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FDA approves new valsartan generic
In response to a medication shortage, the Food and Drug Administration has approved a new generic of valsartan (Diovan), produced by Alkem Laboratories, for the treatment of high blood pressure and heart failure, the regulatory agency announced in a statement.
The FDA conducted an investigation into generic angiotensin II receptor blocker (ARB) products following reports of N-nitrosodimethylamine impurities being found in a separate valsartan product in the summer of 2018. Since that time, nitrosamine impurities have been detected in multiple ARBs, and as of March 1, 2019, hundreds of lots of ARBs produced by several companies have been recalled. The FDA has implemented new rules to prevent further contamination, but the ongoing recalls have caused a significant shortage.
“[To] address the public health consequences of these shortages, we’ve prioritized the review of generic applications for these valsartan products,” FDA commissioner Scott Gottlieb, MD, said in the statement.
For the new generic’s approval, the FDA assessed Alkem Laboratories’ manufacturing process and ensured that the company used proper testing methods to rule out the presence of nitrosamine impurities.
“We hope that today’s approval of this new generic will help reduce the valsartan shortage, and we remain committed to implementing measures to prevent the formation of these impurities during drug manufacturing processes for existing and future products,” Dr. Gottlieb said.
In response to a medication shortage, the Food and Drug Administration has approved a new generic of valsartan (Diovan), produced by Alkem Laboratories, for the treatment of high blood pressure and heart failure, the regulatory agency announced in a statement.
The FDA conducted an investigation into generic angiotensin II receptor blocker (ARB) products following reports of N-nitrosodimethylamine impurities being found in a separate valsartan product in the summer of 2018. Since that time, nitrosamine impurities have been detected in multiple ARBs, and as of March 1, 2019, hundreds of lots of ARBs produced by several companies have been recalled. The FDA has implemented new rules to prevent further contamination, but the ongoing recalls have caused a significant shortage.
“[To] address the public health consequences of these shortages, we’ve prioritized the review of generic applications for these valsartan products,” FDA commissioner Scott Gottlieb, MD, said in the statement.
For the new generic’s approval, the FDA assessed Alkem Laboratories’ manufacturing process and ensured that the company used proper testing methods to rule out the presence of nitrosamine impurities.
“We hope that today’s approval of this new generic will help reduce the valsartan shortage, and we remain committed to implementing measures to prevent the formation of these impurities during drug manufacturing processes for existing and future products,” Dr. Gottlieb said.
In response to a medication shortage, the Food and Drug Administration has approved a new generic of valsartan (Diovan), produced by Alkem Laboratories, for the treatment of high blood pressure and heart failure, the regulatory agency announced in a statement.
The FDA conducted an investigation into generic angiotensin II receptor blocker (ARB) products following reports of N-nitrosodimethylamine impurities being found in a separate valsartan product in the summer of 2018. Since that time, nitrosamine impurities have been detected in multiple ARBs, and as of March 1, 2019, hundreds of lots of ARBs produced by several companies have been recalled. The FDA has implemented new rules to prevent further contamination, but the ongoing recalls have caused a significant shortage.
“[To] address the public health consequences of these shortages, we’ve prioritized the review of generic applications for these valsartan products,” FDA commissioner Scott Gottlieb, MD, said in the statement.
For the new generic’s approval, the FDA assessed Alkem Laboratories’ manufacturing process and ensured that the company used proper testing methods to rule out the presence of nitrosamine impurities.
“We hope that today’s approval of this new generic will help reduce the valsartan shortage, and we remain committed to implementing measures to prevent the formation of these impurities during drug manufacturing processes for existing and future products,” Dr. Gottlieb said.
Interventional cardiology pioneer reflects on field’s past, future
SNOWMASS, COLO. – When Spencer B. King III, MD, shared his thoughts about the future of interventional cardiology at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology, he felt compelled to offer a cautionary note about his past accuracy as a prognosticator.
It was way back at a poster session during the 1976 annual meeting of the American Heart Association in Miami Beach that he first met Andreas Gruentzig, MD, the father of percutaneous coronary intervention (PCI), who was presenting his initial revolutionary work on what he called “coronary transluminal angioplasty” in dogs.
“I looked at the poster and told him it would never work,” recalled Dr. King, professor emeritus of medicine at Emory University in Atlanta.
He soon changed his mind, however, because, to great acclaim, Dr. Gruentzig performed his successful first in-human coronary angioplasty the next year.
He noted that the Snowmass conference has played a significant role in the development of interventional cardiology in the United States. Dr. Gruentzig attended the conference in 1980, and Dr. King and others took that opportunity to persuade him to leave the bureaucratic confines of Zurich and join him at Emory later that year. The two cardiologists worked closely thereafter, refining angioplasty and conducting clinical trials until Dr. Gruentzig’s death in an airplane crash in Georgia in 1985 at age 46 years.
Turning to the future, Dr. King addressed a number of recent developments in interventional cardiology and rated their chances of significantly improving outcomes in patients with stable ischemic heart disease. He graded the innovations’ potential with use of a four-bar schema, akin to the WiFi signal power rating on a cell phone.
Noninvasive diagnostics to assess anatomy and physiology
“I think coronary CT angiography [CTA] will become the new diagnostic angiogram,” he predicted. “CTA has gotten much better. Outside the United States, in Europe and particularly in Japan and increasingly in China, CTA is becoming extremely common.”
Dr. King cited a recent multicenter study of blinded heart team treatment decision making on the basis of either CTA or conventional invasive angiography in 223 patients with left main or triple-vessel coronary artery disease (CAD). The level of agreement was impressively high: Coronary artery bypass grafting (CABG) was recommended for 28% of patients on the basis of CTA and 26% with conventional angiography, which suggests the feasibility of treatment decision making based solely on noninvasive imaging, history, and clinical examination (Eur Heart J. 2018 Nov 1;39[41]:3689-98).
“The other thing I like about the potential for noninvasive imaging to guide our interventions is that it may [replace] the diagnostic angiogram, which has largely become extinct,” the cardiologist continued. “If you think about it, patients are referred for an angiogram, and as far as informed consent is concerned, the patient is told to pack his bags, go off to some other city, get in the cath lab, and take the family because of what they might do to you. They might put stents in you, they might operate on you. We don’t have any idea because we don’t know what you have. And the patient has to buy into this. With CTA, the potential is there for people to actually know what you’re going to do to them before you do it.”
Coronary artery calcium scoring for primary risk assessment has taken on a prominent role in the latest practice guidelines. “I think it’s mostly helpful in getting people out of the system because they don’t have any calcium,” in Dr. King’s view.
PET and MRI will remain secondary noninvasive technologies. They will be used mostly to diagnose microvascular disease, but that’s information that doesn’t have much influence on whether interventional procedures are performed.
Overall, he gave noninvasive diagnostic tools high marks for their potential to improve outcomes in patients with stable ischemic heart disease.
“I give it a pretty robust three bars. Maybe you could give it four,” he said.
New pharmacologic therapies
Citing in particular the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. King declared, “It may be that the biggest, newest device in interventional cardiology going forward is not a device at all, it’s medical therapy.”
Interventional cardiologists either need to become expert in advanced medical therapies or else have access to someone in their group who prescribes those medications deftly.
“The future care of our patients will require more than percutaneous coronary intervention,” he emphasized.
So, four bars for the new medical therapies.
PCI and coronary artery bypass surgery
Both get one bar.
“PCI will be a partner of advanced antiatherosclerotic therapies, but will not be replaced by limiting antianginal therapy to medical treatment only,” Dr. King predicted.
Regarding CABG, he highlighted a recent systematic review and pooled analysis of 11,518 patients with stable ischemic heart disease randomized to CABG or PCI using drug-eluting or bare-metal stents in 11 clinical trials. CABG demonstrated a significant mortality benefit over PCI in patients with multivessel disease, particularly among those with diabetes or a higher degree of coronary disease complexity. However, there was no benefit in terms of 5-year all-cause mortality for CABG over PCI in those with left main disease (Lancet. 2018 Mar 10;391[10124]:9399-48).
“CABG will not go away. I predict that about 25% of revascularizations will continue to be done by surgery,” the cardiologist said. “For patients who can have complete revascularization by PCI, it’ll be done with advanced technology, but probably only by a subset of operators. We have a huge number of interventional cardiologists in this country, and some of them do a lot of these kinds of cases and some don’t.”
Endovascular imaging to optimize stent deployment and characterize plaque
Studies suggest that the use of intravascular ultrasound and other endovascular imaging technologies ends up providing better results than when they’re not employed.
“We see greatly increased use of IVUS [intravascular ultrasound], and not so much of optical coherence tomography, because of technical problems. So I give this at least two bars as far as moving practice forward,” according to Dr. King.
Bioresorbable scaffolds
This technology, which he noted “was supposed to solve all of our problems,” has tripped and fallen because of its associated increased risk of scaffold thrombosis. He cited a recent network meta-analysis of 91 randomized, controlled trials comparing bioresorbable scaffolds to current-generation metallic drug-eluting stents in more than 105,000 patients. The bioresorbable scaffolds had a significantly higher rate of scaffold thrombosis in the first 30 days after implantation, as well as from 31 days through 1 year and also beyond 1 year. In fact, there was a rising trend for scaffold thrombosis in the bioresorbable device group after the 1 year mark through a mean 3.7 years of follow-up (EuroIntervention. 2018 Mar 20;13[16]:1904-13).
“The overall impact of bioresorbable scaffolds has been nil. We don’t have them. Bioresorbable scaffolds may become noninferior to the best metal stents, but to become mainstream, they should show superiority,” the cardiologist said.
One bar, based on the uncertain possibility that new bioresorbable scaffolds now in early stages of development ultimately pan out.
Future training needs
PCI operator volumes are low, and that raises a host of issues regarding future training needs. Should fewer interventionalists be trained? Should training in endovascular imaging be a mandatory part of PCI training? Should interventional cardiology be divided into distinct coronary, structural heart, and peripheral vascular subspecialty domains involving different people, a change that is already informally underway in many places? How are operators who are interested in becoming experts in PCI for chronic total occlusion, diffuse disease, left main disease, or other complex cases going to get enough experience to be able to concentrate in those areas?
These are questions that will need to be addressed in the coming years. The answers will surely affect the delivery of interventional cardiology care.
Dr. King reported having no financial conflicts regarding his presentation.
SOURCE: King SB.
SNOWMASS, COLO. – When Spencer B. King III, MD, shared his thoughts about the future of interventional cardiology at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology, he felt compelled to offer a cautionary note about his past accuracy as a prognosticator.
It was way back at a poster session during the 1976 annual meeting of the American Heart Association in Miami Beach that he first met Andreas Gruentzig, MD, the father of percutaneous coronary intervention (PCI), who was presenting his initial revolutionary work on what he called “coronary transluminal angioplasty” in dogs.
“I looked at the poster and told him it would never work,” recalled Dr. King, professor emeritus of medicine at Emory University in Atlanta.
He soon changed his mind, however, because, to great acclaim, Dr. Gruentzig performed his successful first in-human coronary angioplasty the next year.
He noted that the Snowmass conference has played a significant role in the development of interventional cardiology in the United States. Dr. Gruentzig attended the conference in 1980, and Dr. King and others took that opportunity to persuade him to leave the bureaucratic confines of Zurich and join him at Emory later that year. The two cardiologists worked closely thereafter, refining angioplasty and conducting clinical trials until Dr. Gruentzig’s death in an airplane crash in Georgia in 1985 at age 46 years.
Turning to the future, Dr. King addressed a number of recent developments in interventional cardiology and rated their chances of significantly improving outcomes in patients with stable ischemic heart disease. He graded the innovations’ potential with use of a four-bar schema, akin to the WiFi signal power rating on a cell phone.
Noninvasive diagnostics to assess anatomy and physiology
“I think coronary CT angiography [CTA] will become the new diagnostic angiogram,” he predicted. “CTA has gotten much better. Outside the United States, in Europe and particularly in Japan and increasingly in China, CTA is becoming extremely common.”
Dr. King cited a recent multicenter study of blinded heart team treatment decision making on the basis of either CTA or conventional invasive angiography in 223 patients with left main or triple-vessel coronary artery disease (CAD). The level of agreement was impressively high: Coronary artery bypass grafting (CABG) was recommended for 28% of patients on the basis of CTA and 26% with conventional angiography, which suggests the feasibility of treatment decision making based solely on noninvasive imaging, history, and clinical examination (Eur Heart J. 2018 Nov 1;39[41]:3689-98).
“The other thing I like about the potential for noninvasive imaging to guide our interventions is that it may [replace] the diagnostic angiogram, which has largely become extinct,” the cardiologist continued. “If you think about it, patients are referred for an angiogram, and as far as informed consent is concerned, the patient is told to pack his bags, go off to some other city, get in the cath lab, and take the family because of what they might do to you. They might put stents in you, they might operate on you. We don’t have any idea because we don’t know what you have. And the patient has to buy into this. With CTA, the potential is there for people to actually know what you’re going to do to them before you do it.”
Coronary artery calcium scoring for primary risk assessment has taken on a prominent role in the latest practice guidelines. “I think it’s mostly helpful in getting people out of the system because they don’t have any calcium,” in Dr. King’s view.
PET and MRI will remain secondary noninvasive technologies. They will be used mostly to diagnose microvascular disease, but that’s information that doesn’t have much influence on whether interventional procedures are performed.
Overall, he gave noninvasive diagnostic tools high marks for their potential to improve outcomes in patients with stable ischemic heart disease.
“I give it a pretty robust three bars. Maybe you could give it four,” he said.
New pharmacologic therapies
Citing in particular the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. King declared, “It may be that the biggest, newest device in interventional cardiology going forward is not a device at all, it’s medical therapy.”
Interventional cardiologists either need to become expert in advanced medical therapies or else have access to someone in their group who prescribes those medications deftly.
“The future care of our patients will require more than percutaneous coronary intervention,” he emphasized.
So, four bars for the new medical therapies.
PCI and coronary artery bypass surgery
Both get one bar.
“PCI will be a partner of advanced antiatherosclerotic therapies, but will not be replaced by limiting antianginal therapy to medical treatment only,” Dr. King predicted.
Regarding CABG, he highlighted a recent systematic review and pooled analysis of 11,518 patients with stable ischemic heart disease randomized to CABG or PCI using drug-eluting or bare-metal stents in 11 clinical trials. CABG demonstrated a significant mortality benefit over PCI in patients with multivessel disease, particularly among those with diabetes or a higher degree of coronary disease complexity. However, there was no benefit in terms of 5-year all-cause mortality for CABG over PCI in those with left main disease (Lancet. 2018 Mar 10;391[10124]:9399-48).
“CABG will not go away. I predict that about 25% of revascularizations will continue to be done by surgery,” the cardiologist said. “For patients who can have complete revascularization by PCI, it’ll be done with advanced technology, but probably only by a subset of operators. We have a huge number of interventional cardiologists in this country, and some of them do a lot of these kinds of cases and some don’t.”
Endovascular imaging to optimize stent deployment and characterize plaque
Studies suggest that the use of intravascular ultrasound and other endovascular imaging technologies ends up providing better results than when they’re not employed.
“We see greatly increased use of IVUS [intravascular ultrasound], and not so much of optical coherence tomography, because of technical problems. So I give this at least two bars as far as moving practice forward,” according to Dr. King.
Bioresorbable scaffolds
This technology, which he noted “was supposed to solve all of our problems,” has tripped and fallen because of its associated increased risk of scaffold thrombosis. He cited a recent network meta-analysis of 91 randomized, controlled trials comparing bioresorbable scaffolds to current-generation metallic drug-eluting stents in more than 105,000 patients. The bioresorbable scaffolds had a significantly higher rate of scaffold thrombosis in the first 30 days after implantation, as well as from 31 days through 1 year and also beyond 1 year. In fact, there was a rising trend for scaffold thrombosis in the bioresorbable device group after the 1 year mark through a mean 3.7 years of follow-up (EuroIntervention. 2018 Mar 20;13[16]:1904-13).
“The overall impact of bioresorbable scaffolds has been nil. We don’t have them. Bioresorbable scaffolds may become noninferior to the best metal stents, but to become mainstream, they should show superiority,” the cardiologist said.
One bar, based on the uncertain possibility that new bioresorbable scaffolds now in early stages of development ultimately pan out.
Future training needs
PCI operator volumes are low, and that raises a host of issues regarding future training needs. Should fewer interventionalists be trained? Should training in endovascular imaging be a mandatory part of PCI training? Should interventional cardiology be divided into distinct coronary, structural heart, and peripheral vascular subspecialty domains involving different people, a change that is already informally underway in many places? How are operators who are interested in becoming experts in PCI for chronic total occlusion, diffuse disease, left main disease, or other complex cases going to get enough experience to be able to concentrate in those areas?
These are questions that will need to be addressed in the coming years. The answers will surely affect the delivery of interventional cardiology care.
Dr. King reported having no financial conflicts regarding his presentation.
SOURCE: King SB.
SNOWMASS, COLO. – When Spencer B. King III, MD, shared his thoughts about the future of interventional cardiology at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology, he felt compelled to offer a cautionary note about his past accuracy as a prognosticator.
It was way back at a poster session during the 1976 annual meeting of the American Heart Association in Miami Beach that he first met Andreas Gruentzig, MD, the father of percutaneous coronary intervention (PCI), who was presenting his initial revolutionary work on what he called “coronary transluminal angioplasty” in dogs.
“I looked at the poster and told him it would never work,” recalled Dr. King, professor emeritus of medicine at Emory University in Atlanta.
He soon changed his mind, however, because, to great acclaim, Dr. Gruentzig performed his successful first in-human coronary angioplasty the next year.
He noted that the Snowmass conference has played a significant role in the development of interventional cardiology in the United States. Dr. Gruentzig attended the conference in 1980, and Dr. King and others took that opportunity to persuade him to leave the bureaucratic confines of Zurich and join him at Emory later that year. The two cardiologists worked closely thereafter, refining angioplasty and conducting clinical trials until Dr. Gruentzig’s death in an airplane crash in Georgia in 1985 at age 46 years.
Turning to the future, Dr. King addressed a number of recent developments in interventional cardiology and rated their chances of significantly improving outcomes in patients with stable ischemic heart disease. He graded the innovations’ potential with use of a four-bar schema, akin to the WiFi signal power rating on a cell phone.
Noninvasive diagnostics to assess anatomy and physiology
“I think coronary CT angiography [CTA] will become the new diagnostic angiogram,” he predicted. “CTA has gotten much better. Outside the United States, in Europe and particularly in Japan and increasingly in China, CTA is becoming extremely common.”
Dr. King cited a recent multicenter study of blinded heart team treatment decision making on the basis of either CTA or conventional invasive angiography in 223 patients with left main or triple-vessel coronary artery disease (CAD). The level of agreement was impressively high: Coronary artery bypass grafting (CABG) was recommended for 28% of patients on the basis of CTA and 26% with conventional angiography, which suggests the feasibility of treatment decision making based solely on noninvasive imaging, history, and clinical examination (Eur Heart J. 2018 Nov 1;39[41]:3689-98).
“The other thing I like about the potential for noninvasive imaging to guide our interventions is that it may [replace] the diagnostic angiogram, which has largely become extinct,” the cardiologist continued. “If you think about it, patients are referred for an angiogram, and as far as informed consent is concerned, the patient is told to pack his bags, go off to some other city, get in the cath lab, and take the family because of what they might do to you. They might put stents in you, they might operate on you. We don’t have any idea because we don’t know what you have. And the patient has to buy into this. With CTA, the potential is there for people to actually know what you’re going to do to them before you do it.”
Coronary artery calcium scoring for primary risk assessment has taken on a prominent role in the latest practice guidelines. “I think it’s mostly helpful in getting people out of the system because they don’t have any calcium,” in Dr. King’s view.
PET and MRI will remain secondary noninvasive technologies. They will be used mostly to diagnose microvascular disease, but that’s information that doesn’t have much influence on whether interventional procedures are performed.
Overall, he gave noninvasive diagnostic tools high marks for their potential to improve outcomes in patients with stable ischemic heart disease.
“I give it a pretty robust three bars. Maybe you could give it four,” he said.
New pharmacologic therapies
Citing in particular the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. King declared, “It may be that the biggest, newest device in interventional cardiology going forward is not a device at all, it’s medical therapy.”
Interventional cardiologists either need to become expert in advanced medical therapies or else have access to someone in their group who prescribes those medications deftly.
“The future care of our patients will require more than percutaneous coronary intervention,” he emphasized.
So, four bars for the new medical therapies.
PCI and coronary artery bypass surgery
Both get one bar.
“PCI will be a partner of advanced antiatherosclerotic therapies, but will not be replaced by limiting antianginal therapy to medical treatment only,” Dr. King predicted.
Regarding CABG, he highlighted a recent systematic review and pooled analysis of 11,518 patients with stable ischemic heart disease randomized to CABG or PCI using drug-eluting or bare-metal stents in 11 clinical trials. CABG demonstrated a significant mortality benefit over PCI in patients with multivessel disease, particularly among those with diabetes or a higher degree of coronary disease complexity. However, there was no benefit in terms of 5-year all-cause mortality for CABG over PCI in those with left main disease (Lancet. 2018 Mar 10;391[10124]:9399-48).
“CABG will not go away. I predict that about 25% of revascularizations will continue to be done by surgery,” the cardiologist said. “For patients who can have complete revascularization by PCI, it’ll be done with advanced technology, but probably only by a subset of operators. We have a huge number of interventional cardiologists in this country, and some of them do a lot of these kinds of cases and some don’t.”
Endovascular imaging to optimize stent deployment and characterize plaque
Studies suggest that the use of intravascular ultrasound and other endovascular imaging technologies ends up providing better results than when they’re not employed.
“We see greatly increased use of IVUS [intravascular ultrasound], and not so much of optical coherence tomography, because of technical problems. So I give this at least two bars as far as moving practice forward,” according to Dr. King.
Bioresorbable scaffolds
This technology, which he noted “was supposed to solve all of our problems,” has tripped and fallen because of its associated increased risk of scaffold thrombosis. He cited a recent network meta-analysis of 91 randomized, controlled trials comparing bioresorbable scaffolds to current-generation metallic drug-eluting stents in more than 105,000 patients. The bioresorbable scaffolds had a significantly higher rate of scaffold thrombosis in the first 30 days after implantation, as well as from 31 days through 1 year and also beyond 1 year. In fact, there was a rising trend for scaffold thrombosis in the bioresorbable device group after the 1 year mark through a mean 3.7 years of follow-up (EuroIntervention. 2018 Mar 20;13[16]:1904-13).
“The overall impact of bioresorbable scaffolds has been nil. We don’t have them. Bioresorbable scaffolds may become noninferior to the best metal stents, but to become mainstream, they should show superiority,” the cardiologist said.
One bar, based on the uncertain possibility that new bioresorbable scaffolds now in early stages of development ultimately pan out.
Future training needs
PCI operator volumes are low, and that raises a host of issues regarding future training needs. Should fewer interventionalists be trained? Should training in endovascular imaging be a mandatory part of PCI training? Should interventional cardiology be divided into distinct coronary, structural heart, and peripheral vascular subspecialty domains involving different people, a change that is already informally underway in many places? How are operators who are interested in becoming experts in PCI for chronic total occlusion, diffuse disease, left main disease, or other complex cases going to get enough experience to be able to concentrate in those areas?
These are questions that will need to be addressed in the coming years. The answers will surely affect the delivery of interventional cardiology care.
Dr. King reported having no financial conflicts regarding his presentation.
SOURCE: King SB.
EXPERT ANALYSIS FROM ACC SNOWMASS 2019
MI, strokes spike during 30 days after cancer diagnosis
HONOLULU – During the first month after a new cancer diagnosis, patients face a substantially elevated risk for an arterial thromboembolic event – an MI or stroke – consistent with the well-described increased risk newly diagnosed cancer patients face from venous thromboembolism, based on findings from a prospective study of more than 4,000 people.
In the new study, 836 patients newly diagnosed with cancer had a 480% increased rate of a fatal or nonfatal MI or stroke during the 30 days following their diagnosis, compared with 3,339 matched people without cancer and after adjustment for baseline differences in demographics and cardiovascular risk factors, Babak B. Navi, MD, said while presenting a poster at the International Stroke Conference sponsored by the American Heart Association.
An additional analysis that focused on 210 of the 836 patients with incident cancer who had any of seven of the cancers known to pose the highest venous thromboembolism risk (lymphoma; gynecologic cancer; or cancer of the pancreas, stomach, lung, bladder, or testes) showed an 1,750% greater rate of incident MI or stroke during the first 30 days after diagnosis, compared with matched people without cancer, reported Dr. Navi, chief of the stroke and hospital neurology at Weill Cornell Medicine, New York.
In contrast, during both the period 1-3 months after the cancer diagnosis and more than 3 months after, the rate of MI or stroke among recently diagnosed cancer patients was not significantly different from the rate in comparator individuals, although the data showed modest trends toward more arterial thromboembolic events after a month, and the lack of statistically significant differences may have been a power issue, Dr. Navi suggested.
The reasons for this acutely increased risk for arterial thromboembolic events, as well as the early spike in venous thromboembolic events, are not completely clear, but they likely result from factors released by tumors, effects from the drugs that patients receive for cancer treatment, stress, and interruption of antithrombotic treatment. Dr. Navi fingered cancer-induced hypercoagulability as likely the biggest culprit. It may now be reasonable to test the idea of treating newly diagnosed cancer patients with agents that could reduce their risk for MI or stroke, such as aspirin or a statin, he said in an interview.
The new analysis used data collected in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, which during 2003-2007 enrolled more than 30,000 U.S. residents who were at least 45 years old. Dr. Navi and his associates used data collected from all REGARDS participants who developed incident cancer and had continuous Medicare coverage for at least 1 year before entering REGARDS, excluding those with cancer before enrollment. They used the Medicare records to identify the cancer diagnoses, and matched each of these people with four similar but cancer-free people enrolled in the study. Follow-up continued through September 2015. The average age of this REGARDS subgroup at enrollment was 72 years old, and nearly half were women. The incident cancers included 640 patients with a solid tumor, 71 with hematologic cancers, 13 with brain tumors, and 112 with an unknown primary cancer site.
Dr. Navi and his associates designed this study to validate previously reported findings of increased arterial thromboembolic events in newly diagnosed cancer patients from studies of insurance claims databases. Although the increased risk for venous thromboembolism in cancer patients is already well established, documenting a similar risk for arterial events is important because they are “generally more impactful for patients than venous thromboembolism,” Dr. Navi said.
REGARDS has received no commercial funding. Dr. Navi reported no disclosures.
SOURCE: Navi BB et al. Stroke. 2019 Feb;50(Suppl_1): Abstract WMP53.
HONOLULU – During the first month after a new cancer diagnosis, patients face a substantially elevated risk for an arterial thromboembolic event – an MI or stroke – consistent with the well-described increased risk newly diagnosed cancer patients face from venous thromboembolism, based on findings from a prospective study of more than 4,000 people.
In the new study, 836 patients newly diagnosed with cancer had a 480% increased rate of a fatal or nonfatal MI or stroke during the 30 days following their diagnosis, compared with 3,339 matched people without cancer and after adjustment for baseline differences in demographics and cardiovascular risk factors, Babak B. Navi, MD, said while presenting a poster at the International Stroke Conference sponsored by the American Heart Association.
An additional analysis that focused on 210 of the 836 patients with incident cancer who had any of seven of the cancers known to pose the highest venous thromboembolism risk (lymphoma; gynecologic cancer; or cancer of the pancreas, stomach, lung, bladder, or testes) showed an 1,750% greater rate of incident MI or stroke during the first 30 days after diagnosis, compared with matched people without cancer, reported Dr. Navi, chief of the stroke and hospital neurology at Weill Cornell Medicine, New York.
In contrast, during both the period 1-3 months after the cancer diagnosis and more than 3 months after, the rate of MI or stroke among recently diagnosed cancer patients was not significantly different from the rate in comparator individuals, although the data showed modest trends toward more arterial thromboembolic events after a month, and the lack of statistically significant differences may have been a power issue, Dr. Navi suggested.
The reasons for this acutely increased risk for arterial thromboembolic events, as well as the early spike in venous thromboembolic events, are not completely clear, but they likely result from factors released by tumors, effects from the drugs that patients receive for cancer treatment, stress, and interruption of antithrombotic treatment. Dr. Navi fingered cancer-induced hypercoagulability as likely the biggest culprit. It may now be reasonable to test the idea of treating newly diagnosed cancer patients with agents that could reduce their risk for MI or stroke, such as aspirin or a statin, he said in an interview.
The new analysis used data collected in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, which during 2003-2007 enrolled more than 30,000 U.S. residents who were at least 45 years old. Dr. Navi and his associates used data collected from all REGARDS participants who developed incident cancer and had continuous Medicare coverage for at least 1 year before entering REGARDS, excluding those with cancer before enrollment. They used the Medicare records to identify the cancer diagnoses, and matched each of these people with four similar but cancer-free people enrolled in the study. Follow-up continued through September 2015. The average age of this REGARDS subgroup at enrollment was 72 years old, and nearly half were women. The incident cancers included 640 patients with a solid tumor, 71 with hematologic cancers, 13 with brain tumors, and 112 with an unknown primary cancer site.
Dr. Navi and his associates designed this study to validate previously reported findings of increased arterial thromboembolic events in newly diagnosed cancer patients from studies of insurance claims databases. Although the increased risk for venous thromboembolism in cancer patients is already well established, documenting a similar risk for arterial events is important because they are “generally more impactful for patients than venous thromboembolism,” Dr. Navi said.
REGARDS has received no commercial funding. Dr. Navi reported no disclosures.
SOURCE: Navi BB et al. Stroke. 2019 Feb;50(Suppl_1): Abstract WMP53.
HONOLULU – During the first month after a new cancer diagnosis, patients face a substantially elevated risk for an arterial thromboembolic event – an MI or stroke – consistent with the well-described increased risk newly diagnosed cancer patients face from venous thromboembolism, based on findings from a prospective study of more than 4,000 people.
In the new study, 836 patients newly diagnosed with cancer had a 480% increased rate of a fatal or nonfatal MI or stroke during the 30 days following their diagnosis, compared with 3,339 matched people without cancer and after adjustment for baseline differences in demographics and cardiovascular risk factors, Babak B. Navi, MD, said while presenting a poster at the International Stroke Conference sponsored by the American Heart Association.
An additional analysis that focused on 210 of the 836 patients with incident cancer who had any of seven of the cancers known to pose the highest venous thromboembolism risk (lymphoma; gynecologic cancer; or cancer of the pancreas, stomach, lung, bladder, or testes) showed an 1,750% greater rate of incident MI or stroke during the first 30 days after diagnosis, compared with matched people without cancer, reported Dr. Navi, chief of the stroke and hospital neurology at Weill Cornell Medicine, New York.
In contrast, during both the period 1-3 months after the cancer diagnosis and more than 3 months after, the rate of MI or stroke among recently diagnosed cancer patients was not significantly different from the rate in comparator individuals, although the data showed modest trends toward more arterial thromboembolic events after a month, and the lack of statistically significant differences may have been a power issue, Dr. Navi suggested.
The reasons for this acutely increased risk for arterial thromboembolic events, as well as the early spike in venous thromboembolic events, are not completely clear, but they likely result from factors released by tumors, effects from the drugs that patients receive for cancer treatment, stress, and interruption of antithrombotic treatment. Dr. Navi fingered cancer-induced hypercoagulability as likely the biggest culprit. It may now be reasonable to test the idea of treating newly diagnosed cancer patients with agents that could reduce their risk for MI or stroke, such as aspirin or a statin, he said in an interview.
The new analysis used data collected in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, which during 2003-2007 enrolled more than 30,000 U.S. residents who were at least 45 years old. Dr. Navi and his associates used data collected from all REGARDS participants who developed incident cancer and had continuous Medicare coverage for at least 1 year before entering REGARDS, excluding those with cancer before enrollment. They used the Medicare records to identify the cancer diagnoses, and matched each of these people with four similar but cancer-free people enrolled in the study. Follow-up continued through September 2015. The average age of this REGARDS subgroup at enrollment was 72 years old, and nearly half were women. The incident cancers included 640 patients with a solid tumor, 71 with hematologic cancers, 13 with brain tumors, and 112 with an unknown primary cancer site.
Dr. Navi and his associates designed this study to validate previously reported findings of increased arterial thromboembolic events in newly diagnosed cancer patients from studies of insurance claims databases. Although the increased risk for venous thromboembolism in cancer patients is already well established, documenting a similar risk for arterial events is important because they are “generally more impactful for patients than venous thromboembolism,” Dr. Navi said.
REGARDS has received no commercial funding. Dr. Navi reported no disclosures.
SOURCE: Navi BB et al. Stroke. 2019 Feb;50(Suppl_1): Abstract WMP53.
REPORTING FROM ISC 2019
Higher blood pressure after thrombectomy links with bad stroke outcomes
HONOLULU – Acute ischemic stroke patients who underwent endovascular thrombectomy and then had a peak systolic blood pressure of greater than 158 mm Hg during the next 24 hours had worse 90-day outcomes than did patients whose peak systolic pressure remained at or below 158 mm Hg in a prospective, multicenter, observational study with 485 patients.
The results hint that maintaining a lower systolic blood pressure after thrombectomy in acute ischemic stroke patients may improve outcomes, but because the current study was observational, the hypothesis that patients benefit when treatment keeps their systolic pressure at or below 158 mm Hg must undergo testing in a prospective, randomized trial, Eva A. Mistry, MBBS, said at the International Stroke Conference, sponsored by the American Heart Association.
The finding from this study that 158 mm Hg provided the best dichotomous division between systolic blood pressures linked with good or bad outcomes is a first step toward trying to devise a more systematic and evidence-based approach to blood pressure management in acute ischemic stroke patients following endovascular thrombectomy, said Dr. Mistry, a neurologist at Vanderbilt University in Nashville, Tenn.
Neither Vanderbilt nor any of the other 11 major U.S. stroke centers that participated in the current study currently have an established protocol for blood pressure management after thrombectomy, Dr. Mistry said in an interview.
“We usually treat to reduce blood pressure, but we don’t have a [broadly agreed on] threshold” to trigger treatment. “It depends on a collective decision” by the various medical specialists who care for an individual acute stroke patient. In addition, no consensus yet exists for the best treatment strategy for blood pressure lowering in acute ischemic stroke patients. Intravenous nicardipine is often the top choice because it is fast-acting and easy to administer and control as an intravenous agent. Those same properties make the beta blocker labetalol a frequently used second drug, she said.
The BEST (Blood Pressure After Endovascular Stroke Therapy) study ran at 12 U.S. centers and enrolled 485 patients who underwent endovascular thrombectomy to treat an acute ischemic stroke. The patients averaged 69 years old, and 48% also underwent thrombolytic treatment. The study’s primary outcome was the percentage of patients with a modified Rankin Scale score of 0-2 at 90 days after their stroke, an outcome reached by 39% of all patients in the study.
Statistical analysis of the collected data showed that a peak systolic blood pressure of 158 mm Hg reached during the 24 hours following thrombectomy best divided patients with good 90-day outcomes from those with worse outcomes. Patients with a postthrombectomy peak systolic pressure above 158 mm Hg had a 2.2-fold increased rate of having a modified Rankin Scale score of 3 or higher after 90 days, a statistically significant relationship, Dr. Mistry reported. However, in an analysis that also adjusted for age, baseline stroke severity, glucose level, time to reperfusion, ASPECTS score, history of hypertension, and recanalization status, the elevated risk for a bad outcome linked with higher systolic pressure dropped to 39% greater than that for patients with systolic pressures that did not rise above 158 mm Hg, a difference that was not statistically significant. This suggests that these adjustments were unable to account for all confounders and further highlighted the need for a prospective, randomized trial to test the value of controlling blood pressure following thrombectomy, Dr. Mistry said. The unadjusted results confirmed a prior report from Dr. Mistry and her associates that found a link between higher blood pressure after stroke thrombectomy and worse outcomes (J Am Heart Assoc. 2017 May 18. doi: 10.1161/JAHA.117.006167).
The analysis also showed that patients who were successfully recanalized by thrombectomy, achieving a thrombolysis in cerebral infarction (TICI) score of 2b or 3, had lower peak systolic blood pressures than did patients who failed to get this level of restored cerebral blood flow from thrombectomy.
BEST received no commercial funding. Dr. Mistry had no disclosures.
SOURCE: Mistry EA et al. Stroke. 2019 Feb;50(Suppl_1): Abstract 94.
HONOLULU – Acute ischemic stroke patients who underwent endovascular thrombectomy and then had a peak systolic blood pressure of greater than 158 mm Hg during the next 24 hours had worse 90-day outcomes than did patients whose peak systolic pressure remained at or below 158 mm Hg in a prospective, multicenter, observational study with 485 patients.
The results hint that maintaining a lower systolic blood pressure after thrombectomy in acute ischemic stroke patients may improve outcomes, but because the current study was observational, the hypothesis that patients benefit when treatment keeps their systolic pressure at or below 158 mm Hg must undergo testing in a prospective, randomized trial, Eva A. Mistry, MBBS, said at the International Stroke Conference, sponsored by the American Heart Association.
The finding from this study that 158 mm Hg provided the best dichotomous division between systolic blood pressures linked with good or bad outcomes is a first step toward trying to devise a more systematic and evidence-based approach to blood pressure management in acute ischemic stroke patients following endovascular thrombectomy, said Dr. Mistry, a neurologist at Vanderbilt University in Nashville, Tenn.
Neither Vanderbilt nor any of the other 11 major U.S. stroke centers that participated in the current study currently have an established protocol for blood pressure management after thrombectomy, Dr. Mistry said in an interview.
“We usually treat to reduce blood pressure, but we don’t have a [broadly agreed on] threshold” to trigger treatment. “It depends on a collective decision” by the various medical specialists who care for an individual acute stroke patient. In addition, no consensus yet exists for the best treatment strategy for blood pressure lowering in acute ischemic stroke patients. Intravenous nicardipine is often the top choice because it is fast-acting and easy to administer and control as an intravenous agent. Those same properties make the beta blocker labetalol a frequently used second drug, she said.
The BEST (Blood Pressure After Endovascular Stroke Therapy) study ran at 12 U.S. centers and enrolled 485 patients who underwent endovascular thrombectomy to treat an acute ischemic stroke. The patients averaged 69 years old, and 48% also underwent thrombolytic treatment. The study’s primary outcome was the percentage of patients with a modified Rankin Scale score of 0-2 at 90 days after their stroke, an outcome reached by 39% of all patients in the study.
Statistical analysis of the collected data showed that a peak systolic blood pressure of 158 mm Hg reached during the 24 hours following thrombectomy best divided patients with good 90-day outcomes from those with worse outcomes. Patients with a postthrombectomy peak systolic pressure above 158 mm Hg had a 2.2-fold increased rate of having a modified Rankin Scale score of 3 or higher after 90 days, a statistically significant relationship, Dr. Mistry reported. However, in an analysis that also adjusted for age, baseline stroke severity, glucose level, time to reperfusion, ASPECTS score, history of hypertension, and recanalization status, the elevated risk for a bad outcome linked with higher systolic pressure dropped to 39% greater than that for patients with systolic pressures that did not rise above 158 mm Hg, a difference that was not statistically significant. This suggests that these adjustments were unable to account for all confounders and further highlighted the need for a prospective, randomized trial to test the value of controlling blood pressure following thrombectomy, Dr. Mistry said. The unadjusted results confirmed a prior report from Dr. Mistry and her associates that found a link between higher blood pressure after stroke thrombectomy and worse outcomes (J Am Heart Assoc. 2017 May 18. doi: 10.1161/JAHA.117.006167).
The analysis also showed that patients who were successfully recanalized by thrombectomy, achieving a thrombolysis in cerebral infarction (TICI) score of 2b or 3, had lower peak systolic blood pressures than did patients who failed to get this level of restored cerebral blood flow from thrombectomy.
BEST received no commercial funding. Dr. Mistry had no disclosures.
SOURCE: Mistry EA et al. Stroke. 2019 Feb;50(Suppl_1): Abstract 94.
HONOLULU – Acute ischemic stroke patients who underwent endovascular thrombectomy and then had a peak systolic blood pressure of greater than 158 mm Hg during the next 24 hours had worse 90-day outcomes than did patients whose peak systolic pressure remained at or below 158 mm Hg in a prospective, multicenter, observational study with 485 patients.
The results hint that maintaining a lower systolic blood pressure after thrombectomy in acute ischemic stroke patients may improve outcomes, but because the current study was observational, the hypothesis that patients benefit when treatment keeps their systolic pressure at or below 158 mm Hg must undergo testing in a prospective, randomized trial, Eva A. Mistry, MBBS, said at the International Stroke Conference, sponsored by the American Heart Association.
The finding from this study that 158 mm Hg provided the best dichotomous division between systolic blood pressures linked with good or bad outcomes is a first step toward trying to devise a more systematic and evidence-based approach to blood pressure management in acute ischemic stroke patients following endovascular thrombectomy, said Dr. Mistry, a neurologist at Vanderbilt University in Nashville, Tenn.
Neither Vanderbilt nor any of the other 11 major U.S. stroke centers that participated in the current study currently have an established protocol for blood pressure management after thrombectomy, Dr. Mistry said in an interview.
“We usually treat to reduce blood pressure, but we don’t have a [broadly agreed on] threshold” to trigger treatment. “It depends on a collective decision” by the various medical specialists who care for an individual acute stroke patient. In addition, no consensus yet exists for the best treatment strategy for blood pressure lowering in acute ischemic stroke patients. Intravenous nicardipine is often the top choice because it is fast-acting and easy to administer and control as an intravenous agent. Those same properties make the beta blocker labetalol a frequently used second drug, she said.
The BEST (Blood Pressure After Endovascular Stroke Therapy) study ran at 12 U.S. centers and enrolled 485 patients who underwent endovascular thrombectomy to treat an acute ischemic stroke. The patients averaged 69 years old, and 48% also underwent thrombolytic treatment. The study’s primary outcome was the percentage of patients with a modified Rankin Scale score of 0-2 at 90 days after their stroke, an outcome reached by 39% of all patients in the study.
Statistical analysis of the collected data showed that a peak systolic blood pressure of 158 mm Hg reached during the 24 hours following thrombectomy best divided patients with good 90-day outcomes from those with worse outcomes. Patients with a postthrombectomy peak systolic pressure above 158 mm Hg had a 2.2-fold increased rate of having a modified Rankin Scale score of 3 or higher after 90 days, a statistically significant relationship, Dr. Mistry reported. However, in an analysis that also adjusted for age, baseline stroke severity, glucose level, time to reperfusion, ASPECTS score, history of hypertension, and recanalization status, the elevated risk for a bad outcome linked with higher systolic pressure dropped to 39% greater than that for patients with systolic pressures that did not rise above 158 mm Hg, a difference that was not statistically significant. This suggests that these adjustments were unable to account for all confounders and further highlighted the need for a prospective, randomized trial to test the value of controlling blood pressure following thrombectomy, Dr. Mistry said. The unadjusted results confirmed a prior report from Dr. Mistry and her associates that found a link between higher blood pressure after stroke thrombectomy and worse outcomes (J Am Heart Assoc. 2017 May 18. doi: 10.1161/JAHA.117.006167).
The analysis also showed that patients who were successfully recanalized by thrombectomy, achieving a thrombolysis in cerebral infarction (TICI) score of 2b or 3, had lower peak systolic blood pressures than did patients who failed to get this level of restored cerebral blood flow from thrombectomy.
BEST received no commercial funding. Dr. Mistry had no disclosures.
SOURCE: Mistry EA et al. Stroke. 2019 Feb;50(Suppl_1): Abstract 94.
REPORTING FROM ISC 2019
Eisenmenger syndrome is a minefield for unwary physicians
SNOWMASS, COLO. – Interventions that are simple and straightforward for other patients – such as therapeutic phlebotomy, bronchoscopy, anticoagulation, administration of IV antibiotics – can quickly have catastrophic results in patients with Eisenmenger syndrome, Carole A. Warnes, MD, cautioned at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
This is why the 2018 ACC/American Heart Association guidelines on the management of patients with adult congenital heart disease recommend as a Class I indication that most patients with ACHD, including all those with Eisenmenger syndrome, be managed in collaboration with a cardiologist at a specialized ACHD center (Circulation. 2018 Aug 16. doi: 10.1161/CIR.0000000000000603), noted Dr. Warnes, professor of medicine at the Mayo Clinic in Rochester, Minn., and director of the Snowmass conference.
“There are lots of mistakes in diagnosis and management because so many physicians are unfamiliar with the kinds of problems these patients face,” the cardiologist said.
She cited as a real-world example a patient with Eisenmenger syndrome admitted for pneumonia. Twenty minutes after being placed on intravenous antibiotics she had a stroke. Why?
“She didn’t have an air filter on her IV line. Any air going into a cyanotic’s blood stream will go to the head and give them a stroke. Something that is simple – routine for other patients – may kill a patient with cyanotic heart disease,” Dr. Warnes said.
Another illustrative case: a patient with Eisenmenger syndrome presents with hemoptysis, an infiltrate in her right lung, a hemoglobin of 19.8 g/dL, and anemia. Should she undergo therapeutic phlebotomy? How about urgent bronchoscopy?
No and no, Dr. Warnes emphasized.
“You do not phlebotomize cyanotic patients unless they have symptoms of hyperviscosity, meaning terrible headache or poor concentration, along with a hemoglobin greater than 20 g/dL. They need that high hemoglobin. They may be blue, and you need those red cells to carry the oxygen around. Otherwise you may make them worse. And if you give them iron for their anemia, you will increase their risk of stroke,” she explained.
Hemoptysis in patients with Eisenmenger syndrome is a life-threatening warning sign. By the time Eisenmenger syndrome patients reach age 40 years, nearly all of them have experienced episodes of hemoptysis. And more and more patients with the syndrome are moving well beyond that milestone and surviving into their 60s and beyond.
“Many Eisenmenger syndrome patients are not dying when they’re 20 or 30. We can get them to a good old age,” according to Dr. Warnes, who founded the ACHD center at the Mayo Clinic.
Most of the time the cause of hemoptysis in patients with Eisenmenger syndrome is an intrapulmonary hemorrhage. Anticoagulation can turn that hemorrhage catastrophic. So can bronchoscopy. Indeed, the cause of death in roughly 30% of patients with this form of congenital heart disease is catastrophic hemoptysis.
“You bar the door from your friendly pulmonologist who wants to bronchoscope these patients. Bronchoscopy never does any good unless the patient is so hypoxic that you need to suck the blood out of their lungs,” Dr. Warnes emphasized.
Anticoagulation is ordinarily to be avoided in patients with Eisenmenger syndrome because of their bleeding risk, even when pulmonary thrombosis is suspected, she added.
So, to summarize: These patients basically need stabilizing, with no anticoagulation, no bronchoscopy, and no phlebotomy, she said.
Another danger zone for patients with Eisenmenger syndrome is pregnancy. The condition is associated with a 30% maternal mortality rate.
Dr. Warnes noted that, even at the Mayo Clinic, which has had a pioneering ACHD center for decades, awareness of key elements of management of affected patients is low among nonspecialists.
“As I’ve done my hospital services in the last couple of months, I sort of felt I was on patrol, snatching these patients from problems,” she recalled.
Dr. Warnes reported having no financial conflicts regarding her presentation.
SNOWMASS, COLO. – Interventions that are simple and straightforward for other patients – such as therapeutic phlebotomy, bronchoscopy, anticoagulation, administration of IV antibiotics – can quickly have catastrophic results in patients with Eisenmenger syndrome, Carole A. Warnes, MD, cautioned at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
This is why the 2018 ACC/American Heart Association guidelines on the management of patients with adult congenital heart disease recommend as a Class I indication that most patients with ACHD, including all those with Eisenmenger syndrome, be managed in collaboration with a cardiologist at a specialized ACHD center (Circulation. 2018 Aug 16. doi: 10.1161/CIR.0000000000000603), noted Dr. Warnes, professor of medicine at the Mayo Clinic in Rochester, Minn., and director of the Snowmass conference.
“There are lots of mistakes in diagnosis and management because so many physicians are unfamiliar with the kinds of problems these patients face,” the cardiologist said.
She cited as a real-world example a patient with Eisenmenger syndrome admitted for pneumonia. Twenty minutes after being placed on intravenous antibiotics she had a stroke. Why?
“She didn’t have an air filter on her IV line. Any air going into a cyanotic’s blood stream will go to the head and give them a stroke. Something that is simple – routine for other patients – may kill a patient with cyanotic heart disease,” Dr. Warnes said.
Another illustrative case: a patient with Eisenmenger syndrome presents with hemoptysis, an infiltrate in her right lung, a hemoglobin of 19.8 g/dL, and anemia. Should she undergo therapeutic phlebotomy? How about urgent bronchoscopy?
No and no, Dr. Warnes emphasized.
“You do not phlebotomize cyanotic patients unless they have symptoms of hyperviscosity, meaning terrible headache or poor concentration, along with a hemoglobin greater than 20 g/dL. They need that high hemoglobin. They may be blue, and you need those red cells to carry the oxygen around. Otherwise you may make them worse. And if you give them iron for their anemia, you will increase their risk of stroke,” she explained.
Hemoptysis in patients with Eisenmenger syndrome is a life-threatening warning sign. By the time Eisenmenger syndrome patients reach age 40 years, nearly all of them have experienced episodes of hemoptysis. And more and more patients with the syndrome are moving well beyond that milestone and surviving into their 60s and beyond.
“Many Eisenmenger syndrome patients are not dying when they’re 20 or 30. We can get them to a good old age,” according to Dr. Warnes, who founded the ACHD center at the Mayo Clinic.
Most of the time the cause of hemoptysis in patients with Eisenmenger syndrome is an intrapulmonary hemorrhage. Anticoagulation can turn that hemorrhage catastrophic. So can bronchoscopy. Indeed, the cause of death in roughly 30% of patients with this form of congenital heart disease is catastrophic hemoptysis.
“You bar the door from your friendly pulmonologist who wants to bronchoscope these patients. Bronchoscopy never does any good unless the patient is so hypoxic that you need to suck the blood out of their lungs,” Dr. Warnes emphasized.
Anticoagulation is ordinarily to be avoided in patients with Eisenmenger syndrome because of their bleeding risk, even when pulmonary thrombosis is suspected, she added.
So, to summarize: These patients basically need stabilizing, with no anticoagulation, no bronchoscopy, and no phlebotomy, she said.
Another danger zone for patients with Eisenmenger syndrome is pregnancy. The condition is associated with a 30% maternal mortality rate.
Dr. Warnes noted that, even at the Mayo Clinic, which has had a pioneering ACHD center for decades, awareness of key elements of management of affected patients is low among nonspecialists.
“As I’ve done my hospital services in the last couple of months, I sort of felt I was on patrol, snatching these patients from problems,” she recalled.
Dr. Warnes reported having no financial conflicts regarding her presentation.
SNOWMASS, COLO. – Interventions that are simple and straightforward for other patients – such as therapeutic phlebotomy, bronchoscopy, anticoagulation, administration of IV antibiotics – can quickly have catastrophic results in patients with Eisenmenger syndrome, Carole A. Warnes, MD, cautioned at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
This is why the 2018 ACC/American Heart Association guidelines on the management of patients with adult congenital heart disease recommend as a Class I indication that most patients with ACHD, including all those with Eisenmenger syndrome, be managed in collaboration with a cardiologist at a specialized ACHD center (Circulation. 2018 Aug 16. doi: 10.1161/CIR.0000000000000603), noted Dr. Warnes, professor of medicine at the Mayo Clinic in Rochester, Minn., and director of the Snowmass conference.
“There are lots of mistakes in diagnosis and management because so many physicians are unfamiliar with the kinds of problems these patients face,” the cardiologist said.
She cited as a real-world example a patient with Eisenmenger syndrome admitted for pneumonia. Twenty minutes after being placed on intravenous antibiotics she had a stroke. Why?
“She didn’t have an air filter on her IV line. Any air going into a cyanotic’s blood stream will go to the head and give them a stroke. Something that is simple – routine for other patients – may kill a patient with cyanotic heart disease,” Dr. Warnes said.
Another illustrative case: a patient with Eisenmenger syndrome presents with hemoptysis, an infiltrate in her right lung, a hemoglobin of 19.8 g/dL, and anemia. Should she undergo therapeutic phlebotomy? How about urgent bronchoscopy?
No and no, Dr. Warnes emphasized.
“You do not phlebotomize cyanotic patients unless they have symptoms of hyperviscosity, meaning terrible headache or poor concentration, along with a hemoglobin greater than 20 g/dL. They need that high hemoglobin. They may be blue, and you need those red cells to carry the oxygen around. Otherwise you may make them worse. And if you give them iron for their anemia, you will increase their risk of stroke,” she explained.
Hemoptysis in patients with Eisenmenger syndrome is a life-threatening warning sign. By the time Eisenmenger syndrome patients reach age 40 years, nearly all of them have experienced episodes of hemoptysis. And more and more patients with the syndrome are moving well beyond that milestone and surviving into their 60s and beyond.
“Many Eisenmenger syndrome patients are not dying when they’re 20 or 30. We can get them to a good old age,” according to Dr. Warnes, who founded the ACHD center at the Mayo Clinic.
Most of the time the cause of hemoptysis in patients with Eisenmenger syndrome is an intrapulmonary hemorrhage. Anticoagulation can turn that hemorrhage catastrophic. So can bronchoscopy. Indeed, the cause of death in roughly 30% of patients with this form of congenital heart disease is catastrophic hemoptysis.
“You bar the door from your friendly pulmonologist who wants to bronchoscope these patients. Bronchoscopy never does any good unless the patient is so hypoxic that you need to suck the blood out of their lungs,” Dr. Warnes emphasized.
Anticoagulation is ordinarily to be avoided in patients with Eisenmenger syndrome because of their bleeding risk, even when pulmonary thrombosis is suspected, she added.
So, to summarize: These patients basically need stabilizing, with no anticoagulation, no bronchoscopy, and no phlebotomy, she said.
Another danger zone for patients with Eisenmenger syndrome is pregnancy. The condition is associated with a 30% maternal mortality rate.
Dr. Warnes noted that, even at the Mayo Clinic, which has had a pioneering ACHD center for decades, awareness of key elements of management of affected patients is low among nonspecialists.
“As I’ve done my hospital services in the last couple of months, I sort of felt I was on patrol, snatching these patients from problems,” she recalled.
Dr. Warnes reported having no financial conflicts regarding her presentation.
REPORTING FROM ACC SNOWMASS 2019
Newer antihyperglycemic drugs have distinctive CV, kidney benefits
The two newer classes of antihyperglycemic drugs that lower cardiovascular risk have different effects on specific cardiovascular and kidney disease outcomes in patients with type 2 diabetes, results of a meta-analysis suggest. Sodium-glucose contransporter-2 (SGLT2) inhibitors significantly reduced hospitalization from heart failure, whereas glucagon-like peptide-1 receptor agonists (GLP-1 RAs) did not, according to the reported results.
The GLP-1–RA class reduced risk of kidney disease progression, largely driven by a reduction in macroalbuminuria, according to the authors, whereas only the SGLT2 inhibitors reduced adverse kidney disease outcomes in a composite excluding that biomarker.
“The prevention of heart failure and progression of kidney disease by SGLT2 [inhibitors] should be considered in the decision-making process when treating patients with type 2 diabetes,” study senior author Marc S. Sabatine, MD, MPH, of Brigham and Women’s Hospital, Boston, and his coauthors wrote in a report on the study appearing in Circulation.
Both GLP-1 RAs and SGLT2 inhibitors significantly reduced major adverse cardiovascular events (MACE) and, as shown in other recent findings, their benefits were confined to patients with established atherosclerotic cardiovascular disease, Dr. Sabatine and his colleagues wrote.
The systematic review and meta-analysis of eight cardiovascular outcomes trials included 77,242 patients, of whom about 56% participated in GLP-1–RA studies and 44% in SGLT2-inhibitor trials. Just under three-quarters of the patients had established atherosclerotic cardiovascular disease, while the remainder had multiple risk factors for it.
Relative risk of hospitalization for heart failure was reduced by 31% with SGLT2 inhibitors, but it was not significantly reduced by GLP-1 RAs, the authors noted.
Risk of kidney disease progression was reduced by 38% with SGLT2 inhibitors and by 18% with GLP-1 RAs when the researchers used a broad composite endpoint including macroalbuminuria, estimated glomerular filtration rate (eGFR), end-stage kidney disease, and death due to renal causes.
By contrast, SGLT2 inhibitors reduced by 45% the relative risk of a narrower kidney outcome that excluded macroalbuminuria, whereas GLP-1 RAs had only a nonsignificant effect on the risk of doubling serum creatinine. That suggests the relative risk reduction of the kidney composite with GLP-1 RAs was driven mainly by a reduction in macroalbuminuria, the authors wrote.
Although albuminuria is an established biomarker for kidney and cardiovascular disease, it is a surrogate marker and can even be absent in patients with reduced eGFR, they said.
“Reduction in eGFR has emerged as a more meaningful endpoint of greater importance and is used in ongoing diabetes trials for kidney outcomes,” the authors said in a discussion of their results.
Relative risk of the composite MACE endpoint, including myocardial infarction, stroke, and cardiovascular death, was reduced by 12% for GLP-1 RAs and by 11% for SGLT2 [inhibitors], according to results of the analysis. However, the benefit was confined to patients with established cardiovascular disease, who had a 14% reduction of risk, compared with no treatment effect in patients who had multiple risk factors only.
Looking at individual MACE components, investigators found that both drug classes significantly reduced relative risk of myocardial infarction and of cardiovascular death, whereas only GLP-1 RAs significantly reduced relative risk of stroke.
Study authors provided disclosures related to AstraZeneca, Amgen, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, and Medimmune, among others.
SOURCE: Zelniker TA et al. Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.
The two newer classes of antihyperglycemic drugs that lower cardiovascular risk have different effects on specific cardiovascular and kidney disease outcomes in patients with type 2 diabetes, results of a meta-analysis suggest. Sodium-glucose contransporter-2 (SGLT2) inhibitors significantly reduced hospitalization from heart failure, whereas glucagon-like peptide-1 receptor agonists (GLP-1 RAs) did not, according to the reported results.
The GLP-1–RA class reduced risk of kidney disease progression, largely driven by a reduction in macroalbuminuria, according to the authors, whereas only the SGLT2 inhibitors reduced adverse kidney disease outcomes in a composite excluding that biomarker.
“The prevention of heart failure and progression of kidney disease by SGLT2 [inhibitors] should be considered in the decision-making process when treating patients with type 2 diabetes,” study senior author Marc S. Sabatine, MD, MPH, of Brigham and Women’s Hospital, Boston, and his coauthors wrote in a report on the study appearing in Circulation.
Both GLP-1 RAs and SGLT2 inhibitors significantly reduced major adverse cardiovascular events (MACE) and, as shown in other recent findings, their benefits were confined to patients with established atherosclerotic cardiovascular disease, Dr. Sabatine and his colleagues wrote.
The systematic review and meta-analysis of eight cardiovascular outcomes trials included 77,242 patients, of whom about 56% participated in GLP-1–RA studies and 44% in SGLT2-inhibitor trials. Just under three-quarters of the patients had established atherosclerotic cardiovascular disease, while the remainder had multiple risk factors for it.
Relative risk of hospitalization for heart failure was reduced by 31% with SGLT2 inhibitors, but it was not significantly reduced by GLP-1 RAs, the authors noted.
Risk of kidney disease progression was reduced by 38% with SGLT2 inhibitors and by 18% with GLP-1 RAs when the researchers used a broad composite endpoint including macroalbuminuria, estimated glomerular filtration rate (eGFR), end-stage kidney disease, and death due to renal causes.
By contrast, SGLT2 inhibitors reduced by 45% the relative risk of a narrower kidney outcome that excluded macroalbuminuria, whereas GLP-1 RAs had only a nonsignificant effect on the risk of doubling serum creatinine. That suggests the relative risk reduction of the kidney composite with GLP-1 RAs was driven mainly by a reduction in macroalbuminuria, the authors wrote.
Although albuminuria is an established biomarker for kidney and cardiovascular disease, it is a surrogate marker and can even be absent in patients with reduced eGFR, they said.
“Reduction in eGFR has emerged as a more meaningful endpoint of greater importance and is used in ongoing diabetes trials for kidney outcomes,” the authors said in a discussion of their results.
Relative risk of the composite MACE endpoint, including myocardial infarction, stroke, and cardiovascular death, was reduced by 12% for GLP-1 RAs and by 11% for SGLT2 [inhibitors], according to results of the analysis. However, the benefit was confined to patients with established cardiovascular disease, who had a 14% reduction of risk, compared with no treatment effect in patients who had multiple risk factors only.
Looking at individual MACE components, investigators found that both drug classes significantly reduced relative risk of myocardial infarction and of cardiovascular death, whereas only GLP-1 RAs significantly reduced relative risk of stroke.
Study authors provided disclosures related to AstraZeneca, Amgen, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, and Medimmune, among others.
SOURCE: Zelniker TA et al. Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.
The two newer classes of antihyperglycemic drugs that lower cardiovascular risk have different effects on specific cardiovascular and kidney disease outcomes in patients with type 2 diabetes, results of a meta-analysis suggest. Sodium-glucose contransporter-2 (SGLT2) inhibitors significantly reduced hospitalization from heart failure, whereas glucagon-like peptide-1 receptor agonists (GLP-1 RAs) did not, according to the reported results.
The GLP-1–RA class reduced risk of kidney disease progression, largely driven by a reduction in macroalbuminuria, according to the authors, whereas only the SGLT2 inhibitors reduced adverse kidney disease outcomes in a composite excluding that biomarker.
“The prevention of heart failure and progression of kidney disease by SGLT2 [inhibitors] should be considered in the decision-making process when treating patients with type 2 diabetes,” study senior author Marc S. Sabatine, MD, MPH, of Brigham and Women’s Hospital, Boston, and his coauthors wrote in a report on the study appearing in Circulation.
Both GLP-1 RAs and SGLT2 inhibitors significantly reduced major adverse cardiovascular events (MACE) and, as shown in other recent findings, their benefits were confined to patients with established atherosclerotic cardiovascular disease, Dr. Sabatine and his colleagues wrote.
The systematic review and meta-analysis of eight cardiovascular outcomes trials included 77,242 patients, of whom about 56% participated in GLP-1–RA studies and 44% in SGLT2-inhibitor trials. Just under three-quarters of the patients had established atherosclerotic cardiovascular disease, while the remainder had multiple risk factors for it.
Relative risk of hospitalization for heart failure was reduced by 31% with SGLT2 inhibitors, but it was not significantly reduced by GLP-1 RAs, the authors noted.
Risk of kidney disease progression was reduced by 38% with SGLT2 inhibitors and by 18% with GLP-1 RAs when the researchers used a broad composite endpoint including macroalbuminuria, estimated glomerular filtration rate (eGFR), end-stage kidney disease, and death due to renal causes.
By contrast, SGLT2 inhibitors reduced by 45% the relative risk of a narrower kidney outcome that excluded macroalbuminuria, whereas GLP-1 RAs had only a nonsignificant effect on the risk of doubling serum creatinine. That suggests the relative risk reduction of the kidney composite with GLP-1 RAs was driven mainly by a reduction in macroalbuminuria, the authors wrote.
Although albuminuria is an established biomarker for kidney and cardiovascular disease, it is a surrogate marker and can even be absent in patients with reduced eGFR, they said.
“Reduction in eGFR has emerged as a more meaningful endpoint of greater importance and is used in ongoing diabetes trials for kidney outcomes,” the authors said in a discussion of their results.
Relative risk of the composite MACE endpoint, including myocardial infarction, stroke, and cardiovascular death, was reduced by 12% for GLP-1 RAs and by 11% for SGLT2 [inhibitors], according to results of the analysis. However, the benefit was confined to patients with established cardiovascular disease, who had a 14% reduction of risk, compared with no treatment effect in patients who had multiple risk factors only.
Looking at individual MACE components, investigators found that both drug classes significantly reduced relative risk of myocardial infarction and of cardiovascular death, whereas only GLP-1 RAs significantly reduced relative risk of stroke.
Study authors provided disclosures related to AstraZeneca, Amgen, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, and Medimmune, among others.
SOURCE: Zelniker TA et al. Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.
FROM CIRCULATION
CHEST updates guidelines on PAH
The American College of Chest Physicians® (CHEST) has published updates to the evidence-based guidelines on therapy for pulmonary arterial hypertension (PAH). In the latest evidence-based guideline, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, experts provide 78 evidence-based recommendations for appropriate use in treating patients with PAH.
“New recommendations and ungraded consensus-based statements were developed in this update based on new studies that were published since the 2014 guidelines. In addition, an evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management,” says CHEST Pulmonary Arterial Hypertension Guidelines Committee Co-Chair, Deborah Jo Levine, MD, FCCP.
As part of the guideline development process, the panel updated the systematic review on the same clinical questions and criteria. Based on the results of the systematic review, the panel developed two new recommendations about pharmacologic therapy for PAH:
•For treatment-naive patients with PAH who are World Health Organization (WHO) functional class II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6-minute walk distance (6MWD).
•For stable or symptomatic patients with PAH on background therapy with ambrisentan, we suggest the addition of tadalafil to improve 6MWD.
The complete guideline article is free to view in the Online First section of the journal CHEST®.
The American College of Chest Physicians® (CHEST) has published updates to the evidence-based guidelines on therapy for pulmonary arterial hypertension (PAH). In the latest evidence-based guideline, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, experts provide 78 evidence-based recommendations for appropriate use in treating patients with PAH.
“New recommendations and ungraded consensus-based statements were developed in this update based on new studies that were published since the 2014 guidelines. In addition, an evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management,” says CHEST Pulmonary Arterial Hypertension Guidelines Committee Co-Chair, Deborah Jo Levine, MD, FCCP.
As part of the guideline development process, the panel updated the systematic review on the same clinical questions and criteria. Based on the results of the systematic review, the panel developed two new recommendations about pharmacologic therapy for PAH:
•For treatment-naive patients with PAH who are World Health Organization (WHO) functional class II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6-minute walk distance (6MWD).
•For stable or symptomatic patients with PAH on background therapy with ambrisentan, we suggest the addition of tadalafil to improve 6MWD.
The complete guideline article is free to view in the Online First section of the journal CHEST®.
The American College of Chest Physicians® (CHEST) has published updates to the evidence-based guidelines on therapy for pulmonary arterial hypertension (PAH). In the latest evidence-based guideline, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, experts provide 78 evidence-based recommendations for appropriate use in treating patients with PAH.
“New recommendations and ungraded consensus-based statements were developed in this update based on new studies that were published since the 2014 guidelines. In addition, an evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management,” says CHEST Pulmonary Arterial Hypertension Guidelines Committee Co-Chair, Deborah Jo Levine, MD, FCCP.
As part of the guideline development process, the panel updated the systematic review on the same clinical questions and criteria. Based on the results of the systematic review, the panel developed two new recommendations about pharmacologic therapy for PAH:
•For treatment-naive patients with PAH who are World Health Organization (WHO) functional class II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6-minute walk distance (6MWD).
•For stable or symptomatic patients with PAH on background therapy with ambrisentan, we suggest the addition of tadalafil to improve 6MWD.
The complete guideline article is free to view in the Online First section of the journal CHEST®.
Low Risk TAVR trial shows 3% mortality at 1 year
WASHINGTON –Anticipating two pivotal trials scheduled for presentation at the 2019 annual meeting of the American College of Cardiology (ACC), an investigator-led study of transaortic valve replacement (TAVR) for aortic stenosis presented as a latebreaker at 2019 CRT meeting produced excellent results.
Not least impressive, “our mortality rates are the lowest ever reported in any TAVR study at one year,” said Ronald Waksman, MD, Associate Director, Division of Cardiology, Medstar Heart Institute, Washington, DC.
In a population of patients with a median age of 71.1 years, all-cause mortality was just 3% at one year while the rate of deaths due to cardiovascular causes was only 1%, according to results of the 200-patient Low Risk TAVR study (LRT 1.0, NCT02628899) that Dr. Waksman presented.
In addition, there were low rates at one year for stroke (2.1%, none of which was deemed disability), myocardial infarction (1%), new onset atrial fibrillation (6.2%), and pacemaker placement (7.3%). The rate of rehospitalization for any cause was 20.4% but only 3.1% were considered related to TAVR. Rehospitalization for any cardiovascular cause at one year occurred in 6.8%.
Although leaflet thickening was observed at one year with imaging in 14%, this has not had any identifiable clinical consequences so far, and hemodynamics have remained stable, according to Dr. Waksman, who presented the interim 30-day outcomes at the 2018 CRT meeting.
These findings are raising expectations for two phase 3 TAVR trials in low-risk patients that are being presented as latebreakers at the 2019 ACC annual meeting. Both are large randomized trials comparing TAVR to surgical aortic valve replacement (SAVR) in low risk patients. Each trial is testing a single type of value and is funded by the valve manufacturers.
In the PARTNER-3 trial, patients randomized to TAVR received the Sapien 3 valve (Edwards Lifesciences). In the other latebreaking trial, patients randomized to TAVR received an Evolut valve (Medtronic Cardiovascular). Both are comparing TAVR to SAVR with a composite primary outcome that includes mortality and stroke measured at 30 days and one year.
In contrast to these trials, LRT 1.0 was conducted with no funding from a third party, according to Dr. Waksman. The eleven centers participated in the study at their own cost. Also, the choice of TAVR device was left to the discretion of the interventional cardiologist. Finally, most of the participating centers, although experienced in TAVR, did not have a high-volume case load. In general, with the exception of Dr. Waksman’s center, most performed 100 to 150 TAVRs per year.
“We were struck by the excellence of the performance of these sites,” said Dr. Waksman, noting that a comparison of outcomes at his center relative to the lower volume centers showed no significant differences in outcome.
This real-world experience raises the bar for the pivotal phase 3 trials, which, if positive, are expected to lead the FDA to grant an indication for TAVR in low-risk patients, according to Dr. Waksman. He announced that an LRT 2.0 trial, which will again include centers performing TAVRs at moderate volumes, is now enrolling.
SOURCE: 2019 Cardiovascular Research Technologies (CRT) Meeting.
WASHINGTON –Anticipating two pivotal trials scheduled for presentation at the 2019 annual meeting of the American College of Cardiology (ACC), an investigator-led study of transaortic valve replacement (TAVR) for aortic stenosis presented as a latebreaker at 2019 CRT meeting produced excellent results.
Not least impressive, “our mortality rates are the lowest ever reported in any TAVR study at one year,” said Ronald Waksman, MD, Associate Director, Division of Cardiology, Medstar Heart Institute, Washington, DC.
In a population of patients with a median age of 71.1 years, all-cause mortality was just 3% at one year while the rate of deaths due to cardiovascular causes was only 1%, according to results of the 200-patient Low Risk TAVR study (LRT 1.0, NCT02628899) that Dr. Waksman presented.
In addition, there were low rates at one year for stroke (2.1%, none of which was deemed disability), myocardial infarction (1%), new onset atrial fibrillation (6.2%), and pacemaker placement (7.3%). The rate of rehospitalization for any cause was 20.4% but only 3.1% were considered related to TAVR. Rehospitalization for any cardiovascular cause at one year occurred in 6.8%.
Although leaflet thickening was observed at one year with imaging in 14%, this has not had any identifiable clinical consequences so far, and hemodynamics have remained stable, according to Dr. Waksman, who presented the interim 30-day outcomes at the 2018 CRT meeting.
These findings are raising expectations for two phase 3 TAVR trials in low-risk patients that are being presented as latebreakers at the 2019 ACC annual meeting. Both are large randomized trials comparing TAVR to surgical aortic valve replacement (SAVR) in low risk patients. Each trial is testing a single type of value and is funded by the valve manufacturers.
In the PARTNER-3 trial, patients randomized to TAVR received the Sapien 3 valve (Edwards Lifesciences). In the other latebreaking trial, patients randomized to TAVR received an Evolut valve (Medtronic Cardiovascular). Both are comparing TAVR to SAVR with a composite primary outcome that includes mortality and stroke measured at 30 days and one year.
In contrast to these trials, LRT 1.0 was conducted with no funding from a third party, according to Dr. Waksman. The eleven centers participated in the study at their own cost. Also, the choice of TAVR device was left to the discretion of the interventional cardiologist. Finally, most of the participating centers, although experienced in TAVR, did not have a high-volume case load. In general, with the exception of Dr. Waksman’s center, most performed 100 to 150 TAVRs per year.
“We were struck by the excellence of the performance of these sites,” said Dr. Waksman, noting that a comparison of outcomes at his center relative to the lower volume centers showed no significant differences in outcome.
This real-world experience raises the bar for the pivotal phase 3 trials, which, if positive, are expected to lead the FDA to grant an indication for TAVR in low-risk patients, according to Dr. Waksman. He announced that an LRT 2.0 trial, which will again include centers performing TAVRs at moderate volumes, is now enrolling.
SOURCE: 2019 Cardiovascular Research Technologies (CRT) Meeting.
WASHINGTON –Anticipating two pivotal trials scheduled for presentation at the 2019 annual meeting of the American College of Cardiology (ACC), an investigator-led study of transaortic valve replacement (TAVR) for aortic stenosis presented as a latebreaker at 2019 CRT meeting produced excellent results.
Not least impressive, “our mortality rates are the lowest ever reported in any TAVR study at one year,” said Ronald Waksman, MD, Associate Director, Division of Cardiology, Medstar Heart Institute, Washington, DC.
In a population of patients with a median age of 71.1 years, all-cause mortality was just 3% at one year while the rate of deaths due to cardiovascular causes was only 1%, according to results of the 200-patient Low Risk TAVR study (LRT 1.0, NCT02628899) that Dr. Waksman presented.
In addition, there were low rates at one year for stroke (2.1%, none of which was deemed disability), myocardial infarction (1%), new onset atrial fibrillation (6.2%), and pacemaker placement (7.3%). The rate of rehospitalization for any cause was 20.4% but only 3.1% were considered related to TAVR. Rehospitalization for any cardiovascular cause at one year occurred in 6.8%.
Although leaflet thickening was observed at one year with imaging in 14%, this has not had any identifiable clinical consequences so far, and hemodynamics have remained stable, according to Dr. Waksman, who presented the interim 30-day outcomes at the 2018 CRT meeting.
These findings are raising expectations for two phase 3 TAVR trials in low-risk patients that are being presented as latebreakers at the 2019 ACC annual meeting. Both are large randomized trials comparing TAVR to surgical aortic valve replacement (SAVR) in low risk patients. Each trial is testing a single type of value and is funded by the valve manufacturers.
In the PARTNER-3 trial, patients randomized to TAVR received the Sapien 3 valve (Edwards Lifesciences). In the other latebreaking trial, patients randomized to TAVR received an Evolut valve (Medtronic Cardiovascular). Both are comparing TAVR to SAVR with a composite primary outcome that includes mortality and stroke measured at 30 days and one year.
In contrast to these trials, LRT 1.0 was conducted with no funding from a third party, according to Dr. Waksman. The eleven centers participated in the study at their own cost. Also, the choice of TAVR device was left to the discretion of the interventional cardiologist. Finally, most of the participating centers, although experienced in TAVR, did not have a high-volume case load. In general, with the exception of Dr. Waksman’s center, most performed 100 to 150 TAVRs per year.
“We were struck by the excellence of the performance of these sites,” said Dr. Waksman, noting that a comparison of outcomes at his center relative to the lower volume centers showed no significant differences in outcome.
This real-world experience raises the bar for the pivotal phase 3 trials, which, if positive, are expected to lead the FDA to grant an indication for TAVR in low-risk patients, according to Dr. Waksman. He announced that an LRT 2.0 trial, which will again include centers performing TAVRs at moderate volumes, is now enrolling.
SOURCE: 2019 Cardiovascular Research Technologies (CRT) Meeting.
REPORTING FROM CRT 2019
Alcohol-mediated renal denervation appears safe for BP reduction
WASHINGTON – Injection of dehydrated alcohol through the wall of the renal artery can be added to a growing list of renal denervation strategies that have been associated with sustained blood pressure reductions, according to data presented as a latebreaker at 2019 CRT meeting.
For the primary efficacy endpoint of change in systolic blood pressure at six months, the mean reduction six months after denervation was 11 mmHg as measured with 24-hour ambulatory blood pressure monitoring (ABPM), according to Horst Sievert, MD, PhD, Director of the CardioVascular Center, Frankfurt, Germany.
“Alcohol denervation was associated with efficient and safe lowering of systolic blood pressure,” reported Dr. Sievert, who said these data have prompted a new set of studies, including a phase 2 controlled trial that will evaluate the effect of renal denervation for control of blood pressure off-medication.
After consent was withdrawn from one patient, study results were available from 44 patients with treatment resistant hypertension who were enrolled in this initial study. Entry requirements included a mean systolic blood pressure greater than 150 mmHg while taking at least three antihypertensive medications from different classes.
In this study, the alcohol was delivered with a proprietary device called the Peregrine System™ infusion catheter (Ablation Solutions). This catheter is equipped with microneedles that remain retracted until the catheter is navigated into position. Once in the renal artery, the microneedles are deployed to inject alcohol into the perivascular space, which produces a neurolytic effect.
The technical success for delivery of the alcohol was achieved in 100% of the study group. There were no serious adverse events associated with treatment. Minor adverse events included those involving the access site, such as pain, as well as two dissections that resolved without treatment. One patient complained of abdominal pain on the day of the procedure, but that also resolved, according to Dr. Sievert.
Over the course of followup, patients remained on the therapies they were taking prior to the intervention. There was no change in antihypertensive therapy during the first month of followup in 84% of treated patients. Of those who did have a change in medication, all but one involved a reduction in medication prompted by improved blood pressure control. At six months, there was no change in medication for 73% of those evaluated.
Following alcohol denervation, there was a mean 7 mmHg reduction in diastolic pressure as measured with 24-hour ABBM.
Based on these data, a trials program is being launched. In addition to the phase 2 multinational off-medication trial, which is enrolling 300 patients who are being randomized to the alcohol denervation therapy or a sham control, an open-label crossover trial will be conducted to confirm the safety and tolerability of this approach.
Delivery of alcohol through the catheter device used in this study requires a renal artery diameter of at least 4 mm. This is a potential limitation for smaller individuals, but several other devices used for denervation share this requirement, according to Dr. Sievert.
The potential advantage of this approach is that “you can stay proximal,” according to Dr. Sievert, contrasting this technique with renal denervation by radiofrequency ablation. He explained that radiofrequency renal denervation requires a relatively distal approach to achieve an appropriate energy penetration for target nerve ablation. Further study is needed to determine whether more proximal delivery has any clinical advantage.
SOURCE: 2019 Cardiovascular Research Technologies (CRT) Meeting.
WASHINGTON – Injection of dehydrated alcohol through the wall of the renal artery can be added to a growing list of renal denervation strategies that have been associated with sustained blood pressure reductions, according to data presented as a latebreaker at 2019 CRT meeting.
For the primary efficacy endpoint of change in systolic blood pressure at six months, the mean reduction six months after denervation was 11 mmHg as measured with 24-hour ambulatory blood pressure monitoring (ABPM), according to Horst Sievert, MD, PhD, Director of the CardioVascular Center, Frankfurt, Germany.
“Alcohol denervation was associated with efficient and safe lowering of systolic blood pressure,” reported Dr. Sievert, who said these data have prompted a new set of studies, including a phase 2 controlled trial that will evaluate the effect of renal denervation for control of blood pressure off-medication.
After consent was withdrawn from one patient, study results were available from 44 patients with treatment resistant hypertension who were enrolled in this initial study. Entry requirements included a mean systolic blood pressure greater than 150 mmHg while taking at least three antihypertensive medications from different classes.
In this study, the alcohol was delivered with a proprietary device called the Peregrine System™ infusion catheter (Ablation Solutions). This catheter is equipped with microneedles that remain retracted until the catheter is navigated into position. Once in the renal artery, the microneedles are deployed to inject alcohol into the perivascular space, which produces a neurolytic effect.
The technical success for delivery of the alcohol was achieved in 100% of the study group. There were no serious adverse events associated with treatment. Minor adverse events included those involving the access site, such as pain, as well as two dissections that resolved without treatment. One patient complained of abdominal pain on the day of the procedure, but that also resolved, according to Dr. Sievert.
Over the course of followup, patients remained on the therapies they were taking prior to the intervention. There was no change in antihypertensive therapy during the first month of followup in 84% of treated patients. Of those who did have a change in medication, all but one involved a reduction in medication prompted by improved blood pressure control. At six months, there was no change in medication for 73% of those evaluated.
Following alcohol denervation, there was a mean 7 mmHg reduction in diastolic pressure as measured with 24-hour ABBM.
Based on these data, a trials program is being launched. In addition to the phase 2 multinational off-medication trial, which is enrolling 300 patients who are being randomized to the alcohol denervation therapy or a sham control, an open-label crossover trial will be conducted to confirm the safety and tolerability of this approach.
Delivery of alcohol through the catheter device used in this study requires a renal artery diameter of at least 4 mm. This is a potential limitation for smaller individuals, but several other devices used for denervation share this requirement, according to Dr. Sievert.
The potential advantage of this approach is that “you can stay proximal,” according to Dr. Sievert, contrasting this technique with renal denervation by radiofrequency ablation. He explained that radiofrequency renal denervation requires a relatively distal approach to achieve an appropriate energy penetration for target nerve ablation. Further study is needed to determine whether more proximal delivery has any clinical advantage.
SOURCE: 2019 Cardiovascular Research Technologies (CRT) Meeting.
WASHINGTON – Injection of dehydrated alcohol through the wall of the renal artery can be added to a growing list of renal denervation strategies that have been associated with sustained blood pressure reductions, according to data presented as a latebreaker at 2019 CRT meeting.
For the primary efficacy endpoint of change in systolic blood pressure at six months, the mean reduction six months after denervation was 11 mmHg as measured with 24-hour ambulatory blood pressure monitoring (ABPM), according to Horst Sievert, MD, PhD, Director of the CardioVascular Center, Frankfurt, Germany.
“Alcohol denervation was associated with efficient and safe lowering of systolic blood pressure,” reported Dr. Sievert, who said these data have prompted a new set of studies, including a phase 2 controlled trial that will evaluate the effect of renal denervation for control of blood pressure off-medication.
After consent was withdrawn from one patient, study results were available from 44 patients with treatment resistant hypertension who were enrolled in this initial study. Entry requirements included a mean systolic blood pressure greater than 150 mmHg while taking at least three antihypertensive medications from different classes.
In this study, the alcohol was delivered with a proprietary device called the Peregrine System™ infusion catheter (Ablation Solutions). This catheter is equipped with microneedles that remain retracted until the catheter is navigated into position. Once in the renal artery, the microneedles are deployed to inject alcohol into the perivascular space, which produces a neurolytic effect.
The technical success for delivery of the alcohol was achieved in 100% of the study group. There were no serious adverse events associated with treatment. Minor adverse events included those involving the access site, such as pain, as well as two dissections that resolved without treatment. One patient complained of abdominal pain on the day of the procedure, but that also resolved, according to Dr. Sievert.
Over the course of followup, patients remained on the therapies they were taking prior to the intervention. There was no change in antihypertensive therapy during the first month of followup in 84% of treated patients. Of those who did have a change in medication, all but one involved a reduction in medication prompted by improved blood pressure control. At six months, there was no change in medication for 73% of those evaluated.
Following alcohol denervation, there was a mean 7 mmHg reduction in diastolic pressure as measured with 24-hour ABBM.
Based on these data, a trials program is being launched. In addition to the phase 2 multinational off-medication trial, which is enrolling 300 patients who are being randomized to the alcohol denervation therapy or a sham control, an open-label crossover trial will be conducted to confirm the safety and tolerability of this approach.
Delivery of alcohol through the catheter device used in this study requires a renal artery diameter of at least 4 mm. This is a potential limitation for smaller individuals, but several other devices used for denervation share this requirement, according to Dr. Sievert.
The potential advantage of this approach is that “you can stay proximal,” according to Dr. Sievert, contrasting this technique with renal denervation by radiofrequency ablation. He explained that radiofrequency renal denervation requires a relatively distal approach to achieve an appropriate energy penetration for target nerve ablation. Further study is needed to determine whether more proximal delivery has any clinical advantage.
SOURCE: 2019 Cardiovascular Research Technologies (CRT) Meeting.
REPORTING FROM CRT 2019
How do these 3 diabetes agents compare in reducing mortality?
ILLUSTRATIVE CASE
A 64-year-old man with taype 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care hemoglobin A1c is 9.5%, and he is currently taking only metformin 1000 mg bid. You are considering adding an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and cardiovascular (CV) mortality risk?
Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people, or 1 of every 11, now struggles to reduce their blood sugar.2 As prevalence of the disease has increased, so has the number of medications available that are aimed at lowering blood sugar and improving diabetes control.2 In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.
The “American Diabetes Association Standards of Medical Care in Diabetes” points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin, and the GLP-1 agonist liraglutide, as agents that should be added to metformin and lifestyle modification in patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.3 Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”3
The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.4 The American Association of Clinical Endocrinologists and the American College of Endocrinology guidelines do include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in strength of recommendations for these classes is noted to be small.5
STUDY SUMMARY
SGLT-2s, GLP-1s are associated with better mortality outcomes than DPP-4s
Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176,310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.
A majority of the patients in both the intervention and control groups were taking additional diabetes medications, such as metformin, prior to enrollment and during the trials. About half of the patients analyzed were enrolled in trials that specifically evaluated patients at elevated CV risk, which is notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.
The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).
Continue to: Results
Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group, hazard ratio [HR]=0.80; 95% credible interval [CrI], 0.71-0.89; absolute risk difference [RD]= –1%; number needed to treat [NNT]=100; GLP-1 agonist group, HR=0.88; 95% CrI, 0.81-0.94; absolute RD= -0.6%; NNT=167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR=1.02; 95% CrI, 0.94-1.11; absolute RD=0.1%). Both the SGLT-2 inhibitor (HR=0.78; 95% CrI, 0.68-0.90; absolute RD= –0.9%; NNT=111) and GLP-1 agonist (HR=0.86; 95% CrI, 0.77-0.96; absolute RD= –0.5%; NNT=200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.
CV endpoints. Similarly, the SGLT-2 inhibitor (HR=0.79; 95% Crl, 0.69-0.91; absolute RD= –0.8%; NNT=125) and GLP-1 agonist (HR=0.85; Crl, 95% 0.77-0.94; absolute RD= –0.5%; NNT=200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR=0.62; 95% CrI, 0.54-0.72; absolute RD= –1.1%; NNT=91) and MIs (HR=0.86; 95% CrI, 0.77–0.97; absolute RD= –0.6%; NNT=167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR=0.67; 95% CrI, 0.57 to 0.80; absolute RD= –0.9; NNT=111) or DPP-4 inhibitors (HR=0.55; 95% CrI, 0.46-0.67; absolute RD= –1.1%; NNT=91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups saw lower rates of HF or MI than the control groups.
Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists, HR=2; 95% CrI, 1.70-2.37; absolute RD=4.7%; number needed to harm [NNH]=21; SGLT-2 inhibitors, HR=1.8; 95% CrI, 1.44-2.25; absolute RD=5.8%; NNH=17; and DPP-4 inhibitors, HR=1.93; 95% CrI, 1.59-2.35; absolute RD=3.1%; NNH=32).
When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR]=4.19; 95% confidence interval [CI], 3.45-5.09; absolute RD=6%; NNH=16), but not of urinary tract infection or lower limb amputation, although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR=1.58; 95% CI, 1.04-2.39; absolute RD=0.1%; NNH=1000) compared with control groups.
WHAT’S NEW
SGLT-2s: Lower mortality, fewer heart failure events
This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than is the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.
Continue to: CAVEATS
CAVEATS
A lack of head-to-head RCTs
This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 classes of medication.
However, there was relatively low heterogeneity among the studies included (I2=12), which lends strength to the meta-analysis.6 Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.
CHALLENGES TO IMPLEMENTATION
Cost, adverse effects, and formulation may represent challenges
The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors, and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists, must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Zheng S, Roddick A, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319:1580-1591.
2. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.
3. American Diabetes Association. Standards of medical care in diabetes–2019. Diabetes Care. 2019;42(suppl 1):S1-S193.
4. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. www.nice.org.uk/guidance/ng28. Published December 2015. Updated May 2017. Accessed March 1, 2019.
5. Garber A, Abrahamson M, Barzilay J, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2018 Executive Summary. Endocr Pract. 2018;24:91-120.
6. Salanti G, Del Giovane C, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS ONE. 2014;9:1-14.
ILLUSTRATIVE CASE
A 64-year-old man with taype 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care hemoglobin A1c is 9.5%, and he is currently taking only metformin 1000 mg bid. You are considering adding an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and cardiovascular (CV) mortality risk?
Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people, or 1 of every 11, now struggles to reduce their blood sugar.2 As prevalence of the disease has increased, so has the number of medications available that are aimed at lowering blood sugar and improving diabetes control.2 In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.
The “American Diabetes Association Standards of Medical Care in Diabetes” points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin, and the GLP-1 agonist liraglutide, as agents that should be added to metformin and lifestyle modification in patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.3 Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”3
The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.4 The American Association of Clinical Endocrinologists and the American College of Endocrinology guidelines do include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in strength of recommendations for these classes is noted to be small.5
STUDY SUMMARY
SGLT-2s, GLP-1s are associated with better mortality outcomes than DPP-4s
Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176,310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.
A majority of the patients in both the intervention and control groups were taking additional diabetes medications, such as metformin, prior to enrollment and during the trials. About half of the patients analyzed were enrolled in trials that specifically evaluated patients at elevated CV risk, which is notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.
The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).
Continue to: Results
Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group, hazard ratio [HR]=0.80; 95% credible interval [CrI], 0.71-0.89; absolute risk difference [RD]= –1%; number needed to treat [NNT]=100; GLP-1 agonist group, HR=0.88; 95% CrI, 0.81-0.94; absolute RD= -0.6%; NNT=167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR=1.02; 95% CrI, 0.94-1.11; absolute RD=0.1%). Both the SGLT-2 inhibitor (HR=0.78; 95% CrI, 0.68-0.90; absolute RD= –0.9%; NNT=111) and GLP-1 agonist (HR=0.86; 95% CrI, 0.77-0.96; absolute RD= –0.5%; NNT=200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.
CV endpoints. Similarly, the SGLT-2 inhibitor (HR=0.79; 95% Crl, 0.69-0.91; absolute RD= –0.8%; NNT=125) and GLP-1 agonist (HR=0.85; Crl, 95% 0.77-0.94; absolute RD= –0.5%; NNT=200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR=0.62; 95% CrI, 0.54-0.72; absolute RD= –1.1%; NNT=91) and MIs (HR=0.86; 95% CrI, 0.77–0.97; absolute RD= –0.6%; NNT=167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR=0.67; 95% CrI, 0.57 to 0.80; absolute RD= –0.9; NNT=111) or DPP-4 inhibitors (HR=0.55; 95% CrI, 0.46-0.67; absolute RD= –1.1%; NNT=91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups saw lower rates of HF or MI than the control groups.
Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists, HR=2; 95% CrI, 1.70-2.37; absolute RD=4.7%; number needed to harm [NNH]=21; SGLT-2 inhibitors, HR=1.8; 95% CrI, 1.44-2.25; absolute RD=5.8%; NNH=17; and DPP-4 inhibitors, HR=1.93; 95% CrI, 1.59-2.35; absolute RD=3.1%; NNH=32).
When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR]=4.19; 95% confidence interval [CI], 3.45-5.09; absolute RD=6%; NNH=16), but not of urinary tract infection or lower limb amputation, although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR=1.58; 95% CI, 1.04-2.39; absolute RD=0.1%; NNH=1000) compared with control groups.
WHAT’S NEW
SGLT-2s: Lower mortality, fewer heart failure events
This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than is the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.
Continue to: CAVEATS
CAVEATS
A lack of head-to-head RCTs
This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 classes of medication.
However, there was relatively low heterogeneity among the studies included (I2=12), which lends strength to the meta-analysis.6 Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.
CHALLENGES TO IMPLEMENTATION
Cost, adverse effects, and formulation may represent challenges
The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors, and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists, must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
A 64-year-old man with taype 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care hemoglobin A1c is 9.5%, and he is currently taking only metformin 1000 mg bid. You are considering adding an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and cardiovascular (CV) mortality risk?
Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people, or 1 of every 11, now struggles to reduce their blood sugar.2 As prevalence of the disease has increased, so has the number of medications available that are aimed at lowering blood sugar and improving diabetes control.2 In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.
The “American Diabetes Association Standards of Medical Care in Diabetes” points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin, and the GLP-1 agonist liraglutide, as agents that should be added to metformin and lifestyle modification in patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.3 Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”3
The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.4 The American Association of Clinical Endocrinologists and the American College of Endocrinology guidelines do include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in strength of recommendations for these classes is noted to be small.5
STUDY SUMMARY
SGLT-2s, GLP-1s are associated with better mortality outcomes than DPP-4s
Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176,310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.
A majority of the patients in both the intervention and control groups were taking additional diabetes medications, such as metformin, prior to enrollment and during the trials. About half of the patients analyzed were enrolled in trials that specifically evaluated patients at elevated CV risk, which is notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.
The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).
Continue to: Results
Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group, hazard ratio [HR]=0.80; 95% credible interval [CrI], 0.71-0.89; absolute risk difference [RD]= –1%; number needed to treat [NNT]=100; GLP-1 agonist group, HR=0.88; 95% CrI, 0.81-0.94; absolute RD= -0.6%; NNT=167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR=1.02; 95% CrI, 0.94-1.11; absolute RD=0.1%). Both the SGLT-2 inhibitor (HR=0.78; 95% CrI, 0.68-0.90; absolute RD= –0.9%; NNT=111) and GLP-1 agonist (HR=0.86; 95% CrI, 0.77-0.96; absolute RD= –0.5%; NNT=200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.
CV endpoints. Similarly, the SGLT-2 inhibitor (HR=0.79; 95% Crl, 0.69-0.91; absolute RD= –0.8%; NNT=125) and GLP-1 agonist (HR=0.85; Crl, 95% 0.77-0.94; absolute RD= –0.5%; NNT=200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR=0.62; 95% CrI, 0.54-0.72; absolute RD= –1.1%; NNT=91) and MIs (HR=0.86; 95% CrI, 0.77–0.97; absolute RD= –0.6%; NNT=167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR=0.67; 95% CrI, 0.57 to 0.80; absolute RD= –0.9; NNT=111) or DPP-4 inhibitors (HR=0.55; 95% CrI, 0.46-0.67; absolute RD= –1.1%; NNT=91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups saw lower rates of HF or MI than the control groups.
Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists, HR=2; 95% CrI, 1.70-2.37; absolute RD=4.7%; number needed to harm [NNH]=21; SGLT-2 inhibitors, HR=1.8; 95% CrI, 1.44-2.25; absolute RD=5.8%; NNH=17; and DPP-4 inhibitors, HR=1.93; 95% CrI, 1.59-2.35; absolute RD=3.1%; NNH=32).
When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR]=4.19; 95% confidence interval [CI], 3.45-5.09; absolute RD=6%; NNH=16), but not of urinary tract infection or lower limb amputation, although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR=1.58; 95% CI, 1.04-2.39; absolute RD=0.1%; NNH=1000) compared with control groups.
WHAT’S NEW
SGLT-2s: Lower mortality, fewer heart failure events
This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than is the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.
Continue to: CAVEATS
CAVEATS
A lack of head-to-head RCTs
This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 classes of medication.
However, there was relatively low heterogeneity among the studies included (I2=12), which lends strength to the meta-analysis.6 Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.
CHALLENGES TO IMPLEMENTATION
Cost, adverse effects, and formulation may represent challenges
The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors, and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists, must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Zheng S, Roddick A, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319:1580-1591.
2. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.
3. American Diabetes Association. Standards of medical care in diabetes–2019. Diabetes Care. 2019;42(suppl 1):S1-S193.
4. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. www.nice.org.uk/guidance/ng28. Published December 2015. Updated May 2017. Accessed March 1, 2019.
5. Garber A, Abrahamson M, Barzilay J, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2018 Executive Summary. Endocr Pract. 2018;24:91-120.
6. Salanti G, Del Giovane C, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS ONE. 2014;9:1-14.
1. Zheng S, Roddick A, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319:1580-1591.
2. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.
3. American Diabetes Association. Standards of medical care in diabetes–2019. Diabetes Care. 2019;42(suppl 1):S1-S193.
4. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. www.nice.org.uk/guidance/ng28. Published December 2015. Updated May 2017. Accessed March 1, 2019.
5. Garber A, Abrahamson M, Barzilay J, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2018 Executive Summary. Endocr Pract. 2018;24:91-120.
6. Salanti G, Del Giovane C, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS ONE. 2014;9:1-14.
PRACTICE CHANGER
Consider adding a sodium-glucose cotransporter 2 (SGLT-2) inhibitor or a glucagon-like peptide 1 (GLP-1) agonist to the treatment regimen of patients with poorly controlled type 2 diabetes—especially those with higher CV risk. Doing so can reduce all-cause and cardiovascular (CV) mortality 1
STRENGTH OF RECOMMENDATION
B: Based on a network meta-analysis of 236 randomized controlled trials.
Zheng S, Roddick A, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319:1580-1591.
