think it’s a very important risk factor,” declared Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.
The ANITSCHKOW study was sponsored by Amgen. Dr. Stroes reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: Evolocumab has no effect on arterial wall inflammation in patients with severely elevated Lp(a).
Major finding: Median Lp(a) declined modestly from 202 nmol/L to 188 nmol/L in response to evolocumab.
Study details: This multicenter, 16-week, double-blind, placebo-controlled study included 128 patients with both elevated LDL and Lp(a).
Disclosures: The ANITSCHKOW study was sponsored by Amgen. The presenter reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.
Comorbidities may cut effectiveness of psoriasis biologics
PARIS – in response to biologic therapy, according to the results of the prospective observational PSO-BIO-REAL study.
The clinical importance of this finding lies in the fact that comorbidities are highly prevalent among patients with moderate to severe psoriasis. Indeed, fully 64% of the 846 participants in PSO-BIO-REAL had at least one major comorbid condition at baseline, Finn Ziegler said at the annual congress of the European Academy of Dermatology and Venereology.
“I think this reflects a picture that has been seen in other studies,” noted Mr. Ziegler, director of global patient access at Leo Pharma in Ballerup, Denmark.
The purpose of the 12-month PSO-BIO-REAL (PSOriasis treated with BIOlogics in REAL life) study was to assess the effectiveness of a variety of biologic agents in a real-world population typical of patients encountered in routine clinical practice, as opposed to more restrictive format of often-cited randomized trials, which generally feature a lengthy list of exclusions. One-third of participants were from the United States, with the rest drawn from four Western European countries. Their mean age was 47 years, with an 18.4-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of 14.3.
Sixty percent of participants were starting treatment with a biologic agent for the first time. The other 40% had prior biologic experience. At physician discretion, 61% of enrollees were put on a tumor necrosis factor inhibitor, either etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade); 30% initiated treatment with the interleukin-12/23 inhibitor ustekinumab (Stelara); and 9% received secukinumab (Cosentyx), an interleukin-17 inhibitor.
The five most common comorbid conditions present at baseline were hypertension, present in 33.5% of participants; psoriatic arthritis (PsA), present in 28.1%; hyperlipidemia, 20.9%; diabetes, 13.9%, and depression, present in 13.7% of the psoriasis patients.
Baseline comorbidities were significantly more common among the biologic-experienced patients. For example, their prevalence of hypertension was 42%, compared with 28% in the biologic-naive group. PsA was present in 35% of the biologic-experienced and 23% of the biologic-naive patients. Nineteen percent of biologic-experienced patients had diabetes at baseline, as did 11% of the biologic-naive group.
During the 12-month study, 3.7% of patients developed a new comorbidity, the most common being anxiety, hypertension, PsA, depression, and hyperlipidemia.
The primary outcome in the study was the complete clearance rate – a PASI 100 response – at 6 months. It ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more. The results were similar at 12 months.
Conversely, an inadequate therapeutic response as defined by a PASI 50 or less at 6 months occurred in 15% of psoriasis patients with no baseline comorbidities, 27% with one, 35% with two comorbid conditions, and 28% with three or more.
The major caveat regarding this study is that the observed association between comorbid conditions and complete clearance rates doesn’t prove causality, Mr. Ziegler noted.
The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma. Mr. Ziegler is a Leo executive.
SOURCE: Ziegler F. EADV Congress, Abstract FC04.01.
PARIS – in response to biologic therapy, according to the results of the prospective observational PSO-BIO-REAL study.
The clinical importance of this finding lies in the fact that comorbidities are highly prevalent among patients with moderate to severe psoriasis. Indeed, fully 64% of the 846 participants in PSO-BIO-REAL had at least one major comorbid condition at baseline, Finn Ziegler said at the annual congress of the European Academy of Dermatology and Venereology.
“I think this reflects a picture that has been seen in other studies,” noted Mr. Ziegler, director of global patient access at Leo Pharma in Ballerup, Denmark.
The purpose of the 12-month PSO-BIO-REAL (PSOriasis treated with BIOlogics in REAL life) study was to assess the effectiveness of a variety of biologic agents in a real-world population typical of patients encountered in routine clinical practice, as opposed to more restrictive format of often-cited randomized trials, which generally feature a lengthy list of exclusions. One-third of participants were from the United States, with the rest drawn from four Western European countries. Their mean age was 47 years, with an 18.4-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of 14.3.
Sixty percent of participants were starting treatment with a biologic agent for the first time. The other 40% had prior biologic experience. At physician discretion, 61% of enrollees were put on a tumor necrosis factor inhibitor, either etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade); 30% initiated treatment with the interleukin-12/23 inhibitor ustekinumab (Stelara); and 9% received secukinumab (Cosentyx), an interleukin-17 inhibitor.
The five most common comorbid conditions present at baseline were hypertension, present in 33.5% of participants; psoriatic arthritis (PsA), present in 28.1%; hyperlipidemia, 20.9%; diabetes, 13.9%, and depression, present in 13.7% of the psoriasis patients.
Baseline comorbidities were significantly more common among the biologic-experienced patients. For example, their prevalence of hypertension was 42%, compared with 28% in the biologic-naive group. PsA was present in 35% of the biologic-experienced and 23% of the biologic-naive patients. Nineteen percent of biologic-experienced patients had diabetes at baseline, as did 11% of the biologic-naive group.
During the 12-month study, 3.7% of patients developed a new comorbidity, the most common being anxiety, hypertension, PsA, depression, and hyperlipidemia.
The primary outcome in the study was the complete clearance rate – a PASI 100 response – at 6 months. It ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more. The results were similar at 12 months.
Conversely, an inadequate therapeutic response as defined by a PASI 50 or less at 6 months occurred in 15% of psoriasis patients with no baseline comorbidities, 27% with one, 35% with two comorbid conditions, and 28% with three or more.
The major caveat regarding this study is that the observed association between comorbid conditions and complete clearance rates doesn’t prove causality, Mr. Ziegler noted.
The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma. Mr. Ziegler is a Leo executive.
SOURCE: Ziegler F. EADV Congress, Abstract FC04.01.
PARIS – in response to biologic therapy, according to the results of the prospective observational PSO-BIO-REAL study.
The clinical importance of this finding lies in the fact that comorbidities are highly prevalent among patients with moderate to severe psoriasis. Indeed, fully 64% of the 846 participants in PSO-BIO-REAL had at least one major comorbid condition at baseline, Finn Ziegler said at the annual congress of the European Academy of Dermatology and Venereology.
“I think this reflects a picture that has been seen in other studies,” noted Mr. Ziegler, director of global patient access at Leo Pharma in Ballerup, Denmark.
The purpose of the 12-month PSO-BIO-REAL (PSOriasis treated with BIOlogics in REAL life) study was to assess the effectiveness of a variety of biologic agents in a real-world population typical of patients encountered in routine clinical practice, as opposed to more restrictive format of often-cited randomized trials, which generally feature a lengthy list of exclusions. One-third of participants were from the United States, with the rest drawn from four Western European countries. Their mean age was 47 years, with an 18.4-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of 14.3.
Sixty percent of participants were starting treatment with a biologic agent for the first time. The other 40% had prior biologic experience. At physician discretion, 61% of enrollees were put on a tumor necrosis factor inhibitor, either etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade); 30% initiated treatment with the interleukin-12/23 inhibitor ustekinumab (Stelara); and 9% received secukinumab (Cosentyx), an interleukin-17 inhibitor.
The five most common comorbid conditions present at baseline were hypertension, present in 33.5% of participants; psoriatic arthritis (PsA), present in 28.1%; hyperlipidemia, 20.9%; diabetes, 13.9%, and depression, present in 13.7% of the psoriasis patients.
Baseline comorbidities were significantly more common among the biologic-experienced patients. For example, their prevalence of hypertension was 42%, compared with 28% in the biologic-naive group. PsA was present in 35% of the biologic-experienced and 23% of the biologic-naive patients. Nineteen percent of biologic-experienced patients had diabetes at baseline, as did 11% of the biologic-naive group.
During the 12-month study, 3.7% of patients developed a new comorbidity, the most common being anxiety, hypertension, PsA, depression, and hyperlipidemia.
The primary outcome in the study was the complete clearance rate – a PASI 100 response – at 6 months. It ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more. The results were similar at 12 months.
Conversely, an inadequate therapeutic response as defined by a PASI 50 or less at 6 months occurred in 15% of psoriasis patients with no baseline comorbidities, 27% with one, 35% with two comorbid conditions, and 28% with three or more.
The major caveat regarding this study is that the observed association between comorbid conditions and complete clearance rates doesn’t prove causality, Mr. Ziegler noted.
The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma. Mr. Ziegler is a Leo executive.
SOURCE: Ziegler F. EADV Congress, Abstract FC04.01.
REPORTING FROM THE EADV CONGRESS
Key clinical point: As the number of baseline comorbid conditions increases, the complete clearance rate in response to biologic agents for psoriasis falls.
Major finding: The complete clearance rate after 6 months of biologic therapy ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more.
Study details: This multinational, prospective, observational, 12-month study included 846 patients initiating biologic therapy for moderate to severe psoriasis.
Disclosures: The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma and was presented by a Leo executive.
Source: Ziegler F. EADV Congress, Abstract FC04.01.
Subclinical hypothyroidism boosts immediate risk of heart failure
CHICAGO – The short-term risk of developing heart failure in patients with newly identified hypothyroidism, be it overt or subclinical, is double that of euthyroid individuals, Caroline H. Noergaard, MD, reported at the American Heart Association scientific sessions.
“This is really important clinically. The association with heart failure has previously been shown in both overt and subclinical hyperthyroidism, but it’s actually new knowledge that hypothyroidism is associated with immediate risk of heart failure. And a lot of people have subclinical hypothyroidism,” said Dr. Noergaard, a PhD student in epidemiology at Aalborg (Denmark) University.
Also at the meeting, Jeffrey L. Anderson, MD, reported that free thyroxine levels within the normal reference range were associated in graded fashion with an increased prevalence and incidence of atrial fibrillation in a large Utah study, a finding that provides independent confirmation of an earlier report by investigators from the population-based Rotterdam Study.
“These findings validate those of the Rotterdam Study in a much larger dataset and may have important clinical implications, including a redefinition of the reference range and the target-free T4 levels for thyroxine replacement therapy,” observed Dr. Anderson, professor of internal medicine at the University of Utah, Salt Lake City, and a research cardiologist at the Intermountain Medical Center Heart Institute.
Hypothyroidism and heart failure
Dr. Noergaard presented a retrospective study of over 1 million Copenhagen-area adults (mean age, 50 years) with no history of heart failure, who had their first thyroid function test. She and her coinvestigators turned to comprehensive Danish national health care registries to determine how many of these individuals were diagnosed with new-onset heart failure within 90 days after their thyroid function test.
Subclinical hypothyroidism was defined by a thyroid-stimulating hormone level greater than 5 mIU/L and a free T4 of 9-22 pmol/L. Overt hypothyroidism required a TSH greater than 5 mIU/L with a free T4 less than 9 pmol/L.
Free T4 predicts atrial fibrillation risk
Dr. Anderson presented a retrospective analysis of 174,914 adult patients in the Intermountain Healthcare EMR database, none of whom were on thyroid replacement at entry. The patients, who were a mean age of 64 years and 65% women, were followed for an average of 6.3 years. Of these, 88.4% had a free T4 within the normal reference range of 0.75-1.5 ng/dL, 7.4% had a value below the cutoff for normal, and 4.2% had a free T4 above the reference range.
Upon dividing the patients within the normal range into quartiles based upon their free T4 level, he and his coinvestigators found that the baseline prevalence of atrial fibrillation was 8.7% in those in quartile 1, 9.3% in quartile 2, 10.5% in quartile 3, and 12.6% in quartile 4. In a multivariate analysis adjusted for potential confounders, the risk of prevalent atrial fibrillation was increased by 11% for patients in quartile 2, compared with those in the first quartile, by 22% in quartile 3, and by 40% in quartile 4.
The incidence of new-onset atrial fibrillation during 3 years of follow-up was 4.1% in patients in normal-range quartile 1, 4.3% in quartile 2, 4.5% in quartile 3, and 5.2% in the top normal-range quartile. The odds of developing atrial fibrillation were increased by 8% and 16% in quartiles 3 and 4, compared with quartile 1.
Serum TSH and free T3 levels showed no consistent relationship with atrial fibrillation.
The Utah findings confirm in a large U.S. population the earlier report from the Rotterdam Study (J Clin Endocrinol Metab. 2015 Oct;100(10):3718-24).
Dr. Noergaard and Dr. Anderson reported having no financial conflicts regarding their studies, which were carried out free of commercial support.
CHICAGO – The short-term risk of developing heart failure in patients with newly identified hypothyroidism, be it overt or subclinical, is double that of euthyroid individuals, Caroline H. Noergaard, MD, reported at the American Heart Association scientific sessions.
“This is really important clinically. The association with heart failure has previously been shown in both overt and subclinical hyperthyroidism, but it’s actually new knowledge that hypothyroidism is associated with immediate risk of heart failure. And a lot of people have subclinical hypothyroidism,” said Dr. Noergaard, a PhD student in epidemiology at Aalborg (Denmark) University.
Also at the meeting, Jeffrey L. Anderson, MD, reported that free thyroxine levels within the normal reference range were associated in graded fashion with an increased prevalence and incidence of atrial fibrillation in a large Utah study, a finding that provides independent confirmation of an earlier report by investigators from the population-based Rotterdam Study.
“These findings validate those of the Rotterdam Study in a much larger dataset and may have important clinical implications, including a redefinition of the reference range and the target-free T4 levels for thyroxine replacement therapy,” observed Dr. Anderson, professor of internal medicine at the University of Utah, Salt Lake City, and a research cardiologist at the Intermountain Medical Center Heart Institute.
Hypothyroidism and heart failure
Dr. Noergaard presented a retrospective study of over 1 million Copenhagen-area adults (mean age, 50 years) with no history of heart failure, who had their first thyroid function test. She and her coinvestigators turned to comprehensive Danish national health care registries to determine how many of these individuals were diagnosed with new-onset heart failure within 90 days after their thyroid function test.
Subclinical hypothyroidism was defined by a thyroid-stimulating hormone level greater than 5 mIU/L and a free T4 of 9-22 pmol/L. Overt hypothyroidism required a TSH greater than 5 mIU/L with a free T4 less than 9 pmol/L.
Free T4 predicts atrial fibrillation risk
Dr. Anderson presented a retrospective analysis of 174,914 adult patients in the Intermountain Healthcare EMR database, none of whom were on thyroid replacement at entry. The patients, who were a mean age of 64 years and 65% women, were followed for an average of 6.3 years. Of these, 88.4% had a free T4 within the normal reference range of 0.75-1.5 ng/dL, 7.4% had a value below the cutoff for normal, and 4.2% had a free T4 above the reference range.
Upon dividing the patients within the normal range into quartiles based upon their free T4 level, he and his coinvestigators found that the baseline prevalence of atrial fibrillation was 8.7% in those in quartile 1, 9.3% in quartile 2, 10.5% in quartile 3, and 12.6% in quartile 4. In a multivariate analysis adjusted for potential confounders, the risk of prevalent atrial fibrillation was increased by 11% for patients in quartile 2, compared with those in the first quartile, by 22% in quartile 3, and by 40% in quartile 4.
The incidence of new-onset atrial fibrillation during 3 years of follow-up was 4.1% in patients in normal-range quartile 1, 4.3% in quartile 2, 4.5% in quartile 3, and 5.2% in the top normal-range quartile. The odds of developing atrial fibrillation were increased by 8% and 16% in quartiles 3 and 4, compared with quartile 1.
Serum TSH and free T3 levels showed no consistent relationship with atrial fibrillation.
The Utah findings confirm in a large U.S. population the earlier report from the Rotterdam Study (J Clin Endocrinol Metab. 2015 Oct;100(10):3718-24).
Dr. Noergaard and Dr. Anderson reported having no financial conflicts regarding their studies, which were carried out free of commercial support.
CHICAGO – The short-term risk of developing heart failure in patients with newly identified hypothyroidism, be it overt or subclinical, is double that of euthyroid individuals, Caroline H. Noergaard, MD, reported at the American Heart Association scientific sessions.
“This is really important clinically. The association with heart failure has previously been shown in both overt and subclinical hyperthyroidism, but it’s actually new knowledge that hypothyroidism is associated with immediate risk of heart failure. And a lot of people have subclinical hypothyroidism,” said Dr. Noergaard, a PhD student in epidemiology at Aalborg (Denmark) University.
Also at the meeting, Jeffrey L. Anderson, MD, reported that free thyroxine levels within the normal reference range were associated in graded fashion with an increased prevalence and incidence of atrial fibrillation in a large Utah study, a finding that provides independent confirmation of an earlier report by investigators from the population-based Rotterdam Study.
“These findings validate those of the Rotterdam Study in a much larger dataset and may have important clinical implications, including a redefinition of the reference range and the target-free T4 levels for thyroxine replacement therapy,” observed Dr. Anderson, professor of internal medicine at the University of Utah, Salt Lake City, and a research cardiologist at the Intermountain Medical Center Heart Institute.
Hypothyroidism and heart failure
Dr. Noergaard presented a retrospective study of over 1 million Copenhagen-area adults (mean age, 50 years) with no history of heart failure, who had their first thyroid function test. She and her coinvestigators turned to comprehensive Danish national health care registries to determine how many of these individuals were diagnosed with new-onset heart failure within 90 days after their thyroid function test.
Subclinical hypothyroidism was defined by a thyroid-stimulating hormone level greater than 5 mIU/L and a free T4 of 9-22 pmol/L. Overt hypothyroidism required a TSH greater than 5 mIU/L with a free T4 less than 9 pmol/L.
Free T4 predicts atrial fibrillation risk
Dr. Anderson presented a retrospective analysis of 174,914 adult patients in the Intermountain Healthcare EMR database, none of whom were on thyroid replacement at entry. The patients, who were a mean age of 64 years and 65% women, were followed for an average of 6.3 years. Of these, 88.4% had a free T4 within the normal reference range of 0.75-1.5 ng/dL, 7.4% had a value below the cutoff for normal, and 4.2% had a free T4 above the reference range.
Upon dividing the patients within the normal range into quartiles based upon their free T4 level, he and his coinvestigators found that the baseline prevalence of atrial fibrillation was 8.7% in those in quartile 1, 9.3% in quartile 2, 10.5% in quartile 3, and 12.6% in quartile 4. In a multivariate analysis adjusted for potential confounders, the risk of prevalent atrial fibrillation was increased by 11% for patients in quartile 2, compared with those in the first quartile, by 22% in quartile 3, and by 40% in quartile 4.
The incidence of new-onset atrial fibrillation during 3 years of follow-up was 4.1% in patients in normal-range quartile 1, 4.3% in quartile 2, 4.5% in quartile 3, and 5.2% in the top normal-range quartile. The odds of developing atrial fibrillation were increased by 8% and 16% in quartiles 3 and 4, compared with quartile 1.
Serum TSH and free T3 levels showed no consistent relationship with atrial fibrillation.
The Utah findings confirm in a large U.S. population the earlier report from the Rotterdam Study (J Clin Endocrinol Metab. 2015 Oct;100(10):3718-24).
Dr. Noergaard and Dr. Anderson reported having no financial conflicts regarding their studies, which were carried out free of commercial support.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Both subclinical and overt hypothyroidism are associated with a 100% increased risk of being diagnosed with heart failure, compared with euthyroid individuals.
Study details: This was a retrospective study of the association between free thyroxine levels and short-term risk of developing heart failure in more than 1 million Copenhagen-area patients.
Disclosures: The presenter reported having no financial conflicts regarding the Danish study, conducted free of commercial support.