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What’s next for Watchman stroke prevention device
SNOWMASS, COLO. – The goal is finally in sight following an odyssey to develop the Watchman left atrial appendage closure device as a safe and effective alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation, Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.
It’s all coming together: The Watchman, a small percutaneously delivered parachute-like device, has received FDA marketing approval as the sole authorized left atrial appendage closure device in this country on the strength of two compellingly positive randomized controlled trials. A recent meta-analysis of those trials showed significantly fewer hemorrhagic strokes, fewer cardiovascular or unexplained deaths, and fewer nonprocedural bleeding events in Watchman recipients than in patients randomized to warfarin. And a cost-effectiveness analysis has concluded that after 8 years, the Watchman becomes “the dominant strategy” – meaning more effective and less costly for stroke prevention in patients with atrial fibrillation (AF) having a contraindication to warfarin – compared with the novel oral anticoagulant apixaban (J Am Coll Cardiol. 2015 Dec 22;66[24]:2728-39).
Moreover, the final pieces required for the Watchman to become a mainstream reimbursable therapy are falling into place. The Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology, and the Heart Rhythm Society (HRS) have jointly issued institutional and operator requirements for left atrial appendage occlusion programs (J Am Coll Cardiol. 2015 Dec 8. pii: S0735-1097[15]07550-6). The ACC’s National Cardiovascular Data Registry has set up a new left atrial occlusion registry. And most important of all from a reimbursement standpoint, the Centers for Medicare and Medicaid Services has released a preliminary National Coverage Determination for left atrial appendage occlusion.
“This will affect your patients and your lives,” noted Dr. Holmes of the Mayo Clinic in Rochester, Minn. He and the Mayo Clinic share a financial interest in the Watchman technology, which has been licensed to Boston Scientific.
The CMS will cover the Watchman only when the catheter procedure is performed by an experienced interventional cardiologist or electrophysiologist in an experienced center as defined by the SCAI/ACC/HRS standards, and only in patients enrolled in the national prospective registry. The registry will monitor operator and device-related complications, stroke and systemic embolism rates, deaths, and major bleeding rates for 5 years post-procedure.
“If you want to be in this field, you will be in that registry because reimbursement will depend on that,” Dr. Holmes explained. “This registry will be incredibly important. It will tell us how we’re doing, what we should be doing, and what we could potentially be doing in the future.”
One hitch is that the preliminary National Coverage Determination states that coverage will be limited to AF patients with high stroke-risk and HAS-BLED scores as well as a contraindication to warfarin, whereas the FDA-approved indication says patients must be deemed by their physician to be suitable for warfarin.
“In this particular case, CMS was not talking with FDA. We don’t know how that will get sorted out,” according to the cardiologist. “But as soon as CMS comes through with their final regulatory coverage determination, I think we will finally be there. We’ll then be able to offer this as a treatment strategy for stroke prevention in selected patients with atrial fibrillation, realizing that with this device there’s a 40% reduction in the composite endpoint of cardiovascular or unexplained death, stroke, and systemic embolism compared to warfarin.”
That figure of a 40% relative risk reduction comes from the 46-month follow-up data in the randomized PROTECT AF trial (JAMA. 2014 Nov 19;312[19]:1988-98).
More recently, Dr. Holmes and his coinvestigators published a patient-level meta-analysis of data from PROTECT AF and PREVAIL, the other randomized trial of the Watchman versus warfarin. They reported that Watchman recipients had a 78% reduction in hemorrhagic strokes, a 52% reduction in cardiovascular or unexplained deaths, and a 49% lower rate of nonprocedural bleeding, compared with patients assigned to warfarin (J Am Coll Cardiol. 2015 Jun 23;65[24]:2614-23).
There have been no randomized trials comparing the Watchman to novel oral anticoagulants.
Dr. Holmes said the worldwide experience to date has been that roughly 95% of AF patients are able to safely go off warfarin or a novel oral anticoagulant 12 months after Watchman placement.
“So instead of taking eight drugs when you’re 75 years old, you can take seven. Most patients think that’s a pretty good deal,” the cardiologist observed.
Session moderator Dr. Samuel J. Asirvatham posed a question: Since recurrence of AF following catheter ablation is common and it’s now thought that up to 20% of AF arises from foci located in the left atrial appendage, what about combining standard catheter ablation of AF via pulmonary vein isolation with placement of the Watchman in a single procedure?
If such a combined procedure can be done efficiently, it should enable recipients of AF catheter ablation to safely go off oral anticoagulation, noted Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic, Rochester, Minn.
Dr. Holmes said several small studies of patients who have received combined AF ablation and Watchman implantation have been published.
“It’s uncertain whether left atrial appendage closure will affect AF recurrence rates post ablation, but it should reduce stroke risk. It’s a terribly important field of exploration that will be pursued in registries both in Europe and the United States,” he said.
SNOWMASS, COLO. – The goal is finally in sight following an odyssey to develop the Watchman left atrial appendage closure device as a safe and effective alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation, Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.
It’s all coming together: The Watchman, a small percutaneously delivered parachute-like device, has received FDA marketing approval as the sole authorized left atrial appendage closure device in this country on the strength of two compellingly positive randomized controlled trials. A recent meta-analysis of those trials showed significantly fewer hemorrhagic strokes, fewer cardiovascular or unexplained deaths, and fewer nonprocedural bleeding events in Watchman recipients than in patients randomized to warfarin. And a cost-effectiveness analysis has concluded that after 8 years, the Watchman becomes “the dominant strategy” – meaning more effective and less costly for stroke prevention in patients with atrial fibrillation (AF) having a contraindication to warfarin – compared with the novel oral anticoagulant apixaban (J Am Coll Cardiol. 2015 Dec 22;66[24]:2728-39).
Moreover, the final pieces required for the Watchman to become a mainstream reimbursable therapy are falling into place. The Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology, and the Heart Rhythm Society (HRS) have jointly issued institutional and operator requirements for left atrial appendage occlusion programs (J Am Coll Cardiol. 2015 Dec 8. pii: S0735-1097[15]07550-6). The ACC’s National Cardiovascular Data Registry has set up a new left atrial occlusion registry. And most important of all from a reimbursement standpoint, the Centers for Medicare and Medicaid Services has released a preliminary National Coverage Determination for left atrial appendage occlusion.
“This will affect your patients and your lives,” noted Dr. Holmes of the Mayo Clinic in Rochester, Minn. He and the Mayo Clinic share a financial interest in the Watchman technology, which has been licensed to Boston Scientific.
The CMS will cover the Watchman only when the catheter procedure is performed by an experienced interventional cardiologist or electrophysiologist in an experienced center as defined by the SCAI/ACC/HRS standards, and only in patients enrolled in the national prospective registry. The registry will monitor operator and device-related complications, stroke and systemic embolism rates, deaths, and major bleeding rates for 5 years post-procedure.
“If you want to be in this field, you will be in that registry because reimbursement will depend on that,” Dr. Holmes explained. “This registry will be incredibly important. It will tell us how we’re doing, what we should be doing, and what we could potentially be doing in the future.”
One hitch is that the preliminary National Coverage Determination states that coverage will be limited to AF patients with high stroke-risk and HAS-BLED scores as well as a contraindication to warfarin, whereas the FDA-approved indication says patients must be deemed by their physician to be suitable for warfarin.
“In this particular case, CMS was not talking with FDA. We don’t know how that will get sorted out,” according to the cardiologist. “But as soon as CMS comes through with their final regulatory coverage determination, I think we will finally be there. We’ll then be able to offer this as a treatment strategy for stroke prevention in selected patients with atrial fibrillation, realizing that with this device there’s a 40% reduction in the composite endpoint of cardiovascular or unexplained death, stroke, and systemic embolism compared to warfarin.”
That figure of a 40% relative risk reduction comes from the 46-month follow-up data in the randomized PROTECT AF trial (JAMA. 2014 Nov 19;312[19]:1988-98).
More recently, Dr. Holmes and his coinvestigators published a patient-level meta-analysis of data from PROTECT AF and PREVAIL, the other randomized trial of the Watchman versus warfarin. They reported that Watchman recipients had a 78% reduction in hemorrhagic strokes, a 52% reduction in cardiovascular or unexplained deaths, and a 49% lower rate of nonprocedural bleeding, compared with patients assigned to warfarin (J Am Coll Cardiol. 2015 Jun 23;65[24]:2614-23).
There have been no randomized trials comparing the Watchman to novel oral anticoagulants.
Dr. Holmes said the worldwide experience to date has been that roughly 95% of AF patients are able to safely go off warfarin or a novel oral anticoagulant 12 months after Watchman placement.
“So instead of taking eight drugs when you’re 75 years old, you can take seven. Most patients think that’s a pretty good deal,” the cardiologist observed.
Session moderator Dr. Samuel J. Asirvatham posed a question: Since recurrence of AF following catheter ablation is common and it’s now thought that up to 20% of AF arises from foci located in the left atrial appendage, what about combining standard catheter ablation of AF via pulmonary vein isolation with placement of the Watchman in a single procedure?
If such a combined procedure can be done efficiently, it should enable recipients of AF catheter ablation to safely go off oral anticoagulation, noted Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic, Rochester, Minn.
Dr. Holmes said several small studies of patients who have received combined AF ablation and Watchman implantation have been published.
“It’s uncertain whether left atrial appendage closure will affect AF recurrence rates post ablation, but it should reduce stroke risk. It’s a terribly important field of exploration that will be pursued in registries both in Europe and the United States,” he said.
SNOWMASS, COLO. – The goal is finally in sight following an odyssey to develop the Watchman left atrial appendage closure device as a safe and effective alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation, Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.
It’s all coming together: The Watchman, a small percutaneously delivered parachute-like device, has received FDA marketing approval as the sole authorized left atrial appendage closure device in this country on the strength of two compellingly positive randomized controlled trials. A recent meta-analysis of those trials showed significantly fewer hemorrhagic strokes, fewer cardiovascular or unexplained deaths, and fewer nonprocedural bleeding events in Watchman recipients than in patients randomized to warfarin. And a cost-effectiveness analysis has concluded that after 8 years, the Watchman becomes “the dominant strategy” – meaning more effective and less costly for stroke prevention in patients with atrial fibrillation (AF) having a contraindication to warfarin – compared with the novel oral anticoagulant apixaban (J Am Coll Cardiol. 2015 Dec 22;66[24]:2728-39).
Moreover, the final pieces required for the Watchman to become a mainstream reimbursable therapy are falling into place. The Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology, and the Heart Rhythm Society (HRS) have jointly issued institutional and operator requirements for left atrial appendage occlusion programs (J Am Coll Cardiol. 2015 Dec 8. pii: S0735-1097[15]07550-6). The ACC’s National Cardiovascular Data Registry has set up a new left atrial occlusion registry. And most important of all from a reimbursement standpoint, the Centers for Medicare and Medicaid Services has released a preliminary National Coverage Determination for left atrial appendage occlusion.
“This will affect your patients and your lives,” noted Dr. Holmes of the Mayo Clinic in Rochester, Minn. He and the Mayo Clinic share a financial interest in the Watchman technology, which has been licensed to Boston Scientific.
The CMS will cover the Watchman only when the catheter procedure is performed by an experienced interventional cardiologist or electrophysiologist in an experienced center as defined by the SCAI/ACC/HRS standards, and only in patients enrolled in the national prospective registry. The registry will monitor operator and device-related complications, stroke and systemic embolism rates, deaths, and major bleeding rates for 5 years post-procedure.
“If you want to be in this field, you will be in that registry because reimbursement will depend on that,” Dr. Holmes explained. “This registry will be incredibly important. It will tell us how we’re doing, what we should be doing, and what we could potentially be doing in the future.”
One hitch is that the preliminary National Coverage Determination states that coverage will be limited to AF patients with high stroke-risk and HAS-BLED scores as well as a contraindication to warfarin, whereas the FDA-approved indication says patients must be deemed by their physician to be suitable for warfarin.
“In this particular case, CMS was not talking with FDA. We don’t know how that will get sorted out,” according to the cardiologist. “But as soon as CMS comes through with their final regulatory coverage determination, I think we will finally be there. We’ll then be able to offer this as a treatment strategy for stroke prevention in selected patients with atrial fibrillation, realizing that with this device there’s a 40% reduction in the composite endpoint of cardiovascular or unexplained death, stroke, and systemic embolism compared to warfarin.”
That figure of a 40% relative risk reduction comes from the 46-month follow-up data in the randomized PROTECT AF trial (JAMA. 2014 Nov 19;312[19]:1988-98).
More recently, Dr. Holmes and his coinvestigators published a patient-level meta-analysis of data from PROTECT AF and PREVAIL, the other randomized trial of the Watchman versus warfarin. They reported that Watchman recipients had a 78% reduction in hemorrhagic strokes, a 52% reduction in cardiovascular or unexplained deaths, and a 49% lower rate of nonprocedural bleeding, compared with patients assigned to warfarin (J Am Coll Cardiol. 2015 Jun 23;65[24]:2614-23).
There have been no randomized trials comparing the Watchman to novel oral anticoagulants.
Dr. Holmes said the worldwide experience to date has been that roughly 95% of AF patients are able to safely go off warfarin or a novel oral anticoagulant 12 months after Watchman placement.
“So instead of taking eight drugs when you’re 75 years old, you can take seven. Most patients think that’s a pretty good deal,” the cardiologist observed.
Session moderator Dr. Samuel J. Asirvatham posed a question: Since recurrence of AF following catheter ablation is common and it’s now thought that up to 20% of AF arises from foci located in the left atrial appendage, what about combining standard catheter ablation of AF via pulmonary vein isolation with placement of the Watchman in a single procedure?
If such a combined procedure can be done efficiently, it should enable recipients of AF catheter ablation to safely go off oral anticoagulation, noted Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic, Rochester, Minn.
Dr. Holmes said several small studies of patients who have received combined AF ablation and Watchman implantation have been published.
“It’s uncertain whether left atrial appendage closure will affect AF recurrence rates post ablation, but it should reduce stroke risk. It’s a terribly important field of exploration that will be pursued in registries both in Europe and the United States,” he said.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
New ACC/AHA Guidelines Will Curb DAPT Duration for Some
SNOWMASS, COLO. – Forthcoming guideline updates addressing the duration of dual-antiplatelet therapy will recommend shorter minimum durations following elective coronary stent placement for patients with stable ischemic heart disease in order to provide physicians with more room to exercise clinical judgment and individualize therapy.
“The American College of Cardiology and the American Heart Association have gone through a several month process of revising all recommendations with respect to antiplatelet therapy across six different guidelines. That should be published in the next few months. I suspect it will be similar to what the Europeans have been espousing,” Dr. Patrick T. O’Gara, ACC immediate past president, said at the Annual Cardiovascular Conference at Snowmass.
“If you look at the European Society of Cardiology guidelines, it’s as little as 30 days of DAPT [dual-antiplatelet therapy] following placement of a bare metal stent in a stable ischemic heart disease patient, 3 months for current generation drug-eluting stents, extending that out a little longer for the bioabsorbable stent platforms,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The impetus for the updated guidelines on DAPT duration, according to the cardiologist, was a growing appreciation of the trade-offs involved in this potent therapy, which reduces the risk of major adverse cardiovascular events at the price of a significant increase in major bleeding.
The new ACC/AHA recommendation calling for as little as 3 months of DAPT following placement of current generation drug-eluting stents in patients with stable ischemic heart disease (IHD) follows from the observation that the risks of late and very late stent thrombosis are extremely low with these devices, whereas the risk of bleeding remains higher, he continued.
The new, shorter recommended minimum DAPT durations are consistent with the underlying histopathology of stable IHD with intermittent claudication. Plaque rupture is unlikely to occur at that stage of atherosclerotic heart disease, in contrast to the inherent instability of the vulnerable plaque with a thin fibrous cap that’s present in an acute coronary syndrome (ACS). Patients with ACS have increased risks of recurrent ischemia or MI, stent thrombosis, bleeding, and death, compared with those with stable IHD.
“It’s just their biology,” Dr. O’Gara explained. “Think of ACS as a prothrombotic state which has a tail of activity over the next 6-12 months.”
That’s why a minimum of 12 months of DAPT featuring aspirin at 81 mg/day following stent placement in patients who present with ACS will continue to be recommended in the update. The same applies to patients who undergo coronary artery bypass grafting after presenting with ACS, although Dr. O’Gara said many surgeons appear to be unaware of this recommendation.
“You’re obligated to complete 12 months of DAPT in that situation. One of the common mistakes made in clinical practice is for surgeons to simply send those patients home on aspirin without a P2Y12 inhibitor,” according to Dr. O’Gara.
The positive outcomes seen with DAPT lasting for longer than 12 months after stent implantation in patients with ACS in the large DAPT trial and the more recent PEGASUS-TIMI 54 trial have put considerable pressure on guideline-writing committees to give a strong endorsement of extended DAPT. But the steep price paid in terms of major bleeding with this prolonged DAPT strategy, he said, gives one pause.
PEGASUS-TIMI 54 randomized more than 21,000 patients with a history of MI nearly 2 years earlier plus one additional high-risk factor such as diabetes to an average of 33 months of double-blind treatment with ticagrelor (Brilinta) at 60 or 90 mg/day or placebo on top of low-dose aspirin (N Engl J Med. 2015 May 7;372[19]:1791-800).
“For every 1,000 patients treated with prolonged DAPT, there were four fewer major ischemic events but three additional major bleeding events per year. Is this a clear winner? For all the enthusiasm there’s been about PEGASUS, those numbers look relatively small. It gets back to the point that individual judgment trumps everything,” Dr. O’Gara said.
He noted that this theme of a close overall risk/benefit balance for prolonged DAPT received further support at last year’s annual meeting of the European Society of Cardiology, where Dr. Jay A. Udell of the University of Toronto presented a meta-analysis of six randomized trials of prolonged DAPT versus aspirin alone in more than 33,000 high-risk patients with a history of MI. The results, which were recently published, showed a 22% reduction in the relative risk of major adverse cardiovascular events with extended DAPT, but a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
The DAPT trial investigators have developed a risk score in an effort to aid clinicians in deciding whether to extend DAPT for more than 12 months after stent placement for ACS in a given individual. The score, which utilizes eight clinical variables, was unveiled at last November’s AHA scientific sessions. For patients with a DAPT score of 2 or more, the number needed to treat for 18 additional months after the initial 12 months of DAPT in order to prevent one major adverse cardiovascular event was 34, with the number needed to harm in the form of major bleeding being 272. For patients with a DAPT score of less than 2, the number needed to treat was 153, and the number needed to harm was 64.
However, Dr. O’Gara said he doesn’t consider the DAPT score ready for use in daily clinical practice for a couple of reasons: It hasn’t yet been validated externally, and it hasn’t yet been published in a peer-reviewed journal.
“I suspect it’s going through a lot of editorial revisions in terms of its statistical underpinnings,” the cardiologist said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – Forthcoming guideline updates addressing the duration of dual-antiplatelet therapy will recommend shorter minimum durations following elective coronary stent placement for patients with stable ischemic heart disease in order to provide physicians with more room to exercise clinical judgment and individualize therapy.
“The American College of Cardiology and the American Heart Association have gone through a several month process of revising all recommendations with respect to antiplatelet therapy across six different guidelines. That should be published in the next few months. I suspect it will be similar to what the Europeans have been espousing,” Dr. Patrick T. O’Gara, ACC immediate past president, said at the Annual Cardiovascular Conference at Snowmass.
“If you look at the European Society of Cardiology guidelines, it’s as little as 30 days of DAPT [dual-antiplatelet therapy] following placement of a bare metal stent in a stable ischemic heart disease patient, 3 months for current generation drug-eluting stents, extending that out a little longer for the bioabsorbable stent platforms,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The impetus for the updated guidelines on DAPT duration, according to the cardiologist, was a growing appreciation of the trade-offs involved in this potent therapy, which reduces the risk of major adverse cardiovascular events at the price of a significant increase in major bleeding.
The new ACC/AHA recommendation calling for as little as 3 months of DAPT following placement of current generation drug-eluting stents in patients with stable ischemic heart disease (IHD) follows from the observation that the risks of late and very late stent thrombosis are extremely low with these devices, whereas the risk of bleeding remains higher, he continued.
The new, shorter recommended minimum DAPT durations are consistent with the underlying histopathology of stable IHD with intermittent claudication. Plaque rupture is unlikely to occur at that stage of atherosclerotic heart disease, in contrast to the inherent instability of the vulnerable plaque with a thin fibrous cap that’s present in an acute coronary syndrome (ACS). Patients with ACS have increased risks of recurrent ischemia or MI, stent thrombosis, bleeding, and death, compared with those with stable IHD.
“It’s just their biology,” Dr. O’Gara explained. “Think of ACS as a prothrombotic state which has a tail of activity over the next 6-12 months.”
That’s why a minimum of 12 months of DAPT featuring aspirin at 81 mg/day following stent placement in patients who present with ACS will continue to be recommended in the update. The same applies to patients who undergo coronary artery bypass grafting after presenting with ACS, although Dr. O’Gara said many surgeons appear to be unaware of this recommendation.
“You’re obligated to complete 12 months of DAPT in that situation. One of the common mistakes made in clinical practice is for surgeons to simply send those patients home on aspirin without a P2Y12 inhibitor,” according to Dr. O’Gara.
The positive outcomes seen with DAPT lasting for longer than 12 months after stent implantation in patients with ACS in the large DAPT trial and the more recent PEGASUS-TIMI 54 trial have put considerable pressure on guideline-writing committees to give a strong endorsement of extended DAPT. But the steep price paid in terms of major bleeding with this prolonged DAPT strategy, he said, gives one pause.
PEGASUS-TIMI 54 randomized more than 21,000 patients with a history of MI nearly 2 years earlier plus one additional high-risk factor such as diabetes to an average of 33 months of double-blind treatment with ticagrelor (Brilinta) at 60 or 90 mg/day or placebo on top of low-dose aspirin (N Engl J Med. 2015 May 7;372[19]:1791-800).
“For every 1,000 patients treated with prolonged DAPT, there were four fewer major ischemic events but three additional major bleeding events per year. Is this a clear winner? For all the enthusiasm there’s been about PEGASUS, those numbers look relatively small. It gets back to the point that individual judgment trumps everything,” Dr. O’Gara said.
He noted that this theme of a close overall risk/benefit balance for prolonged DAPT received further support at last year’s annual meeting of the European Society of Cardiology, where Dr. Jay A. Udell of the University of Toronto presented a meta-analysis of six randomized trials of prolonged DAPT versus aspirin alone in more than 33,000 high-risk patients with a history of MI. The results, which were recently published, showed a 22% reduction in the relative risk of major adverse cardiovascular events with extended DAPT, but a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
The DAPT trial investigators have developed a risk score in an effort to aid clinicians in deciding whether to extend DAPT for more than 12 months after stent placement for ACS in a given individual. The score, which utilizes eight clinical variables, was unveiled at last November’s AHA scientific sessions. For patients with a DAPT score of 2 or more, the number needed to treat for 18 additional months after the initial 12 months of DAPT in order to prevent one major adverse cardiovascular event was 34, with the number needed to harm in the form of major bleeding being 272. For patients with a DAPT score of less than 2, the number needed to treat was 153, and the number needed to harm was 64.
However, Dr. O’Gara said he doesn’t consider the DAPT score ready for use in daily clinical practice for a couple of reasons: It hasn’t yet been validated externally, and it hasn’t yet been published in a peer-reviewed journal.
“I suspect it’s going through a lot of editorial revisions in terms of its statistical underpinnings,” the cardiologist said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – Forthcoming guideline updates addressing the duration of dual-antiplatelet therapy will recommend shorter minimum durations following elective coronary stent placement for patients with stable ischemic heart disease in order to provide physicians with more room to exercise clinical judgment and individualize therapy.
“The American College of Cardiology and the American Heart Association have gone through a several month process of revising all recommendations with respect to antiplatelet therapy across six different guidelines. That should be published in the next few months. I suspect it will be similar to what the Europeans have been espousing,” Dr. Patrick T. O’Gara, ACC immediate past president, said at the Annual Cardiovascular Conference at Snowmass.
“If you look at the European Society of Cardiology guidelines, it’s as little as 30 days of DAPT [dual-antiplatelet therapy] following placement of a bare metal stent in a stable ischemic heart disease patient, 3 months for current generation drug-eluting stents, extending that out a little longer for the bioabsorbable stent platforms,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The impetus for the updated guidelines on DAPT duration, according to the cardiologist, was a growing appreciation of the trade-offs involved in this potent therapy, which reduces the risk of major adverse cardiovascular events at the price of a significant increase in major bleeding.
The new ACC/AHA recommendation calling for as little as 3 months of DAPT following placement of current generation drug-eluting stents in patients with stable ischemic heart disease (IHD) follows from the observation that the risks of late and very late stent thrombosis are extremely low with these devices, whereas the risk of bleeding remains higher, he continued.
The new, shorter recommended minimum DAPT durations are consistent with the underlying histopathology of stable IHD with intermittent claudication. Plaque rupture is unlikely to occur at that stage of atherosclerotic heart disease, in contrast to the inherent instability of the vulnerable plaque with a thin fibrous cap that’s present in an acute coronary syndrome (ACS). Patients with ACS have increased risks of recurrent ischemia or MI, stent thrombosis, bleeding, and death, compared with those with stable IHD.
“It’s just their biology,” Dr. O’Gara explained. “Think of ACS as a prothrombotic state which has a tail of activity over the next 6-12 months.”
That’s why a minimum of 12 months of DAPT featuring aspirin at 81 mg/day following stent placement in patients who present with ACS will continue to be recommended in the update. The same applies to patients who undergo coronary artery bypass grafting after presenting with ACS, although Dr. O’Gara said many surgeons appear to be unaware of this recommendation.
“You’re obligated to complete 12 months of DAPT in that situation. One of the common mistakes made in clinical practice is for surgeons to simply send those patients home on aspirin without a P2Y12 inhibitor,” according to Dr. O’Gara.
The positive outcomes seen with DAPT lasting for longer than 12 months after stent implantation in patients with ACS in the large DAPT trial and the more recent PEGASUS-TIMI 54 trial have put considerable pressure on guideline-writing committees to give a strong endorsement of extended DAPT. But the steep price paid in terms of major bleeding with this prolonged DAPT strategy, he said, gives one pause.
PEGASUS-TIMI 54 randomized more than 21,000 patients with a history of MI nearly 2 years earlier plus one additional high-risk factor such as diabetes to an average of 33 months of double-blind treatment with ticagrelor (Brilinta) at 60 or 90 mg/day or placebo on top of low-dose aspirin (N Engl J Med. 2015 May 7;372[19]:1791-800).
“For every 1,000 patients treated with prolonged DAPT, there were four fewer major ischemic events but three additional major bleeding events per year. Is this a clear winner? For all the enthusiasm there’s been about PEGASUS, those numbers look relatively small. It gets back to the point that individual judgment trumps everything,” Dr. O’Gara said.
He noted that this theme of a close overall risk/benefit balance for prolonged DAPT received further support at last year’s annual meeting of the European Society of Cardiology, where Dr. Jay A. Udell of the University of Toronto presented a meta-analysis of six randomized trials of prolonged DAPT versus aspirin alone in more than 33,000 high-risk patients with a history of MI. The results, which were recently published, showed a 22% reduction in the relative risk of major adverse cardiovascular events with extended DAPT, but a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
The DAPT trial investigators have developed a risk score in an effort to aid clinicians in deciding whether to extend DAPT for more than 12 months after stent placement for ACS in a given individual. The score, which utilizes eight clinical variables, was unveiled at last November’s AHA scientific sessions. For patients with a DAPT score of 2 or more, the number needed to treat for 18 additional months after the initial 12 months of DAPT in order to prevent one major adverse cardiovascular event was 34, with the number needed to harm in the form of major bleeding being 272. For patients with a DAPT score of less than 2, the number needed to treat was 153, and the number needed to harm was 64.
However, Dr. O’Gara said he doesn’t consider the DAPT score ready for use in daily clinical practice for a couple of reasons: It hasn’t yet been validated externally, and it hasn’t yet been published in a peer-reviewed journal.
“I suspect it’s going through a lot of editorial revisions in terms of its statistical underpinnings,” the cardiologist said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
New ACC/AHA guidelines will curb DAPT duration for some
SNOWMASS, COLO. – Forthcoming guideline updates addressing the duration of dual-antiplatelet therapy will recommend shorter minimum durations following elective coronary stent placement for patients with stable ischemic heart disease in order to provide physicians with more room to exercise clinical judgment and individualize therapy.
“The American College of Cardiology and the American Heart Association have gone through a several month process of revising all recommendations with respect to antiplatelet therapy across six different guidelines. That should be published in the next few months. I suspect it will be similar to what the Europeans have been espousing,” Dr. Patrick T. O’Gara, ACC immediate past president, said at the Annual Cardiovascular Conference at Snowmass.
“If you look at the European Society of Cardiology guidelines, it’s as little as 30 days of DAPT [dual-antiplatelet therapy] following placement of a bare metal stent in a stable ischemic heart disease patient, 3 months for current generation drug-eluting stents, extending that out a little longer for the bioabsorbable stent platforms,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The impetus for the updated guidelines on DAPT duration, according to the cardiologist, was a growing appreciation of the trade-offs involved in this potent therapy, which reduces the risk of major adverse cardiovascular events at the price of a significant increase in major bleeding.
The new ACC/AHA recommendation calling for as little as 3 months of DAPT following placement of current generation drug-eluting stents in patients with stable ischemic heart disease (IHD) follows from the observation that the risks of late and very late stent thrombosis are extremely low with these devices, whereas the risk of bleeding remains higher, he continued.
The new, shorter recommended minimum DAPT durations are consistent with the underlying histopathology of stable IHD with intermittent claudication. Plaque rupture is unlikely to occur at that stage of atherosclerotic heart disease, in contrast to the inherent instability of the vulnerable plaque with a thin fibrous cap that’s present in an acute coronary syndrome (ACS). Patients with ACS have increased risks of recurrent ischemia or MI, stent thrombosis, bleeding, and death, compared with those with stable IHD.
“It’s just their biology,” Dr. O’Gara explained. “Think of ACS as a prothrombotic state which has a tail of activity over the next 6-12 months.”
That’s why a minimum of 12 months of DAPT featuring aspirin at 81 mg/day following stent placement in patients who present with ACS will continue to be recommended in the update. The same applies to patients who undergo coronary artery bypass grafting after presenting with ACS, although Dr. O’Gara said many surgeons appear to be unaware of this recommendation.
“You’re obligated to complete 12 months of DAPT in that situation. One of the common mistakes made in clinical practice is for surgeons to simply send those patients home on aspirin without a P2Y12 inhibitor,” according to Dr. O’Gara.
The positive outcomes seen with DAPT lasting for longer than 12 months after stent implantation in patients with ACS in the large DAPT trial and the more recent PEGASUS-TIMI 54 trial have put considerable pressure on guideline-writing committees to give a strong endorsement of extended DAPT. But the steep price paid in terms of major bleeding with this prolonged DAPT strategy, he said, gives one pause.
PEGASUS-TIMI 54 randomized more than 21,000 patients with a history of MI nearly 2 years earlier plus one additional high-risk factor such as diabetes to an average of 33 months of double-blind treatment with ticagrelor (Brilinta) at 60 or 90 mg/day or placebo on top of low-dose aspirin (N Engl J Med. 2015 May 7;372[19]:1791-800).
“For every 1,000 patients treated with prolonged DAPT, there were four fewer major ischemic events but three additional major bleeding events per year. Is this a clear winner? For all the enthusiasm there’s been about PEGASUS, those numbers look relatively small. It gets back to the point that individual judgment trumps everything,” Dr. O’Gara said.
He noted that this theme of a close overall risk/benefit balance for prolonged DAPT received further support at last year’s annual meeting of the European Society of Cardiology, where Dr. Jay A. Udell of the University of Toronto presented a meta-analysis of six randomized trials of prolonged DAPT versus aspirin alone in more than 33,000 high-risk patients with a history of MI. The results, which were recently published, showed a 22% reduction in the relative risk of major adverse cardiovascular events with extended DAPT, but a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
The DAPT trial investigators have developed a risk score in an effort to aid clinicians in deciding whether to extend DAPT for more than 12 months after stent placement for ACS in a given individual. The score, which utilizes eight clinical variables, was unveiled at last November’s AHA scientific sessions. For patients with a DAPT score of 2 or more, the number needed to treat for 18 additional months after the initial 12 months of DAPT in order to prevent one major adverse cardiovascular event was 34, with the number needed to harm in the form of major bleeding being 272. For patients with a DAPT score of less than 2, the number needed to treat was 153, and the number needed to harm was 64.
However, Dr. O’Gara said he doesn’t consider the DAPT score ready for use in daily clinical practice for a couple of reasons: It hasn’t yet been validated externally, and it hasn’t yet been published in a peer-reviewed journal.
“I suspect it’s going through a lot of editorial revisions in terms of its statistical underpinnings,” the cardiologist said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – Forthcoming guideline updates addressing the duration of dual-antiplatelet therapy will recommend shorter minimum durations following elective coronary stent placement for patients with stable ischemic heart disease in order to provide physicians with more room to exercise clinical judgment and individualize therapy.
“The American College of Cardiology and the American Heart Association have gone through a several month process of revising all recommendations with respect to antiplatelet therapy across six different guidelines. That should be published in the next few months. I suspect it will be similar to what the Europeans have been espousing,” Dr. Patrick T. O’Gara, ACC immediate past president, said at the Annual Cardiovascular Conference at Snowmass.
“If you look at the European Society of Cardiology guidelines, it’s as little as 30 days of DAPT [dual-antiplatelet therapy] following placement of a bare metal stent in a stable ischemic heart disease patient, 3 months for current generation drug-eluting stents, extending that out a little longer for the bioabsorbable stent platforms,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The impetus for the updated guidelines on DAPT duration, according to the cardiologist, was a growing appreciation of the trade-offs involved in this potent therapy, which reduces the risk of major adverse cardiovascular events at the price of a significant increase in major bleeding.
The new ACC/AHA recommendation calling for as little as 3 months of DAPT following placement of current generation drug-eluting stents in patients with stable ischemic heart disease (IHD) follows from the observation that the risks of late and very late stent thrombosis are extremely low with these devices, whereas the risk of bleeding remains higher, he continued.
The new, shorter recommended minimum DAPT durations are consistent with the underlying histopathology of stable IHD with intermittent claudication. Plaque rupture is unlikely to occur at that stage of atherosclerotic heart disease, in contrast to the inherent instability of the vulnerable plaque with a thin fibrous cap that’s present in an acute coronary syndrome (ACS). Patients with ACS have increased risks of recurrent ischemia or MI, stent thrombosis, bleeding, and death, compared with those with stable IHD.
“It’s just their biology,” Dr. O’Gara explained. “Think of ACS as a prothrombotic state which has a tail of activity over the next 6-12 months.”
That’s why a minimum of 12 months of DAPT featuring aspirin at 81 mg/day following stent placement in patients who present with ACS will continue to be recommended in the update. The same applies to patients who undergo coronary artery bypass grafting after presenting with ACS, although Dr. O’Gara said many surgeons appear to be unaware of this recommendation.
“You’re obligated to complete 12 months of DAPT in that situation. One of the common mistakes made in clinical practice is for surgeons to simply send those patients home on aspirin without a P2Y12 inhibitor,” according to Dr. O’Gara.
The positive outcomes seen with DAPT lasting for longer than 12 months after stent implantation in patients with ACS in the large DAPT trial and the more recent PEGASUS-TIMI 54 trial have put considerable pressure on guideline-writing committees to give a strong endorsement of extended DAPT. But the steep price paid in terms of major bleeding with this prolonged DAPT strategy, he said, gives one pause.
PEGASUS-TIMI 54 randomized more than 21,000 patients with a history of MI nearly 2 years earlier plus one additional high-risk factor such as diabetes to an average of 33 months of double-blind treatment with ticagrelor (Brilinta) at 60 or 90 mg/day or placebo on top of low-dose aspirin (N Engl J Med. 2015 May 7;372[19]:1791-800).
“For every 1,000 patients treated with prolonged DAPT, there were four fewer major ischemic events but three additional major bleeding events per year. Is this a clear winner? For all the enthusiasm there’s been about PEGASUS, those numbers look relatively small. It gets back to the point that individual judgment trumps everything,” Dr. O’Gara said.
He noted that this theme of a close overall risk/benefit balance for prolonged DAPT received further support at last year’s annual meeting of the European Society of Cardiology, where Dr. Jay A. Udell of the University of Toronto presented a meta-analysis of six randomized trials of prolonged DAPT versus aspirin alone in more than 33,000 high-risk patients with a history of MI. The results, which were recently published, showed a 22% reduction in the relative risk of major adverse cardiovascular events with extended DAPT, but a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
The DAPT trial investigators have developed a risk score in an effort to aid clinicians in deciding whether to extend DAPT for more than 12 months after stent placement for ACS in a given individual. The score, which utilizes eight clinical variables, was unveiled at last November’s AHA scientific sessions. For patients with a DAPT score of 2 or more, the number needed to treat for 18 additional months after the initial 12 months of DAPT in order to prevent one major adverse cardiovascular event was 34, with the number needed to harm in the form of major bleeding being 272. For patients with a DAPT score of less than 2, the number needed to treat was 153, and the number needed to harm was 64.
However, Dr. O’Gara said he doesn’t consider the DAPT score ready for use in daily clinical practice for a couple of reasons: It hasn’t yet been validated externally, and it hasn’t yet been published in a peer-reviewed journal.
“I suspect it’s going through a lot of editorial revisions in terms of its statistical underpinnings,” the cardiologist said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – Forthcoming guideline updates addressing the duration of dual-antiplatelet therapy will recommend shorter minimum durations following elective coronary stent placement for patients with stable ischemic heart disease in order to provide physicians with more room to exercise clinical judgment and individualize therapy.
“The American College of Cardiology and the American Heart Association have gone through a several month process of revising all recommendations with respect to antiplatelet therapy across six different guidelines. That should be published in the next few months. I suspect it will be similar to what the Europeans have been espousing,” Dr. Patrick T. O’Gara, ACC immediate past president, said at the Annual Cardiovascular Conference at Snowmass.
“If you look at the European Society of Cardiology guidelines, it’s as little as 30 days of DAPT [dual-antiplatelet therapy] following placement of a bare metal stent in a stable ischemic heart disease patient, 3 months for current generation drug-eluting stents, extending that out a little longer for the bioabsorbable stent platforms,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The impetus for the updated guidelines on DAPT duration, according to the cardiologist, was a growing appreciation of the trade-offs involved in this potent therapy, which reduces the risk of major adverse cardiovascular events at the price of a significant increase in major bleeding.
The new ACC/AHA recommendation calling for as little as 3 months of DAPT following placement of current generation drug-eluting stents in patients with stable ischemic heart disease (IHD) follows from the observation that the risks of late and very late stent thrombosis are extremely low with these devices, whereas the risk of bleeding remains higher, he continued.
The new, shorter recommended minimum DAPT durations are consistent with the underlying histopathology of stable IHD with intermittent claudication. Plaque rupture is unlikely to occur at that stage of atherosclerotic heart disease, in contrast to the inherent instability of the vulnerable plaque with a thin fibrous cap that’s present in an acute coronary syndrome (ACS). Patients with ACS have increased risks of recurrent ischemia or MI, stent thrombosis, bleeding, and death, compared with those with stable IHD.
“It’s just their biology,” Dr. O’Gara explained. “Think of ACS as a prothrombotic state which has a tail of activity over the next 6-12 months.”
That’s why a minimum of 12 months of DAPT featuring aspirin at 81 mg/day following stent placement in patients who present with ACS will continue to be recommended in the update. The same applies to patients who undergo coronary artery bypass grafting after presenting with ACS, although Dr. O’Gara said many surgeons appear to be unaware of this recommendation.
“You’re obligated to complete 12 months of DAPT in that situation. One of the common mistakes made in clinical practice is for surgeons to simply send those patients home on aspirin without a P2Y12 inhibitor,” according to Dr. O’Gara.
The positive outcomes seen with DAPT lasting for longer than 12 months after stent implantation in patients with ACS in the large DAPT trial and the more recent PEGASUS-TIMI 54 trial have put considerable pressure on guideline-writing committees to give a strong endorsement of extended DAPT. But the steep price paid in terms of major bleeding with this prolonged DAPT strategy, he said, gives one pause.
PEGASUS-TIMI 54 randomized more than 21,000 patients with a history of MI nearly 2 years earlier plus one additional high-risk factor such as diabetes to an average of 33 months of double-blind treatment with ticagrelor (Brilinta) at 60 or 90 mg/day or placebo on top of low-dose aspirin (N Engl J Med. 2015 May 7;372[19]:1791-800).
“For every 1,000 patients treated with prolonged DAPT, there were four fewer major ischemic events but three additional major bleeding events per year. Is this a clear winner? For all the enthusiasm there’s been about PEGASUS, those numbers look relatively small. It gets back to the point that individual judgment trumps everything,” Dr. O’Gara said.
He noted that this theme of a close overall risk/benefit balance for prolonged DAPT received further support at last year’s annual meeting of the European Society of Cardiology, where Dr. Jay A. Udell of the University of Toronto presented a meta-analysis of six randomized trials of prolonged DAPT versus aspirin alone in more than 33,000 high-risk patients with a history of MI. The results, which were recently published, showed a 22% reduction in the relative risk of major adverse cardiovascular events with extended DAPT, but a 73% increase in the risk of major bleeding (Eur Heart J. 2016 Jan 21;37[4]:390-9).
The DAPT trial investigators have developed a risk score in an effort to aid clinicians in deciding whether to extend DAPT for more than 12 months after stent placement for ACS in a given individual. The score, which utilizes eight clinical variables, was unveiled at last November’s AHA scientific sessions. For patients with a DAPT score of 2 or more, the number needed to treat for 18 additional months after the initial 12 months of DAPT in order to prevent one major adverse cardiovascular event was 34, with the number needed to harm in the form of major bleeding being 272. For patients with a DAPT score of less than 2, the number needed to treat was 153, and the number needed to harm was 64.
However, Dr. O’Gara said he doesn’t consider the DAPT score ready for use in daily clinical practice for a couple of reasons: It hasn’t yet been validated externally, and it hasn’t yet been published in a peer-reviewed journal.
“I suspect it’s going through a lot of editorial revisions in terms of its statistical underpinnings,” the cardiologist said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Compelling case for NOACs in VTE
SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.
He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.
In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).
“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.
Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.
It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.
In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.
“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.
In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.
Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.
He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.
In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).
“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.
Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.
It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.
In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.
“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.
In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.
Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.
He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.
In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).
“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.
Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.
It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.
In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.
“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.
In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.
Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
In refractory AF, think weight loss before ablation
SNOWMASS, COLO. – Don’t be in a rush to refer a patient with drug-refractory, symptomatic atrial fibrillation (AF) for catheter ablation of the arrhythmia, a prominent electrophysiologist advised at the Annual Cardiovascular Conference at Snowmass.
“AF ablation is not salvation – and that’s coming from somebody who does these procedures. One really needs to be very selective in referring patients for this,” said Dr. N.A. Mark Estes III, professor of medicine and director of cardiac arrhythmia services at Tufts University, Boston.
Misconceptions about AF catheter ablation outcomes abound among nonelectrophysiologists. Results have often been overstated, Dr. Estes continued. And there’s a far more attractive alternative treatment option for those AF patients who are overweight or obese: weight loss.
In the Australian LEGACY study, which he considers practice changing, patients with AF who had a body mass index of at least 27 kg/m2 who participated in a simple structured weight management program and achieved a sustained loss of at least 10% of their body weight had a 65% reduction in their AF burden as objectively documented by repeated 7-day ambulatory monitoring over 5 years of follow-up. Moreover, 46% of patients who maintained that degree of weight reduction were totally free of AF without use of drugs or ablation procedures (J Am Coll Cardiol. 2015 May 26;65[20]:2159-69).
In a related study, the Australian investigators, led by Dr. Rajeev K. Pathak of the University of Adelaide, showed in the same study population that participation in a tailored exercise program paid added dividends on top of the weight loss. Patients who achieved at least a 2-MET increase in cardiorespiratory fitness had a significantly greater rate of freedom from AF than those who didn’t reach that fitness threshold (J Am Coll Cardiol. Sep 1;66[9]:985-96).
“The data are compelling for improved outcomes, including reduced AF burden, with lifestyle modification in obese patients with AF. This is first-line therapy. You can bet it will be in the guidelines soon. It should be in your practice now,” Dr. Estes declared.
“The starting point is weight reduction, even before sending patients to an electrophysiologist for ablation,” he continued. “And if you’ve got patients on drugs who’ve had ablation in whom there continues to be AF, weight reduction – particularly reaching that 10% threshold – results in a dramatic decline in the burden of AF,” he said.
One of the common misconceptions about catheter ablation for AF is that if the pulmonary vein isolation procedure is successful in eliminating the arrhythmia, then the patient can discontinue oral anticoagulant therapy.
“That rationale, while logical, doesn’t really hold up. In many of the ablation trials, including the AFFIRM trial, if you discontinue anticoagulation in patients in sinus rhythm the stroke rate goes back to the same as in patients with AF,” according to the cardiologist.
In a meta-analysis of prospective studies published through 2007, the single-procedure success rate for radiofrequency ablation in achieving sinus rhythm without the use of antiarrhythmic drugs was 57%, climbing to 71% with multiple ablation procedures. In contrast, antiarrhythmic drugs were substantially less successful, with about a 50% success rate as compared with a 25% placebo response (Circ Arrhythm Electrophysiol. 2009 Aug;2[4]:349-61).
“It’s notable that antiarrhythmic drug development has almost been stopped because the drugs don’t work, with the possible exception of amiodarone, which requires an individualized risk/benefit assessment,” according to Dr. Estes.
There is a major caveat regarding the ablation studies: They’ve mainly enrolled patients who are in their 50s, when AF is far less common than in later decades.
“Whether these results are going to hold up long-term in elderly patients who are hypertensive, diabetic, and may have sleep apnea really remains an unanswered question,” Dr. Estes observed.
Also, significant periprocedural complications occur in roughly 1 in 20 patients undergoing radiofrequency catheter ablation, although the safety data for cryoablation look somewhat better, he continued.
Dr. Estes predicted that the future of catheter ablation of AF hangs on three major ongoing rigorous randomized clinical trials comparing it to drug therapy with hard endpoints including all-cause mortality and cardiovascular hospitalizations. These are CASTLE-AF, with 420 patients; CABANA, with 2,200; and the German EAST study, with roughly 3,000 patients. Results are expected in 2018-2019.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
SNOWMASS, COLO. – Don’t be in a rush to refer a patient with drug-refractory, symptomatic atrial fibrillation (AF) for catheter ablation of the arrhythmia, a prominent electrophysiologist advised at the Annual Cardiovascular Conference at Snowmass.
“AF ablation is not salvation – and that’s coming from somebody who does these procedures. One really needs to be very selective in referring patients for this,” said Dr. N.A. Mark Estes III, professor of medicine and director of cardiac arrhythmia services at Tufts University, Boston.
Misconceptions about AF catheter ablation outcomes abound among nonelectrophysiologists. Results have often been overstated, Dr. Estes continued. And there’s a far more attractive alternative treatment option for those AF patients who are overweight or obese: weight loss.
In the Australian LEGACY study, which he considers practice changing, patients with AF who had a body mass index of at least 27 kg/m2 who participated in a simple structured weight management program and achieved a sustained loss of at least 10% of their body weight had a 65% reduction in their AF burden as objectively documented by repeated 7-day ambulatory monitoring over 5 years of follow-up. Moreover, 46% of patients who maintained that degree of weight reduction were totally free of AF without use of drugs or ablation procedures (J Am Coll Cardiol. 2015 May 26;65[20]:2159-69).
In a related study, the Australian investigators, led by Dr. Rajeev K. Pathak of the University of Adelaide, showed in the same study population that participation in a tailored exercise program paid added dividends on top of the weight loss. Patients who achieved at least a 2-MET increase in cardiorespiratory fitness had a significantly greater rate of freedom from AF than those who didn’t reach that fitness threshold (J Am Coll Cardiol. Sep 1;66[9]:985-96).
“The data are compelling for improved outcomes, including reduced AF burden, with lifestyle modification in obese patients with AF. This is first-line therapy. You can bet it will be in the guidelines soon. It should be in your practice now,” Dr. Estes declared.
“The starting point is weight reduction, even before sending patients to an electrophysiologist for ablation,” he continued. “And if you’ve got patients on drugs who’ve had ablation in whom there continues to be AF, weight reduction – particularly reaching that 10% threshold – results in a dramatic decline in the burden of AF,” he said.
One of the common misconceptions about catheter ablation for AF is that if the pulmonary vein isolation procedure is successful in eliminating the arrhythmia, then the patient can discontinue oral anticoagulant therapy.
“That rationale, while logical, doesn’t really hold up. In many of the ablation trials, including the AFFIRM trial, if you discontinue anticoagulation in patients in sinus rhythm the stroke rate goes back to the same as in patients with AF,” according to the cardiologist.
In a meta-analysis of prospective studies published through 2007, the single-procedure success rate for radiofrequency ablation in achieving sinus rhythm without the use of antiarrhythmic drugs was 57%, climbing to 71% with multiple ablation procedures. In contrast, antiarrhythmic drugs were substantially less successful, with about a 50% success rate as compared with a 25% placebo response (Circ Arrhythm Electrophysiol. 2009 Aug;2[4]:349-61).
“It’s notable that antiarrhythmic drug development has almost been stopped because the drugs don’t work, with the possible exception of amiodarone, which requires an individualized risk/benefit assessment,” according to Dr. Estes.
There is a major caveat regarding the ablation studies: They’ve mainly enrolled patients who are in their 50s, when AF is far less common than in later decades.
“Whether these results are going to hold up long-term in elderly patients who are hypertensive, diabetic, and may have sleep apnea really remains an unanswered question,” Dr. Estes observed.
Also, significant periprocedural complications occur in roughly 1 in 20 patients undergoing radiofrequency catheter ablation, although the safety data for cryoablation look somewhat better, he continued.
Dr. Estes predicted that the future of catheter ablation of AF hangs on three major ongoing rigorous randomized clinical trials comparing it to drug therapy with hard endpoints including all-cause mortality and cardiovascular hospitalizations. These are CASTLE-AF, with 420 patients; CABANA, with 2,200; and the German EAST study, with roughly 3,000 patients. Results are expected in 2018-2019.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
SNOWMASS, COLO. – Don’t be in a rush to refer a patient with drug-refractory, symptomatic atrial fibrillation (AF) for catheter ablation of the arrhythmia, a prominent electrophysiologist advised at the Annual Cardiovascular Conference at Snowmass.
“AF ablation is not salvation – and that’s coming from somebody who does these procedures. One really needs to be very selective in referring patients for this,” said Dr. N.A. Mark Estes III, professor of medicine and director of cardiac arrhythmia services at Tufts University, Boston.
Misconceptions about AF catheter ablation outcomes abound among nonelectrophysiologists. Results have often been overstated, Dr. Estes continued. And there’s a far more attractive alternative treatment option for those AF patients who are overweight or obese: weight loss.
In the Australian LEGACY study, which he considers practice changing, patients with AF who had a body mass index of at least 27 kg/m2 who participated in a simple structured weight management program and achieved a sustained loss of at least 10% of their body weight had a 65% reduction in their AF burden as objectively documented by repeated 7-day ambulatory monitoring over 5 years of follow-up. Moreover, 46% of patients who maintained that degree of weight reduction were totally free of AF without use of drugs or ablation procedures (J Am Coll Cardiol. 2015 May 26;65[20]:2159-69).
In a related study, the Australian investigators, led by Dr. Rajeev K. Pathak of the University of Adelaide, showed in the same study population that participation in a tailored exercise program paid added dividends on top of the weight loss. Patients who achieved at least a 2-MET increase in cardiorespiratory fitness had a significantly greater rate of freedom from AF than those who didn’t reach that fitness threshold (J Am Coll Cardiol. Sep 1;66[9]:985-96).
“The data are compelling for improved outcomes, including reduced AF burden, with lifestyle modification in obese patients with AF. This is first-line therapy. You can bet it will be in the guidelines soon. It should be in your practice now,” Dr. Estes declared.
“The starting point is weight reduction, even before sending patients to an electrophysiologist for ablation,” he continued. “And if you’ve got patients on drugs who’ve had ablation in whom there continues to be AF, weight reduction – particularly reaching that 10% threshold – results in a dramatic decline in the burden of AF,” he said.
One of the common misconceptions about catheter ablation for AF is that if the pulmonary vein isolation procedure is successful in eliminating the arrhythmia, then the patient can discontinue oral anticoagulant therapy.
“That rationale, while logical, doesn’t really hold up. In many of the ablation trials, including the AFFIRM trial, if you discontinue anticoagulation in patients in sinus rhythm the stroke rate goes back to the same as in patients with AF,” according to the cardiologist.
In a meta-analysis of prospective studies published through 2007, the single-procedure success rate for radiofrequency ablation in achieving sinus rhythm without the use of antiarrhythmic drugs was 57%, climbing to 71% with multiple ablation procedures. In contrast, antiarrhythmic drugs were substantially less successful, with about a 50% success rate as compared with a 25% placebo response (Circ Arrhythm Electrophysiol. 2009 Aug;2[4]:349-61).
“It’s notable that antiarrhythmic drug development has almost been stopped because the drugs don’t work, with the possible exception of amiodarone, which requires an individualized risk/benefit assessment,” according to Dr. Estes.
There is a major caveat regarding the ablation studies: They’ve mainly enrolled patients who are in their 50s, when AF is far less common than in later decades.
“Whether these results are going to hold up long-term in elderly patients who are hypertensive, diabetic, and may have sleep apnea really remains an unanswered question,” Dr. Estes observed.
Also, significant periprocedural complications occur in roughly 1 in 20 patients undergoing radiofrequency catheter ablation, although the safety data for cryoablation look somewhat better, he continued.
Dr. Estes predicted that the future of catheter ablation of AF hangs on three major ongoing rigorous randomized clinical trials comparing it to drug therapy with hard endpoints including all-cause mortality and cardiovascular hospitalizations. These are CASTLE-AF, with 420 patients; CABANA, with 2,200; and the German EAST study, with roughly 3,000 patients. Results are expected in 2018-2019.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Therapeutic hypothermia called biggest recent advance in cardiac arrest
SNOWMASS, COLO. – By far the most-important contributor to improved outcomes following out-of-hospital cardiac arrest during the past decade has been therapeutic hypothermia, Dr. N.A. Mark Estes III said at the Annual Cardiovascular Conference at Snowmass.
The No. 1 cause of in-hospital death in patients who arrive at the hospital with a perfusable rhythm following resuscitation from out-of-hospital cardiac arrest isn’t sepsis, hepatic or renal failure, or cardiogenic shock. It’s neurologic death caused by anoxic brain injury, which begins several hours after cardiac arrest and continues for about 48 hours. This is where therapeutic hypothermia has made a huge difference, said Dr. Estes, professor of medicine and director of cardiac arrhythmia services at Tufts University, Boston.
“One-half of out-of-hospital cardiac arrest survivors experience secondary anoxic brain damage of varying degrees. Until recently, there was no treatment with documented efficacy in preventing this damage. Despite multiple agents being looked at for neuroprevention, none really has worked. But therapeutic hypothermia has drastically improved outcomes. More than half of patients who arrive at the hospital with a perfusable rhythm and receive therapeutic hypothermia are discharged relatively neurologically intact. That’s a huge difference from what we used to see,” the electrophysiologist observed.
Indeed, the proportion of U.S. patients who experience out-of-hospital cardiac arrest and survive to hospital discharge neurologically intact is “dismal” at about 10%, he noted.
Virtually all specialized cardiac arrest centers now provide therapeutic hypothermia using various protocols. The demonstrated effectiveness of this postresuscitation therapy was an impetus for the American Heart Association policy statement calling for creation of regional cardiac resuscitation systems of care (Circulation. 2010 Feb 9;121[5]:709-29). To date, however, such organized systems exist in only a handful of states or portions of states.
Nonetheless, when an out-of-hospital cardiac arrest patient arrives at a community hospital that can’t provide emergency coronary angiography and therapeutic hypothermia, it’s appropriate to stabilize that patient in the emergency department and then transfer to a hospital that can, according to Dr. Estes.
The mechanism by which therapeutic hypothermia works has been well elucidated. The treatment curbs the process by which ischemia as a second blow triggers formation of oxygen free radicals, glutamate release, calcium shifts, and mitochondrial dysfunction, with resultant destruction of brain tissue.
Roughly 250,000 sudden cardiac deaths (SCDs) occur annually in this country. In addition to more widespread availability of therapeutic hypothermia and other forms of specialized postresuscitation care through creation of regional systems of care for out-of-hospital cardiac arrest, there are other opportunities for improving outcomes. These include earlier activation of the chain of survival that begins with a bystander dialing 911 as well as greater availability of public access defibrillation.
Dr. Estes emphasized that while these measures will further improve outcomes of cardiac arrest, they won’t actually reduce its frequency. By far the greatest opportunity in that realm lies in primordial prevention of coronary artery disease; that is, prevention of the risk factors for CAD. After all, he noted, 80% of all SCDs are associated with underlying ischemic heart disease. In 30% of SCDs, the fatal event is the first manifestation of previously unrecognized CAD. Another one-third of SCDs occur in patients with known CAD, but who weren’t considered at high risk for SCD because of their preserved left ventricular ejection fraction.
“There are a number of luminaries in the field who feel that if we’re really going to make an impact on sudden cardiac death, it’s going to be through primordial prevention of CAD,” the cardiologist said.
For this reason, he was thrilled to hear Dr. Robert A. Vogel elsewhere at the conference describe research by investigators at Affiris AG in Vienna who’ve created a peptide-based vaccine that inhibits PCSK9. Moreover, they showed it to be effective in sharply lowering LDL in mice (PLoS One. 2014 Dec 4;9[12]:e114469).
“I believe that in my lifetime, we will have an antiatherosclerotic vaccine that will lower LDL to an extent where this disease will not disappear but may get to a manageable extent, perhaps a 10% lifetime risk instead of the 55% lifetime risk of MI or stroke that we as Americans currently have,” predicted Dr. Vogel of the University of Colorado, Denver.
Dr. Vogel reported serving as a consultant to the National Football League and the Pritikin Longevity Center as well as acting as the national coordinator for the Sanofi-sponsored ODYSSEY Outcomes trial studying the PCSK9 inhibitor alirocumab (Praluent).
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
SNOWMASS, COLO. – By far the most-important contributor to improved outcomes following out-of-hospital cardiac arrest during the past decade has been therapeutic hypothermia, Dr. N.A. Mark Estes III said at the Annual Cardiovascular Conference at Snowmass.
The No. 1 cause of in-hospital death in patients who arrive at the hospital with a perfusable rhythm following resuscitation from out-of-hospital cardiac arrest isn’t sepsis, hepatic or renal failure, or cardiogenic shock. It’s neurologic death caused by anoxic brain injury, which begins several hours after cardiac arrest and continues for about 48 hours. This is where therapeutic hypothermia has made a huge difference, said Dr. Estes, professor of medicine and director of cardiac arrhythmia services at Tufts University, Boston.
“One-half of out-of-hospital cardiac arrest survivors experience secondary anoxic brain damage of varying degrees. Until recently, there was no treatment with documented efficacy in preventing this damage. Despite multiple agents being looked at for neuroprevention, none really has worked. But therapeutic hypothermia has drastically improved outcomes. More than half of patients who arrive at the hospital with a perfusable rhythm and receive therapeutic hypothermia are discharged relatively neurologically intact. That’s a huge difference from what we used to see,” the electrophysiologist observed.
Indeed, the proportion of U.S. patients who experience out-of-hospital cardiac arrest and survive to hospital discharge neurologically intact is “dismal” at about 10%, he noted.
Virtually all specialized cardiac arrest centers now provide therapeutic hypothermia using various protocols. The demonstrated effectiveness of this postresuscitation therapy was an impetus for the American Heart Association policy statement calling for creation of regional cardiac resuscitation systems of care (Circulation. 2010 Feb 9;121[5]:709-29). To date, however, such organized systems exist in only a handful of states or portions of states.
Nonetheless, when an out-of-hospital cardiac arrest patient arrives at a community hospital that can’t provide emergency coronary angiography and therapeutic hypothermia, it’s appropriate to stabilize that patient in the emergency department and then transfer to a hospital that can, according to Dr. Estes.
The mechanism by which therapeutic hypothermia works has been well elucidated. The treatment curbs the process by which ischemia as a second blow triggers formation of oxygen free radicals, glutamate release, calcium shifts, and mitochondrial dysfunction, with resultant destruction of brain tissue.
Roughly 250,000 sudden cardiac deaths (SCDs) occur annually in this country. In addition to more widespread availability of therapeutic hypothermia and other forms of specialized postresuscitation care through creation of regional systems of care for out-of-hospital cardiac arrest, there are other opportunities for improving outcomes. These include earlier activation of the chain of survival that begins with a bystander dialing 911 as well as greater availability of public access defibrillation.
Dr. Estes emphasized that while these measures will further improve outcomes of cardiac arrest, they won’t actually reduce its frequency. By far the greatest opportunity in that realm lies in primordial prevention of coronary artery disease; that is, prevention of the risk factors for CAD. After all, he noted, 80% of all SCDs are associated with underlying ischemic heart disease. In 30% of SCDs, the fatal event is the first manifestation of previously unrecognized CAD. Another one-third of SCDs occur in patients with known CAD, but who weren’t considered at high risk for SCD because of their preserved left ventricular ejection fraction.
“There are a number of luminaries in the field who feel that if we’re really going to make an impact on sudden cardiac death, it’s going to be through primordial prevention of CAD,” the cardiologist said.
For this reason, he was thrilled to hear Dr. Robert A. Vogel elsewhere at the conference describe research by investigators at Affiris AG in Vienna who’ve created a peptide-based vaccine that inhibits PCSK9. Moreover, they showed it to be effective in sharply lowering LDL in mice (PLoS One. 2014 Dec 4;9[12]:e114469).
“I believe that in my lifetime, we will have an antiatherosclerotic vaccine that will lower LDL to an extent where this disease will not disappear but may get to a manageable extent, perhaps a 10% lifetime risk instead of the 55% lifetime risk of MI or stroke that we as Americans currently have,” predicted Dr. Vogel of the University of Colorado, Denver.
Dr. Vogel reported serving as a consultant to the National Football League and the Pritikin Longevity Center as well as acting as the national coordinator for the Sanofi-sponsored ODYSSEY Outcomes trial studying the PCSK9 inhibitor alirocumab (Praluent).
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
SNOWMASS, COLO. – By far the most-important contributor to improved outcomes following out-of-hospital cardiac arrest during the past decade has been therapeutic hypothermia, Dr. N.A. Mark Estes III said at the Annual Cardiovascular Conference at Snowmass.
The No. 1 cause of in-hospital death in patients who arrive at the hospital with a perfusable rhythm following resuscitation from out-of-hospital cardiac arrest isn’t sepsis, hepatic or renal failure, or cardiogenic shock. It’s neurologic death caused by anoxic brain injury, which begins several hours after cardiac arrest and continues for about 48 hours. This is where therapeutic hypothermia has made a huge difference, said Dr. Estes, professor of medicine and director of cardiac arrhythmia services at Tufts University, Boston.
“One-half of out-of-hospital cardiac arrest survivors experience secondary anoxic brain damage of varying degrees. Until recently, there was no treatment with documented efficacy in preventing this damage. Despite multiple agents being looked at for neuroprevention, none really has worked. But therapeutic hypothermia has drastically improved outcomes. More than half of patients who arrive at the hospital with a perfusable rhythm and receive therapeutic hypothermia are discharged relatively neurologically intact. That’s a huge difference from what we used to see,” the electrophysiologist observed.
Indeed, the proportion of U.S. patients who experience out-of-hospital cardiac arrest and survive to hospital discharge neurologically intact is “dismal” at about 10%, he noted.
Virtually all specialized cardiac arrest centers now provide therapeutic hypothermia using various protocols. The demonstrated effectiveness of this postresuscitation therapy was an impetus for the American Heart Association policy statement calling for creation of regional cardiac resuscitation systems of care (Circulation. 2010 Feb 9;121[5]:709-29). To date, however, such organized systems exist in only a handful of states or portions of states.
Nonetheless, when an out-of-hospital cardiac arrest patient arrives at a community hospital that can’t provide emergency coronary angiography and therapeutic hypothermia, it’s appropriate to stabilize that patient in the emergency department and then transfer to a hospital that can, according to Dr. Estes.
The mechanism by which therapeutic hypothermia works has been well elucidated. The treatment curbs the process by which ischemia as a second blow triggers formation of oxygen free radicals, glutamate release, calcium shifts, and mitochondrial dysfunction, with resultant destruction of brain tissue.
Roughly 250,000 sudden cardiac deaths (SCDs) occur annually in this country. In addition to more widespread availability of therapeutic hypothermia and other forms of specialized postresuscitation care through creation of regional systems of care for out-of-hospital cardiac arrest, there are other opportunities for improving outcomes. These include earlier activation of the chain of survival that begins with a bystander dialing 911 as well as greater availability of public access defibrillation.
Dr. Estes emphasized that while these measures will further improve outcomes of cardiac arrest, they won’t actually reduce its frequency. By far the greatest opportunity in that realm lies in primordial prevention of coronary artery disease; that is, prevention of the risk factors for CAD. After all, he noted, 80% of all SCDs are associated with underlying ischemic heart disease. In 30% of SCDs, the fatal event is the first manifestation of previously unrecognized CAD. Another one-third of SCDs occur in patients with known CAD, but who weren’t considered at high risk for SCD because of their preserved left ventricular ejection fraction.
“There are a number of luminaries in the field who feel that if we’re really going to make an impact on sudden cardiac death, it’s going to be through primordial prevention of CAD,” the cardiologist said.
For this reason, he was thrilled to hear Dr. Robert A. Vogel elsewhere at the conference describe research by investigators at Affiris AG in Vienna who’ve created a peptide-based vaccine that inhibits PCSK9. Moreover, they showed it to be effective in sharply lowering LDL in mice (PLoS One. 2014 Dec 4;9[12]:e114469).
“I believe that in my lifetime, we will have an antiatherosclerotic vaccine that will lower LDL to an extent where this disease will not disappear but may get to a manageable extent, perhaps a 10% lifetime risk instead of the 55% lifetime risk of MI or stroke that we as Americans currently have,” predicted Dr. Vogel of the University of Colorado, Denver.
Dr. Vogel reported serving as a consultant to the National Football League and the Pritikin Longevity Center as well as acting as the national coordinator for the Sanofi-sponsored ODYSSEY Outcomes trial studying the PCSK9 inhibitor alirocumab (Praluent).
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Heightened Emphasis on Sex-specific Cardiovascular Risk Factors
SNOWMASS, COLO. – Achieving continued reductions in cardiovascular deaths in U.S. women will require that physicians make greater use of sex-specific risk factors that aren’t incorporated in the ACC/AHA atherosclerotic cardiovascular disease risk score, Dr. Jennifer H. Mieres asserted at the Annual Cardiovascular Conference at Snowmass.
In the 13-year period beginning in 2000, with the launch of a national initiative to boost the research focus on cardiovascular disease in women, the annual number of women dying from cardiovascular disease has dropped by roughly 30%. That’s a steeper decline than in men. One of the keys to further reductions in women is more widespread physician evaluation of sex-specific risk factors – such as a history of elevated blood pressure in pregnancy, polycystic ovarian syndrome, or radiation therapy for breast cancer – as part of routine cardiovascular risk assessment in women, said Dr. Mieres, senior vice president office of community and public health at Hofstra Northwell in Hempstead, N.Y.
Hypertension in pregnancy as a harbinger of premature cardiovascular disease and other chronic diseases has been a topic of particularly fruitful research in the past few years.
“The ongoing hypothesis is that pregnancy is a sort of stress test. Pregnancy-related complications indicate an inability to adequately adapt to the physiologic stress of pregnancy and thus reveal the presence of underlying susceptibility to ischemic heart disease,” according to the cardiologist.
She cited a landmark prospective study of 10,314 women born in Northern Finland in 1966 and followed for an average of more than 39 years after a singleton pregnancy. The investigators showed that any elevation in blood pressure during pregnancy, including isolated systolic or diastolic hypertension that resolved during or shortly after pregnancy, was associated with increased future risks of various forms of cardiovascular disease.
For example, de novo gestational hypertension without proteinuria was associated with significantly increased risks of subsequent ischemic cerebrovascular disease, chronic kidney disease, diabetes, ischemic heart disease, acute MI, chronic hypertension, and heart failure. The MIs that occurred in Finns with a history of gestational hypertension were more serious, too, with an associated threefold greater risk of being fatal than MIs in women who had been normotensive in pregnancy (Circulation. 2013 Feb 12;127[6]:681-90).
New-onset isolated systolic or diastolic hypertension emerged during pregnancy in about 17% of the Finnish women. Roughly 30% of them had a cardiovascular event before their late 60s. This translated to a 14%-18% greater risk than in women who remained normotensive in pregnancy.
The highest risk of all in the Finnish study was seen in women with preeclampsia/eclampsia superimposed on a background of chronic hypertension. They had a 3.18-fold greater risk of subsequent MI than did women who were normotensive in pregnancy, a 3.32-fold increased risk of heart failure, and a 2.22-fold greater risk of developing diabetes.
In addition to the growing appreciation that it’s important to consider sex-specific cardiovascular risk factors, recent evidence shows that many of the traditional risk factors are stronger predictors of ischemic heart disease in women than men. These include diabetes, smoking, obesity, and hypertension, Dr. Mieres observed.
For example, a recent meta-analysis of 26 studies including more than 214,000 subjects concluded that women with type 1 diabetes had a 2.5-fold greater risk of incident coronary heart disease than did men with type 1 diabetes. The women with type 1 diabetes also had an 86% greater risk of fatal cardiovascular diseases, a 44% increase in the risk of fatal kidney disease, a 37% greater risk of stroke, and a 37% increase in all-cause mortality relative to type 1 diabetic men (Lancet Diabetes Endocrinol. 2015 Mar;3[3]:198-206).
A wealth of accumulating data indicates that type 2 diabetes, too, is a much stronger risk factor for cardiovascular diseases in women than in men. The evidence prompted a recent formal scientific statement to that effect by the American Heart Association (Circulation. 2015 Dec 22;132[25]:2424-47).
Dr. Mieres reported having no financial conflicts of interest regarding her presentation.
SNOWMASS, COLO. – Achieving continued reductions in cardiovascular deaths in U.S. women will require that physicians make greater use of sex-specific risk factors that aren’t incorporated in the ACC/AHA atherosclerotic cardiovascular disease risk score, Dr. Jennifer H. Mieres asserted at the Annual Cardiovascular Conference at Snowmass.
In the 13-year period beginning in 2000, with the launch of a national initiative to boost the research focus on cardiovascular disease in women, the annual number of women dying from cardiovascular disease has dropped by roughly 30%. That’s a steeper decline than in men. One of the keys to further reductions in women is more widespread physician evaluation of sex-specific risk factors – such as a history of elevated blood pressure in pregnancy, polycystic ovarian syndrome, or radiation therapy for breast cancer – as part of routine cardiovascular risk assessment in women, said Dr. Mieres, senior vice president office of community and public health at Hofstra Northwell in Hempstead, N.Y.
Hypertension in pregnancy as a harbinger of premature cardiovascular disease and other chronic diseases has been a topic of particularly fruitful research in the past few years.
“The ongoing hypothesis is that pregnancy is a sort of stress test. Pregnancy-related complications indicate an inability to adequately adapt to the physiologic stress of pregnancy and thus reveal the presence of underlying susceptibility to ischemic heart disease,” according to the cardiologist.
She cited a landmark prospective study of 10,314 women born in Northern Finland in 1966 and followed for an average of more than 39 years after a singleton pregnancy. The investigators showed that any elevation in blood pressure during pregnancy, including isolated systolic or diastolic hypertension that resolved during or shortly after pregnancy, was associated with increased future risks of various forms of cardiovascular disease.
For example, de novo gestational hypertension without proteinuria was associated with significantly increased risks of subsequent ischemic cerebrovascular disease, chronic kidney disease, diabetes, ischemic heart disease, acute MI, chronic hypertension, and heart failure. The MIs that occurred in Finns with a history of gestational hypertension were more serious, too, with an associated threefold greater risk of being fatal than MIs in women who had been normotensive in pregnancy (Circulation. 2013 Feb 12;127[6]:681-90).
New-onset isolated systolic or diastolic hypertension emerged during pregnancy in about 17% of the Finnish women. Roughly 30% of them had a cardiovascular event before their late 60s. This translated to a 14%-18% greater risk than in women who remained normotensive in pregnancy.
The highest risk of all in the Finnish study was seen in women with preeclampsia/eclampsia superimposed on a background of chronic hypertension. They had a 3.18-fold greater risk of subsequent MI than did women who were normotensive in pregnancy, a 3.32-fold increased risk of heart failure, and a 2.22-fold greater risk of developing diabetes.
In addition to the growing appreciation that it’s important to consider sex-specific cardiovascular risk factors, recent evidence shows that many of the traditional risk factors are stronger predictors of ischemic heart disease in women than men. These include diabetes, smoking, obesity, and hypertension, Dr. Mieres observed.
For example, a recent meta-analysis of 26 studies including more than 214,000 subjects concluded that women with type 1 diabetes had a 2.5-fold greater risk of incident coronary heart disease than did men with type 1 diabetes. The women with type 1 diabetes also had an 86% greater risk of fatal cardiovascular diseases, a 44% increase in the risk of fatal kidney disease, a 37% greater risk of stroke, and a 37% increase in all-cause mortality relative to type 1 diabetic men (Lancet Diabetes Endocrinol. 2015 Mar;3[3]:198-206).
A wealth of accumulating data indicates that type 2 diabetes, too, is a much stronger risk factor for cardiovascular diseases in women than in men. The evidence prompted a recent formal scientific statement to that effect by the American Heart Association (Circulation. 2015 Dec 22;132[25]:2424-47).
Dr. Mieres reported having no financial conflicts of interest regarding her presentation.
SNOWMASS, COLO. – Achieving continued reductions in cardiovascular deaths in U.S. women will require that physicians make greater use of sex-specific risk factors that aren’t incorporated in the ACC/AHA atherosclerotic cardiovascular disease risk score, Dr. Jennifer H. Mieres asserted at the Annual Cardiovascular Conference at Snowmass.
In the 13-year period beginning in 2000, with the launch of a national initiative to boost the research focus on cardiovascular disease in women, the annual number of women dying from cardiovascular disease has dropped by roughly 30%. That’s a steeper decline than in men. One of the keys to further reductions in women is more widespread physician evaluation of sex-specific risk factors – such as a history of elevated blood pressure in pregnancy, polycystic ovarian syndrome, or radiation therapy for breast cancer – as part of routine cardiovascular risk assessment in women, said Dr. Mieres, senior vice president office of community and public health at Hofstra Northwell in Hempstead, N.Y.
Hypertension in pregnancy as a harbinger of premature cardiovascular disease and other chronic diseases has been a topic of particularly fruitful research in the past few years.
“The ongoing hypothesis is that pregnancy is a sort of stress test. Pregnancy-related complications indicate an inability to adequately adapt to the physiologic stress of pregnancy and thus reveal the presence of underlying susceptibility to ischemic heart disease,” according to the cardiologist.
She cited a landmark prospective study of 10,314 women born in Northern Finland in 1966 and followed for an average of more than 39 years after a singleton pregnancy. The investigators showed that any elevation in blood pressure during pregnancy, including isolated systolic or diastolic hypertension that resolved during or shortly after pregnancy, was associated with increased future risks of various forms of cardiovascular disease.
For example, de novo gestational hypertension without proteinuria was associated with significantly increased risks of subsequent ischemic cerebrovascular disease, chronic kidney disease, diabetes, ischemic heart disease, acute MI, chronic hypertension, and heart failure. The MIs that occurred in Finns with a history of gestational hypertension were more serious, too, with an associated threefold greater risk of being fatal than MIs in women who had been normotensive in pregnancy (Circulation. 2013 Feb 12;127[6]:681-90).
New-onset isolated systolic or diastolic hypertension emerged during pregnancy in about 17% of the Finnish women. Roughly 30% of them had a cardiovascular event before their late 60s. This translated to a 14%-18% greater risk than in women who remained normotensive in pregnancy.
The highest risk of all in the Finnish study was seen in women with preeclampsia/eclampsia superimposed on a background of chronic hypertension. They had a 3.18-fold greater risk of subsequent MI than did women who were normotensive in pregnancy, a 3.32-fold increased risk of heart failure, and a 2.22-fold greater risk of developing diabetes.
In addition to the growing appreciation that it’s important to consider sex-specific cardiovascular risk factors, recent evidence shows that many of the traditional risk factors are stronger predictors of ischemic heart disease in women than men. These include diabetes, smoking, obesity, and hypertension, Dr. Mieres observed.
For example, a recent meta-analysis of 26 studies including more than 214,000 subjects concluded that women with type 1 diabetes had a 2.5-fold greater risk of incident coronary heart disease than did men with type 1 diabetes. The women with type 1 diabetes also had an 86% greater risk of fatal cardiovascular diseases, a 44% increase in the risk of fatal kidney disease, a 37% greater risk of stroke, and a 37% increase in all-cause mortality relative to type 1 diabetic men (Lancet Diabetes Endocrinol. 2015 Mar;3[3]:198-206).
A wealth of accumulating data indicates that type 2 diabetes, too, is a much stronger risk factor for cardiovascular diseases in women than in men. The evidence prompted a recent formal scientific statement to that effect by the American Heart Association (Circulation. 2015 Dec 22;132[25]:2424-47).
Dr. Mieres reported having no financial conflicts of interest regarding her presentation.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Heightened emphasis on sex-specific cardiovascular risk factors
SNOWMASS, COLO. – Achieving continued reductions in cardiovascular deaths in U.S. women will require that physicians make greater use of sex-specific risk factors that aren’t incorporated in the ACC/AHA atherosclerotic cardiovascular disease risk score, Dr. Jennifer H. Mieres asserted at the Annual Cardiovascular Conference at Snowmass.
In the 13-year period beginning in 2000, with the launch of a national initiative to boost the research focus on cardiovascular disease in women, the annual number of women dying from cardiovascular disease has dropped by roughly 30%. That’s a steeper decline than in men. One of the keys to further reductions in women is more widespread physician evaluation of sex-specific risk factors – such as a history of elevated blood pressure in pregnancy, polycystic ovarian syndrome, or radiation therapy for breast cancer – as part of routine cardiovascular risk assessment in women, said Dr. Mieres, senior vice president office of community and public health at Hofstra Northwell in Hempstead, N.Y.
Hypertension in pregnancy as a harbinger of premature cardiovascular disease and other chronic diseases has been a topic of particularly fruitful research in the past few years.
“The ongoing hypothesis is that pregnancy is a sort of stress test. Pregnancy-related complications indicate an inability to adequately adapt to the physiologic stress of pregnancy and thus reveal the presence of underlying susceptibility to ischemic heart disease,” according to the cardiologist.
She cited a landmark prospective study of 10,314 women born in Northern Finland in 1966 and followed for an average of more than 39 years after a singleton pregnancy. The investigators showed that any elevation in blood pressure during pregnancy, including isolated systolic or diastolic hypertension that resolved during or shortly after pregnancy, was associated with increased future risks of various forms of cardiovascular disease.
For example, de novo gestational hypertension without proteinuria was associated with significantly increased risks of subsequent ischemic cerebrovascular disease, chronic kidney disease, diabetes, ischemic heart disease, acute MI, chronic hypertension, and heart failure. The MIs that occurred in Finns with a history of gestational hypertension were more serious, too, with an associated threefold greater risk of being fatal than MIs in women who had been normotensive in pregnancy (Circulation. 2013 Feb 12;127[6]:681-90).
New-onset isolated systolic or diastolic hypertension emerged during pregnancy in about 17% of the Finnish women. Roughly 30% of them had a cardiovascular event before their late 60s. This translated to a 14%-18% greater risk than in women who remained normotensive in pregnancy.
The highest risk of all in the Finnish study was seen in women with preeclampsia/eclampsia superimposed on a background of chronic hypertension. They had a 3.18-fold greater risk of subsequent MI than did women who were normotensive in pregnancy, a 3.32-fold increased risk of heart failure, and a 2.22-fold greater risk of developing diabetes.
In addition to the growing appreciation that it’s important to consider sex-specific cardiovascular risk factors, recent evidence shows that many of the traditional risk factors are stronger predictors of ischemic heart disease in women than men. These include diabetes, smoking, obesity, and hypertension, Dr. Mieres observed.
For example, a recent meta-analysis of 26 studies including more than 214,000 subjects concluded that women with type 1 diabetes had a 2.5-fold greater risk of incident coronary heart disease than did men with type 1 diabetes. The women with type 1 diabetes also had an 86% greater risk of fatal cardiovascular diseases, a 44% increase in the risk of fatal kidney disease, a 37% greater risk of stroke, and a 37% increase in all-cause mortality relative to type 1 diabetic men (Lancet Diabetes Endocrinol. 2015 Mar;3[3]:198-206).
A wealth of accumulating data indicates that type 2 diabetes, too, is a much stronger risk factor for cardiovascular diseases in women than in men. The evidence prompted a recent formal scientific statement to that effect by the American Heart Association (Circulation. 2015 Dec 22;132[25]:2424-47).
Dr. Mieres reported having no financial conflicts of interest regarding her presentation.
SNOWMASS, COLO. – Achieving continued reductions in cardiovascular deaths in U.S. women will require that physicians make greater use of sex-specific risk factors that aren’t incorporated in the ACC/AHA atherosclerotic cardiovascular disease risk score, Dr. Jennifer H. Mieres asserted at the Annual Cardiovascular Conference at Snowmass.
In the 13-year period beginning in 2000, with the launch of a national initiative to boost the research focus on cardiovascular disease in women, the annual number of women dying from cardiovascular disease has dropped by roughly 30%. That’s a steeper decline than in men. One of the keys to further reductions in women is more widespread physician evaluation of sex-specific risk factors – such as a history of elevated blood pressure in pregnancy, polycystic ovarian syndrome, or radiation therapy for breast cancer – as part of routine cardiovascular risk assessment in women, said Dr. Mieres, senior vice president office of community and public health at Hofstra Northwell in Hempstead, N.Y.
Hypertension in pregnancy as a harbinger of premature cardiovascular disease and other chronic diseases has been a topic of particularly fruitful research in the past few years.
“The ongoing hypothesis is that pregnancy is a sort of stress test. Pregnancy-related complications indicate an inability to adequately adapt to the physiologic stress of pregnancy and thus reveal the presence of underlying susceptibility to ischemic heart disease,” according to the cardiologist.
She cited a landmark prospective study of 10,314 women born in Northern Finland in 1966 and followed for an average of more than 39 years after a singleton pregnancy. The investigators showed that any elevation in blood pressure during pregnancy, including isolated systolic or diastolic hypertension that resolved during or shortly after pregnancy, was associated with increased future risks of various forms of cardiovascular disease.
For example, de novo gestational hypertension without proteinuria was associated with significantly increased risks of subsequent ischemic cerebrovascular disease, chronic kidney disease, diabetes, ischemic heart disease, acute MI, chronic hypertension, and heart failure. The MIs that occurred in Finns with a history of gestational hypertension were more serious, too, with an associated threefold greater risk of being fatal than MIs in women who had been normotensive in pregnancy (Circulation. 2013 Feb 12;127[6]:681-90).
New-onset isolated systolic or diastolic hypertension emerged during pregnancy in about 17% of the Finnish women. Roughly 30% of them had a cardiovascular event before their late 60s. This translated to a 14%-18% greater risk than in women who remained normotensive in pregnancy.
The highest risk of all in the Finnish study was seen in women with preeclampsia/eclampsia superimposed on a background of chronic hypertension. They had a 3.18-fold greater risk of subsequent MI than did women who were normotensive in pregnancy, a 3.32-fold increased risk of heart failure, and a 2.22-fold greater risk of developing diabetes.
In addition to the growing appreciation that it’s important to consider sex-specific cardiovascular risk factors, recent evidence shows that many of the traditional risk factors are stronger predictors of ischemic heart disease in women than men. These include diabetes, smoking, obesity, and hypertension, Dr. Mieres observed.
For example, a recent meta-analysis of 26 studies including more than 214,000 subjects concluded that women with type 1 diabetes had a 2.5-fold greater risk of incident coronary heart disease than did men with type 1 diabetes. The women with type 1 diabetes also had an 86% greater risk of fatal cardiovascular diseases, a 44% increase in the risk of fatal kidney disease, a 37% greater risk of stroke, and a 37% increase in all-cause mortality relative to type 1 diabetic men (Lancet Diabetes Endocrinol. 2015 Mar;3[3]:198-206).
A wealth of accumulating data indicates that type 2 diabetes, too, is a much stronger risk factor for cardiovascular diseases in women than in men. The evidence prompted a recent formal scientific statement to that effect by the American Heart Association (Circulation. 2015 Dec 22;132[25]:2424-47).
Dr. Mieres reported having no financial conflicts of interest regarding her presentation.
SNOWMASS, COLO. – Achieving continued reductions in cardiovascular deaths in U.S. women will require that physicians make greater use of sex-specific risk factors that aren’t incorporated in the ACC/AHA atherosclerotic cardiovascular disease risk score, Dr. Jennifer H. Mieres asserted at the Annual Cardiovascular Conference at Snowmass.
In the 13-year period beginning in 2000, with the launch of a national initiative to boost the research focus on cardiovascular disease in women, the annual number of women dying from cardiovascular disease has dropped by roughly 30%. That’s a steeper decline than in men. One of the keys to further reductions in women is more widespread physician evaluation of sex-specific risk factors – such as a history of elevated blood pressure in pregnancy, polycystic ovarian syndrome, or radiation therapy for breast cancer – as part of routine cardiovascular risk assessment in women, said Dr. Mieres, senior vice president office of community and public health at Hofstra Northwell in Hempstead, N.Y.
Hypertension in pregnancy as a harbinger of premature cardiovascular disease and other chronic diseases has been a topic of particularly fruitful research in the past few years.
“The ongoing hypothesis is that pregnancy is a sort of stress test. Pregnancy-related complications indicate an inability to adequately adapt to the physiologic stress of pregnancy and thus reveal the presence of underlying susceptibility to ischemic heart disease,” according to the cardiologist.
She cited a landmark prospective study of 10,314 women born in Northern Finland in 1966 and followed for an average of more than 39 years after a singleton pregnancy. The investigators showed that any elevation in blood pressure during pregnancy, including isolated systolic or diastolic hypertension that resolved during or shortly after pregnancy, was associated with increased future risks of various forms of cardiovascular disease.
For example, de novo gestational hypertension without proteinuria was associated with significantly increased risks of subsequent ischemic cerebrovascular disease, chronic kidney disease, diabetes, ischemic heart disease, acute MI, chronic hypertension, and heart failure. The MIs that occurred in Finns with a history of gestational hypertension were more serious, too, with an associated threefold greater risk of being fatal than MIs in women who had been normotensive in pregnancy (Circulation. 2013 Feb 12;127[6]:681-90).
New-onset isolated systolic or diastolic hypertension emerged during pregnancy in about 17% of the Finnish women. Roughly 30% of them had a cardiovascular event before their late 60s. This translated to a 14%-18% greater risk than in women who remained normotensive in pregnancy.
The highest risk of all in the Finnish study was seen in women with preeclampsia/eclampsia superimposed on a background of chronic hypertension. They had a 3.18-fold greater risk of subsequent MI than did women who were normotensive in pregnancy, a 3.32-fold increased risk of heart failure, and a 2.22-fold greater risk of developing diabetes.
In addition to the growing appreciation that it’s important to consider sex-specific cardiovascular risk factors, recent evidence shows that many of the traditional risk factors are stronger predictors of ischemic heart disease in women than men. These include diabetes, smoking, obesity, and hypertension, Dr. Mieres observed.
For example, a recent meta-analysis of 26 studies including more than 214,000 subjects concluded that women with type 1 diabetes had a 2.5-fold greater risk of incident coronary heart disease than did men with type 1 diabetes. The women with type 1 diabetes also had an 86% greater risk of fatal cardiovascular diseases, a 44% increase in the risk of fatal kidney disease, a 37% greater risk of stroke, and a 37% increase in all-cause mortality relative to type 1 diabetic men (Lancet Diabetes Endocrinol. 2015 Mar;3[3]:198-206).
A wealth of accumulating data indicates that type 2 diabetes, too, is a much stronger risk factor for cardiovascular diseases in women than in men. The evidence prompted a recent formal scientific statement to that effect by the American Heart Association (Circulation. 2015 Dec 22;132[25]:2424-47).
Dr. Mieres reported having no financial conflicts of interest regarding her presentation.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Ischemic mitral regurgitation: valve repair vs. replacement
SNOWMASS, COLO. – A clear message from the first-ever randomized trial of surgical mitral valve repair versus replacement for patients with severe ischemic mitral regurgitation is that replacement should be utilized more liberally, Dr. Michael J. Mack said at the Annual Cardiovascular Conference at Snowmass.
The results of prosthetic valve implantation proved far more durable than repair. At 2 years of follow-up in this 251-patient multicenter trial conducted by the Cardiothoracic Surgical Trials Network (CSTN), the incidence of recurrent moderate or severe mitral regurgitation was just 3.8% in the valve replacement group, compared with 58.8% with repair via restrictive annuloplasty. As a result, the repair group had significantly more heart failure–related adverse events and cardiovascular hospitalizations and a lower rate of clinically meaningful improvement in quality of life scores, noted Dr. Mack, an investigator in the trial and medical director of the Baylor Health Care System in Plano, Tex.
“I think surgical mitral valve replacement has had a bad name over the years, and one of the reasons is because of the worse left ventricular function afterwards. However, that was a casualty of excising the mitral valve and the subvalvular apparatus, causing atrial-ventricular disconnection. We’ve gotten smarter about this. The techniques we now use are valve sparing,” the cardiothoracic surgeon said.
He was quick to add, however, that the CSTN study results are by no means the death knell for restrictive mitral annuloplasty. Indeed, participants in the mitral valve repair group who didn’t develop recurrent regurgitation actually experienced significant positive reverse remodeling as reflected by improvement in their left ventricular end-systolic volume index, the primary endpoint of the study (N Engl J Med. 2016;374:344-35).
The key to successful outcomes in mitral valve repair is to save the procedure for patients who are unlikely to develop recurrent regurgitation. And a substudy of the CTSN trial led by Dr. Irving L. Kron, professor of surgery at the University of Virginia, Charlottesville, provides practical guidance on that score. The investigators conducted a logistic regression analysis of the mitral valve repair group’s baseline echocardiographic and clinical characteristics and identified a collection of strong predictors of recurrent regurgitation within 2 years (J Thorac Cardiovasc Surg. 2015 Mar;149[3]:752-61).
“The bottom line is, the more tethering you have of the mitral valve leaflets, the more likely you are to have recurrent mitral regurgitation after mitral valve annuloplasty,” Dr. Mack said.
The predictors of recurrent regurgitation included a coaptation depth greater than 10 mm, a posterior leaflet angle in excess of 45 degrees, a distal anterior leaflet angle greater than 25 degrees, inferior basal aneurysm, mitral annular calcification, and a left ventricular end diastolic diameter greater than 65 mm, as well as other indices of advanced left ventricular remodeling.
No or only mild annular dilation, as occurs, for example, in patients whose mitral regurgitation is caused by atrial fibrillation, is another independent predictor of recurrent regurgitation post repair.
“Shrinking the annulus isn’t going to make a difference if the annulus wasn’t dilated to begin with,” the surgeon observed. “If surgery is performed, we now know those patients who are most likely to recur – and they should have mitral valve replacement. If those factors are not present, then repair is still a viable option,” according to Dr. Mack.
That being said, it’s still not known whether correcting severe ischemic mitral regurgitation prolongs life or improves quality of life long term, compared with guideline-directed medical therapy, he stressed.
“Secondary mitral regurgitation is a disease of the left ventricle, not the mitral valve. So it’s possible that mitral regurgitation reduction has no benefit because the regurgitation is a surrogate marker not causally related to outcome. I don’t think so, but it is a possibility,” Dr. Mack conceded.
This is a clinically important unresolved question because secondary mitral regurgitation is extremely common. In a retrospective echocardiographic study of 558 heart failure patients with a left ventricular ejection fraction of 35% or less and class III-IV symptoms, 90% of them had some degree of mitral regurgitation (J Card Fail. 2004 Aug;10[4]:285-91).
Together with Columbia University cardiologist Dr. Gregg W. Stone, Dr. Mack is coprincipal investigator of the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, which is expected to provide an answer to this key question. The multicenter U.S. study involves a planned 420 patients with severely symptomatic secondary mitral regurgitation who are deemed at prohibitive risk for surgery. They are to be randomized to guideline-directed medical therapy with or without transcatheter mitral valve repair using the MitraClip device. Enrollment should be completed by May, with initial results available in late 2017.
Dr. Mack reported receiving research grants from Abbott Vascular, which is sponsoring the COAPT trial, as well as from Edwards Lifesciences.
SNOWMASS, COLO. – A clear message from the first-ever randomized trial of surgical mitral valve repair versus replacement for patients with severe ischemic mitral regurgitation is that replacement should be utilized more liberally, Dr. Michael J. Mack said at the Annual Cardiovascular Conference at Snowmass.
The results of prosthetic valve implantation proved far more durable than repair. At 2 years of follow-up in this 251-patient multicenter trial conducted by the Cardiothoracic Surgical Trials Network (CSTN), the incidence of recurrent moderate or severe mitral regurgitation was just 3.8% in the valve replacement group, compared with 58.8% with repair via restrictive annuloplasty. As a result, the repair group had significantly more heart failure–related adverse events and cardiovascular hospitalizations and a lower rate of clinically meaningful improvement in quality of life scores, noted Dr. Mack, an investigator in the trial and medical director of the Baylor Health Care System in Plano, Tex.
“I think surgical mitral valve replacement has had a bad name over the years, and one of the reasons is because of the worse left ventricular function afterwards. However, that was a casualty of excising the mitral valve and the subvalvular apparatus, causing atrial-ventricular disconnection. We’ve gotten smarter about this. The techniques we now use are valve sparing,” the cardiothoracic surgeon said.
He was quick to add, however, that the CSTN study results are by no means the death knell for restrictive mitral annuloplasty. Indeed, participants in the mitral valve repair group who didn’t develop recurrent regurgitation actually experienced significant positive reverse remodeling as reflected by improvement in their left ventricular end-systolic volume index, the primary endpoint of the study (N Engl J Med. 2016;374:344-35).
The key to successful outcomes in mitral valve repair is to save the procedure for patients who are unlikely to develop recurrent regurgitation. And a substudy of the CTSN trial led by Dr. Irving L. Kron, professor of surgery at the University of Virginia, Charlottesville, provides practical guidance on that score. The investigators conducted a logistic regression analysis of the mitral valve repair group’s baseline echocardiographic and clinical characteristics and identified a collection of strong predictors of recurrent regurgitation within 2 years (J Thorac Cardiovasc Surg. 2015 Mar;149[3]:752-61).
“The bottom line is, the more tethering you have of the mitral valve leaflets, the more likely you are to have recurrent mitral regurgitation after mitral valve annuloplasty,” Dr. Mack said.
The predictors of recurrent regurgitation included a coaptation depth greater than 10 mm, a posterior leaflet angle in excess of 45 degrees, a distal anterior leaflet angle greater than 25 degrees, inferior basal aneurysm, mitral annular calcification, and a left ventricular end diastolic diameter greater than 65 mm, as well as other indices of advanced left ventricular remodeling.
No or only mild annular dilation, as occurs, for example, in patients whose mitral regurgitation is caused by atrial fibrillation, is another independent predictor of recurrent regurgitation post repair.
“Shrinking the annulus isn’t going to make a difference if the annulus wasn’t dilated to begin with,” the surgeon observed. “If surgery is performed, we now know those patients who are most likely to recur – and they should have mitral valve replacement. If those factors are not present, then repair is still a viable option,” according to Dr. Mack.
That being said, it’s still not known whether correcting severe ischemic mitral regurgitation prolongs life or improves quality of life long term, compared with guideline-directed medical therapy, he stressed.
“Secondary mitral regurgitation is a disease of the left ventricle, not the mitral valve. So it’s possible that mitral regurgitation reduction has no benefit because the regurgitation is a surrogate marker not causally related to outcome. I don’t think so, but it is a possibility,” Dr. Mack conceded.
This is a clinically important unresolved question because secondary mitral regurgitation is extremely common. In a retrospective echocardiographic study of 558 heart failure patients with a left ventricular ejection fraction of 35% or less and class III-IV symptoms, 90% of them had some degree of mitral regurgitation (J Card Fail. 2004 Aug;10[4]:285-91).
Together with Columbia University cardiologist Dr. Gregg W. Stone, Dr. Mack is coprincipal investigator of the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, which is expected to provide an answer to this key question. The multicenter U.S. study involves a planned 420 patients with severely symptomatic secondary mitral regurgitation who are deemed at prohibitive risk for surgery. They are to be randomized to guideline-directed medical therapy with or without transcatheter mitral valve repair using the MitraClip device. Enrollment should be completed by May, with initial results available in late 2017.
Dr. Mack reported receiving research grants from Abbott Vascular, which is sponsoring the COAPT trial, as well as from Edwards Lifesciences.
SNOWMASS, COLO. – A clear message from the first-ever randomized trial of surgical mitral valve repair versus replacement for patients with severe ischemic mitral regurgitation is that replacement should be utilized more liberally, Dr. Michael J. Mack said at the Annual Cardiovascular Conference at Snowmass.
The results of prosthetic valve implantation proved far more durable than repair. At 2 years of follow-up in this 251-patient multicenter trial conducted by the Cardiothoracic Surgical Trials Network (CSTN), the incidence of recurrent moderate or severe mitral regurgitation was just 3.8% in the valve replacement group, compared with 58.8% with repair via restrictive annuloplasty. As a result, the repair group had significantly more heart failure–related adverse events and cardiovascular hospitalizations and a lower rate of clinically meaningful improvement in quality of life scores, noted Dr. Mack, an investigator in the trial and medical director of the Baylor Health Care System in Plano, Tex.
“I think surgical mitral valve replacement has had a bad name over the years, and one of the reasons is because of the worse left ventricular function afterwards. However, that was a casualty of excising the mitral valve and the subvalvular apparatus, causing atrial-ventricular disconnection. We’ve gotten smarter about this. The techniques we now use are valve sparing,” the cardiothoracic surgeon said.
He was quick to add, however, that the CSTN study results are by no means the death knell for restrictive mitral annuloplasty. Indeed, participants in the mitral valve repair group who didn’t develop recurrent regurgitation actually experienced significant positive reverse remodeling as reflected by improvement in their left ventricular end-systolic volume index, the primary endpoint of the study (N Engl J Med. 2016;374:344-35).
The key to successful outcomes in mitral valve repair is to save the procedure for patients who are unlikely to develop recurrent regurgitation. And a substudy of the CTSN trial led by Dr. Irving L. Kron, professor of surgery at the University of Virginia, Charlottesville, provides practical guidance on that score. The investigators conducted a logistic regression analysis of the mitral valve repair group’s baseline echocardiographic and clinical characteristics and identified a collection of strong predictors of recurrent regurgitation within 2 years (J Thorac Cardiovasc Surg. 2015 Mar;149[3]:752-61).
“The bottom line is, the more tethering you have of the mitral valve leaflets, the more likely you are to have recurrent mitral regurgitation after mitral valve annuloplasty,” Dr. Mack said.
The predictors of recurrent regurgitation included a coaptation depth greater than 10 mm, a posterior leaflet angle in excess of 45 degrees, a distal anterior leaflet angle greater than 25 degrees, inferior basal aneurysm, mitral annular calcification, and a left ventricular end diastolic diameter greater than 65 mm, as well as other indices of advanced left ventricular remodeling.
No or only mild annular dilation, as occurs, for example, in patients whose mitral regurgitation is caused by atrial fibrillation, is another independent predictor of recurrent regurgitation post repair.
“Shrinking the annulus isn’t going to make a difference if the annulus wasn’t dilated to begin with,” the surgeon observed. “If surgery is performed, we now know those patients who are most likely to recur – and they should have mitral valve replacement. If those factors are not present, then repair is still a viable option,” according to Dr. Mack.
That being said, it’s still not known whether correcting severe ischemic mitral regurgitation prolongs life or improves quality of life long term, compared with guideline-directed medical therapy, he stressed.
“Secondary mitral regurgitation is a disease of the left ventricle, not the mitral valve. So it’s possible that mitral regurgitation reduction has no benefit because the regurgitation is a surrogate marker not causally related to outcome. I don’t think so, but it is a possibility,” Dr. Mack conceded.
This is a clinically important unresolved question because secondary mitral regurgitation is extremely common. In a retrospective echocardiographic study of 558 heart failure patients with a left ventricular ejection fraction of 35% or less and class III-IV symptoms, 90% of them had some degree of mitral regurgitation (J Card Fail. 2004 Aug;10[4]:285-91).
Together with Columbia University cardiologist Dr. Gregg W. Stone, Dr. Mack is coprincipal investigator of the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, which is expected to provide an answer to this key question. The multicenter U.S. study involves a planned 420 patients with severely symptomatic secondary mitral regurgitation who are deemed at prohibitive risk for surgery. They are to be randomized to guideline-directed medical therapy with or without transcatheter mitral valve repair using the MitraClip device. Enrollment should be completed by May, with initial results available in late 2017.
Dr. Mack reported receiving research grants from Abbott Vascular, which is sponsoring the COAPT trial, as well as from Edwards Lifesciences.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
How to use two new game-changing heart failure drugs
SNOWMASS, COLO. – Ivabradine and sacubitril/valsartan are paradigm-changing drugs approved last year for the treatment of heart failure with reduced ejection fraction – and it’s entirely reasonable to begin using them now in the appropriate patients, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.
The impressive positive results seen in the pivotal trials for these novel agents – the SHIFT trial for ivabradine (Corlanor) and PARADIGM-HF for sacubitril/valsartan (Entresto) – have rocked the heart failure world.
The studies showed that, in the right patients, these two medications improve heart failure morbidity and mortality significantly beyond what’s achievable with the current gold standard, guideline-directed medical therapy. That’s exciting because even though great therapeutic strides have been made during the past 15 years, symptomatic patients with heart failure with reduced ejection fraction (HFrEF) treated with optimal guideline-directed pharmacotherapy still have substantial residual risk for heart failure hospitalization and death, noted Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.
The U.S. heart failure guidelines panel hasn’t yet addressed the use of either of these recently approved drugs, but Dr. Desai provided his best sense of the data and how he thinks physicians might start using them now.
Ivabradine and sacubitril/valsartan are first-in-class agents with novel mechanisms of action. Ivabradine’s demonstrated safety and efficacy in the SHIFT trial confirmed the hypothesis that elevated heart rate is a legitimate therapeutic target in HFrEF.
Sacubitril/valsartan, an angiotensin II receptor/neprilysin inhibitor formerly known as LCZ696, provides what is to date a unique ability to enhance the activity of endogenous vasoactive peptides, including natriuretic peptides, bradykinin, substance P, adrenomedullin, and calcitonin gene–related peptide. These peptides are antifibrotic, antihypertrophic, and they promote vasodilation and diuresis, thus counteracting the adverse effects of neurohormonal activation. But in HFrEF, these vasoactive peptides are less active and patients are less sensitive to them.
Ivabradine
This selective sinus node inhibitor decreases heart rate and has essentially no other effects. The drug has been available for years in Europe, and the European Society of Cardiology (ESC) has had sufficient time to integrate ivabradine into its guidelines for pharmacotherapy in HFrEF.
The ESC treatment algorithm for HFrEF (Eur Heart J. 2012 Jul;33[14]:1787-847) is built upon a foundation of thiazide diuretics to relieve signs and symptoms of congestion along with a beta-blocker and an ACE inhibitor or angiotensin receptor blocker (ARB). In a patient who still has New York Heart Association class II-IV symptoms after those drugs are titrated to guideline-recommended target levels or maximally tolerated doses, a mineralocorticoid receptor antagonist – either spironolactone or eplerenone – is added. And, in a patient who still remains symptomatic, has a left ventricular ejection fraction of 35% or less, is in sinus rhythm, and has a heart rate of 70 beats per minute or more, it’s time to consider adding ivabradine.
“This is how our own guidelines may elect to incorporate ivabradine, but of course, we don’t know yet,” Dr. Desai observed.
In the randomized, double-blind SHIFT trial involving 6,558 HFrEF patients who fit the description of ivabradine candidates described in the ESC guidelines, those who received ivabradine titrated to a maximum of 7.5 mg twice daily experienced a 26% reduction in hospital admissions for worsening heart failure, compared with placebo, a 26% reduction in deaths from heart failure, and fewer adverse events than the control group (Lancet. 2010 Sep 11;376[9744]:875-85).
The important question is who should get ivabradine and who should just get a little more beta-blocker in order to slow the heart rate. The fact is, many heart failure patients simply can’t tolerate the guideline-recommended target dose of beta-blocker therapy, which is 12.5 mg twice daily of carvedilol or its equivalent. Indeed, only 26% of SHIFT participants were able to do so.
“My interpretation of the SHIFT trial is that the goal is to reduce heart rate by any means necessary; preferentially, with a beta-blocker, and with ivabradine as an adjunct in patients who can’t get to target doses,” the cardiologist said.
Sacubitril/valsartan
In the landmark double-blind, 8,442-patient PARADIGM-HF trial, the group randomized to sacubitril/valsartan had a 20% reduction in the primary endpoint of cardiovascular death or heart failure hospitalization over 27 months of follow-up, compared with controls on enalapril at the guideline-recommended dose of 10 mg twice a day. The number needed to treat (NNT) was 21. Moreover, all-cause mortality was reduced by 16% (N Engl J Med. 2014 Sep 11;37[11]:993-1004).
In a recent follow-up cause of death analysis, Dr. Desai and his coinvestigators reported that 81% of all deaths in PARADIGM-HF were cardiovascular in nature. The NNT for sacubitril/valsartan in order to prevent one cardiovascular death was 32. The risk of sudden cardiac death was reduced by 80%, while the risk of death due to worsening heart failure was decreased by 21% (Eur Heart J 2015 Aug 7;36[30]:1990-7).
In another secondary analysis from the PARADIGM-HF investigators, the use of the angiotensin receptor/neprilysin inhibitor was shown to prevent clinical progression of surviving patients with heart failure much more effectively than enalapril. The sacubitril/valsartan group was 34% less likely to have an emergency department visit for worsening heart failure, 18% less likely to require intensive care, and 22% less likely to receive an implantable heart failure device or undergo cardiac transplantation. The reduction in the rate of heart failure hospitalization became significant within the first 30 days (Circulation. 2015 Jan 6;131[1]:54-61).
Moreover, the absolute benefit of sacubitril/valsartan in PARADIGM-HF was consistent across the full spectrum of patient risk (J Am Coll Cardiol. 2015 Nov 10;66[19]:2059-71).
To put this into perspective, Dr. Desai continued, for every 1,000 HFrEF patients switched from an ACE inhibitor or ARB to sacubitril/valsartan, the absolute benefit over the course of 27 months includes 31 fewer cardiovascular deaths, 28 fewer hospitalizations for heart failure, and 37 fewer hospitalizations for any reason.
“This is potent therapy for patients with HFrEF who have the right phenotype,” he observed.
While substitution of sacubitril/valsartan for an ACE inhibitor or ARB may be appropriate in many patients with chronic HFrEF who continue to have NYHA Class II-IV symptoms on guideline-directed medical therapy, several caveats apply, according to Dr. Desai.
It’s important to be aware of the PARADIGM-HF eligibility criteria, because it’s only in patients who fit that profile that sacubitril/valsartan provides evidence-based therapy. There are as yet no data to support the drug’s use in patients with new-onset HFrEF, acute decompensated HFrEF, in patients who are immediately post-MI, or in those with advanced chronic kidney disease, he emphasized.
“I think you have to be mindful of eligibility because the label that’s applied to this drug is basically ‘patients with HFrEF who are treated with guideline-directed medical therapy.’ There’s no specific requirement that you follow the detailed eligibility criteria of the PARADIGM-HF trial, but you should realize that the drug is known to be effective only in patients who fit the PARADIGM-HF eligibility profile,” he said.
Dr. Desai gave a few clinical pearls for prescribing sacubitril/valsartan. For most patients, the initial recommended dose is 49/51 mg twice daily. In those with low baseline blood pressure and tenuous hemodynamics, it’s appropriate to initiate therapy at 24/26 mg BID. It’s important to halt ACE inhibitor therapy 36 hours prior to starting sacubitril/valsartan so as to avoid overlap and consequent increased risk of angioedema. And while serum n-terminal prohormone brain natriuretic peptide (NT-proBNP) remains a useful biomarker to monitor heart rate severity and response to treatment while a patient is on sacubitril/valsartan, BNP is not because serum levels of that biomarker rise with neprilysin inhibition.
Dr. Desai reported receiving research support from Novartis and St. Jude Medical and serving as a consultant to those companies as well as Merck and Relypsa.
SNOWMASS, COLO. – Ivabradine and sacubitril/valsartan are paradigm-changing drugs approved last year for the treatment of heart failure with reduced ejection fraction – and it’s entirely reasonable to begin using them now in the appropriate patients, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.
The impressive positive results seen in the pivotal trials for these novel agents – the SHIFT trial for ivabradine (Corlanor) and PARADIGM-HF for sacubitril/valsartan (Entresto) – have rocked the heart failure world.
The studies showed that, in the right patients, these two medications improve heart failure morbidity and mortality significantly beyond what’s achievable with the current gold standard, guideline-directed medical therapy. That’s exciting because even though great therapeutic strides have been made during the past 15 years, symptomatic patients with heart failure with reduced ejection fraction (HFrEF) treated with optimal guideline-directed pharmacotherapy still have substantial residual risk for heart failure hospitalization and death, noted Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.
The U.S. heart failure guidelines panel hasn’t yet addressed the use of either of these recently approved drugs, but Dr. Desai provided his best sense of the data and how he thinks physicians might start using them now.
Ivabradine and sacubitril/valsartan are first-in-class agents with novel mechanisms of action. Ivabradine’s demonstrated safety and efficacy in the SHIFT trial confirmed the hypothesis that elevated heart rate is a legitimate therapeutic target in HFrEF.
Sacubitril/valsartan, an angiotensin II receptor/neprilysin inhibitor formerly known as LCZ696, provides what is to date a unique ability to enhance the activity of endogenous vasoactive peptides, including natriuretic peptides, bradykinin, substance P, adrenomedullin, and calcitonin gene–related peptide. These peptides are antifibrotic, antihypertrophic, and they promote vasodilation and diuresis, thus counteracting the adverse effects of neurohormonal activation. But in HFrEF, these vasoactive peptides are less active and patients are less sensitive to them.
Ivabradine
This selective sinus node inhibitor decreases heart rate and has essentially no other effects. The drug has been available for years in Europe, and the European Society of Cardiology (ESC) has had sufficient time to integrate ivabradine into its guidelines for pharmacotherapy in HFrEF.
The ESC treatment algorithm for HFrEF (Eur Heart J. 2012 Jul;33[14]:1787-847) is built upon a foundation of thiazide diuretics to relieve signs and symptoms of congestion along with a beta-blocker and an ACE inhibitor or angiotensin receptor blocker (ARB). In a patient who still has New York Heart Association class II-IV symptoms after those drugs are titrated to guideline-recommended target levels or maximally tolerated doses, a mineralocorticoid receptor antagonist – either spironolactone or eplerenone – is added. And, in a patient who still remains symptomatic, has a left ventricular ejection fraction of 35% or less, is in sinus rhythm, and has a heart rate of 70 beats per minute or more, it’s time to consider adding ivabradine.
“This is how our own guidelines may elect to incorporate ivabradine, but of course, we don’t know yet,” Dr. Desai observed.
In the randomized, double-blind SHIFT trial involving 6,558 HFrEF patients who fit the description of ivabradine candidates described in the ESC guidelines, those who received ivabradine titrated to a maximum of 7.5 mg twice daily experienced a 26% reduction in hospital admissions for worsening heart failure, compared with placebo, a 26% reduction in deaths from heart failure, and fewer adverse events than the control group (Lancet. 2010 Sep 11;376[9744]:875-85).
The important question is who should get ivabradine and who should just get a little more beta-blocker in order to slow the heart rate. The fact is, many heart failure patients simply can’t tolerate the guideline-recommended target dose of beta-blocker therapy, which is 12.5 mg twice daily of carvedilol or its equivalent. Indeed, only 26% of SHIFT participants were able to do so.
“My interpretation of the SHIFT trial is that the goal is to reduce heart rate by any means necessary; preferentially, with a beta-blocker, and with ivabradine as an adjunct in patients who can’t get to target doses,” the cardiologist said.
Sacubitril/valsartan
In the landmark double-blind, 8,442-patient PARADIGM-HF trial, the group randomized to sacubitril/valsartan had a 20% reduction in the primary endpoint of cardiovascular death or heart failure hospitalization over 27 months of follow-up, compared with controls on enalapril at the guideline-recommended dose of 10 mg twice a day. The number needed to treat (NNT) was 21. Moreover, all-cause mortality was reduced by 16% (N Engl J Med. 2014 Sep 11;37[11]:993-1004).
In a recent follow-up cause of death analysis, Dr. Desai and his coinvestigators reported that 81% of all deaths in PARADIGM-HF were cardiovascular in nature. The NNT for sacubitril/valsartan in order to prevent one cardiovascular death was 32. The risk of sudden cardiac death was reduced by 80%, while the risk of death due to worsening heart failure was decreased by 21% (Eur Heart J 2015 Aug 7;36[30]:1990-7).
In another secondary analysis from the PARADIGM-HF investigators, the use of the angiotensin receptor/neprilysin inhibitor was shown to prevent clinical progression of surviving patients with heart failure much more effectively than enalapril. The sacubitril/valsartan group was 34% less likely to have an emergency department visit for worsening heart failure, 18% less likely to require intensive care, and 22% less likely to receive an implantable heart failure device or undergo cardiac transplantation. The reduction in the rate of heart failure hospitalization became significant within the first 30 days (Circulation. 2015 Jan 6;131[1]:54-61).
Moreover, the absolute benefit of sacubitril/valsartan in PARADIGM-HF was consistent across the full spectrum of patient risk (J Am Coll Cardiol. 2015 Nov 10;66[19]:2059-71).
To put this into perspective, Dr. Desai continued, for every 1,000 HFrEF patients switched from an ACE inhibitor or ARB to sacubitril/valsartan, the absolute benefit over the course of 27 months includes 31 fewer cardiovascular deaths, 28 fewer hospitalizations for heart failure, and 37 fewer hospitalizations for any reason.
“This is potent therapy for patients with HFrEF who have the right phenotype,” he observed.
While substitution of sacubitril/valsartan for an ACE inhibitor or ARB may be appropriate in many patients with chronic HFrEF who continue to have NYHA Class II-IV symptoms on guideline-directed medical therapy, several caveats apply, according to Dr. Desai.
It’s important to be aware of the PARADIGM-HF eligibility criteria, because it’s only in patients who fit that profile that sacubitril/valsartan provides evidence-based therapy. There are as yet no data to support the drug’s use in patients with new-onset HFrEF, acute decompensated HFrEF, in patients who are immediately post-MI, or in those with advanced chronic kidney disease, he emphasized.
“I think you have to be mindful of eligibility because the label that’s applied to this drug is basically ‘patients with HFrEF who are treated with guideline-directed medical therapy.’ There’s no specific requirement that you follow the detailed eligibility criteria of the PARADIGM-HF trial, but you should realize that the drug is known to be effective only in patients who fit the PARADIGM-HF eligibility profile,” he said.
Dr. Desai gave a few clinical pearls for prescribing sacubitril/valsartan. For most patients, the initial recommended dose is 49/51 mg twice daily. In those with low baseline blood pressure and tenuous hemodynamics, it’s appropriate to initiate therapy at 24/26 mg BID. It’s important to halt ACE inhibitor therapy 36 hours prior to starting sacubitril/valsartan so as to avoid overlap and consequent increased risk of angioedema. And while serum n-terminal prohormone brain natriuretic peptide (NT-proBNP) remains a useful biomarker to monitor heart rate severity and response to treatment while a patient is on sacubitril/valsartan, BNP is not because serum levels of that biomarker rise with neprilysin inhibition.
Dr. Desai reported receiving research support from Novartis and St. Jude Medical and serving as a consultant to those companies as well as Merck and Relypsa.
SNOWMASS, COLO. – Ivabradine and sacubitril/valsartan are paradigm-changing drugs approved last year for the treatment of heart failure with reduced ejection fraction – and it’s entirely reasonable to begin using them now in the appropriate patients, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.
The impressive positive results seen in the pivotal trials for these novel agents – the SHIFT trial for ivabradine (Corlanor) and PARADIGM-HF for sacubitril/valsartan (Entresto) – have rocked the heart failure world.
The studies showed that, in the right patients, these two medications improve heart failure morbidity and mortality significantly beyond what’s achievable with the current gold standard, guideline-directed medical therapy. That’s exciting because even though great therapeutic strides have been made during the past 15 years, symptomatic patients with heart failure with reduced ejection fraction (HFrEF) treated with optimal guideline-directed pharmacotherapy still have substantial residual risk for heart failure hospitalization and death, noted Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.
The U.S. heart failure guidelines panel hasn’t yet addressed the use of either of these recently approved drugs, but Dr. Desai provided his best sense of the data and how he thinks physicians might start using them now.
Ivabradine and sacubitril/valsartan are first-in-class agents with novel mechanisms of action. Ivabradine’s demonstrated safety and efficacy in the SHIFT trial confirmed the hypothesis that elevated heart rate is a legitimate therapeutic target in HFrEF.
Sacubitril/valsartan, an angiotensin II receptor/neprilysin inhibitor formerly known as LCZ696, provides what is to date a unique ability to enhance the activity of endogenous vasoactive peptides, including natriuretic peptides, bradykinin, substance P, adrenomedullin, and calcitonin gene–related peptide. These peptides are antifibrotic, antihypertrophic, and they promote vasodilation and diuresis, thus counteracting the adverse effects of neurohormonal activation. But in HFrEF, these vasoactive peptides are less active and patients are less sensitive to them.
Ivabradine
This selective sinus node inhibitor decreases heart rate and has essentially no other effects. The drug has been available for years in Europe, and the European Society of Cardiology (ESC) has had sufficient time to integrate ivabradine into its guidelines for pharmacotherapy in HFrEF.
The ESC treatment algorithm for HFrEF (Eur Heart J. 2012 Jul;33[14]:1787-847) is built upon a foundation of thiazide diuretics to relieve signs and symptoms of congestion along with a beta-blocker and an ACE inhibitor or angiotensin receptor blocker (ARB). In a patient who still has New York Heart Association class II-IV symptoms after those drugs are titrated to guideline-recommended target levels or maximally tolerated doses, a mineralocorticoid receptor antagonist – either spironolactone or eplerenone – is added. And, in a patient who still remains symptomatic, has a left ventricular ejection fraction of 35% or less, is in sinus rhythm, and has a heart rate of 70 beats per minute or more, it’s time to consider adding ivabradine.
“This is how our own guidelines may elect to incorporate ivabradine, but of course, we don’t know yet,” Dr. Desai observed.
In the randomized, double-blind SHIFT trial involving 6,558 HFrEF patients who fit the description of ivabradine candidates described in the ESC guidelines, those who received ivabradine titrated to a maximum of 7.5 mg twice daily experienced a 26% reduction in hospital admissions for worsening heart failure, compared with placebo, a 26% reduction in deaths from heart failure, and fewer adverse events than the control group (Lancet. 2010 Sep 11;376[9744]:875-85).
The important question is who should get ivabradine and who should just get a little more beta-blocker in order to slow the heart rate. The fact is, many heart failure patients simply can’t tolerate the guideline-recommended target dose of beta-blocker therapy, which is 12.5 mg twice daily of carvedilol or its equivalent. Indeed, only 26% of SHIFT participants were able to do so.
“My interpretation of the SHIFT trial is that the goal is to reduce heart rate by any means necessary; preferentially, with a beta-blocker, and with ivabradine as an adjunct in patients who can’t get to target doses,” the cardiologist said.
Sacubitril/valsartan
In the landmark double-blind, 8,442-patient PARADIGM-HF trial, the group randomized to sacubitril/valsartan had a 20% reduction in the primary endpoint of cardiovascular death or heart failure hospitalization over 27 months of follow-up, compared with controls on enalapril at the guideline-recommended dose of 10 mg twice a day. The number needed to treat (NNT) was 21. Moreover, all-cause mortality was reduced by 16% (N Engl J Med. 2014 Sep 11;37[11]:993-1004).
In a recent follow-up cause of death analysis, Dr. Desai and his coinvestigators reported that 81% of all deaths in PARADIGM-HF were cardiovascular in nature. The NNT for sacubitril/valsartan in order to prevent one cardiovascular death was 32. The risk of sudden cardiac death was reduced by 80%, while the risk of death due to worsening heart failure was decreased by 21% (Eur Heart J 2015 Aug 7;36[30]:1990-7).
In another secondary analysis from the PARADIGM-HF investigators, the use of the angiotensin receptor/neprilysin inhibitor was shown to prevent clinical progression of surviving patients with heart failure much more effectively than enalapril. The sacubitril/valsartan group was 34% less likely to have an emergency department visit for worsening heart failure, 18% less likely to require intensive care, and 22% less likely to receive an implantable heart failure device or undergo cardiac transplantation. The reduction in the rate of heart failure hospitalization became significant within the first 30 days (Circulation. 2015 Jan 6;131[1]:54-61).
Moreover, the absolute benefit of sacubitril/valsartan in PARADIGM-HF was consistent across the full spectrum of patient risk (J Am Coll Cardiol. 2015 Nov 10;66[19]:2059-71).
To put this into perspective, Dr. Desai continued, for every 1,000 HFrEF patients switched from an ACE inhibitor or ARB to sacubitril/valsartan, the absolute benefit over the course of 27 months includes 31 fewer cardiovascular deaths, 28 fewer hospitalizations for heart failure, and 37 fewer hospitalizations for any reason.
“This is potent therapy for patients with HFrEF who have the right phenotype,” he observed.
While substitution of sacubitril/valsartan for an ACE inhibitor or ARB may be appropriate in many patients with chronic HFrEF who continue to have NYHA Class II-IV symptoms on guideline-directed medical therapy, several caveats apply, according to Dr. Desai.
It’s important to be aware of the PARADIGM-HF eligibility criteria, because it’s only in patients who fit that profile that sacubitril/valsartan provides evidence-based therapy. There are as yet no data to support the drug’s use in patients with new-onset HFrEF, acute decompensated HFrEF, in patients who are immediately post-MI, or in those with advanced chronic kidney disease, he emphasized.
“I think you have to be mindful of eligibility because the label that’s applied to this drug is basically ‘patients with HFrEF who are treated with guideline-directed medical therapy.’ There’s no specific requirement that you follow the detailed eligibility criteria of the PARADIGM-HF trial, but you should realize that the drug is known to be effective only in patients who fit the PARADIGM-HF eligibility profile,” he said.
Dr. Desai gave a few clinical pearls for prescribing sacubitril/valsartan. For most patients, the initial recommended dose is 49/51 mg twice daily. In those with low baseline blood pressure and tenuous hemodynamics, it’s appropriate to initiate therapy at 24/26 mg BID. It’s important to halt ACE inhibitor therapy 36 hours prior to starting sacubitril/valsartan so as to avoid overlap and consequent increased risk of angioedema. And while serum n-terminal prohormone brain natriuretic peptide (NT-proBNP) remains a useful biomarker to monitor heart rate severity and response to treatment while a patient is on sacubitril/valsartan, BNP is not because serum levels of that biomarker rise with neprilysin inhibition.
Dr. Desai reported receiving research support from Novartis and St. Jude Medical and serving as a consultant to those companies as well as Merck and Relypsa.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
