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A refined strategy for confirming diagnosis in suspected NSTEMI
ORLANDO – A novel diagnostic strategy of performing CT angiography or cardiovascular MRI first in patients with suspected non-ST-elevation MI safely improved appropriate selection for invasive coronary angiography in the Dutch randomized CARMENTA trial.
The strategy of using noninvasive imaging first significantly cut down on the high proportion of diagnostic invasive angiography procedures that end up showing no significant obstructive coronary artery disease in the current era of high-sensitivity cardiac troponin assays, Martijn W. Smulders, MD, reported at the annual meeting of the American College of Cardiology.
CARMENTA (Cardiovascular Magnetic Resonance Imaging and Computed Tomography Angiography) was a single-center, prospective, randomized trial including 207 patients with suspected NSTEMI on the basis of acute chest pain, an elevated high-sensitivity cardiac troponin level, and an inconclusive ECG. They were randomized to one of three diagnostic strategies: a routine invasive strategy in which they were sent straight to the cardiac catheterization lab for invasive coronary angiography, or either CTA- or CMR-first as gatekeeper strategies in which referral for invasive angiography was reserved for only those patients whose noninvasive imaging demonstrated myocardial ischemia, infarction, or obstructive CAD with at least a 70% stenosis.
The impetus for the trial was the investigators’ concern that widespread embrace of high-sensitivity cardiac troponin assays has resulted in a serious clinical problem: Although these assays offer very high sensitivity for rapid detection of acute MI, their positive predictive value is only 56%, compared with 76% for the older troponin assays.
“That means almost one out of two patients with acute chest pain and an elevated high-sensitivity troponin level does not have a type 1 MI. We see a twofold higher incidence of elevated troponin levels with these assays, so there has been a significant increase in referrals for invasive angiography – and up to one-third of these patients with suspected NSTEMI don’t have an obstructive stenosis. We need a strategy to improve patient selection,” explained Dr. Smulders of Maastricht (the Netherlands) University.
The CARMENTA strategy worked. The primary outcome – the proportion of patients with suspected NSTEMI who underwent invasive coronary angiography during their initial hospitalization – was 65% in the CTA-first group and 77% in the CMR group, compared with 100% in the routine invasive-strategy control group. Moreover, fully 38% of patients in the control group turned out not to have obstructive CAD, compared with 15% who were sent for invasive angiography only after CTA and 31% who first had CMR.
Procedure-related complications, a secondary outcome, occurred in 12% of the CMR-first group, 13% of the CTA-first group, and 16% of patients in the routine invasive strategy control group. Major adverse cardiac events during 1 year of follow-up, which was the other secondary outcome, occurred in 9% of the CMR group, 6% of the CTA group, and 9% of the control group.
A limitation of the CARMENTA trial was that, even though it was scheduled to enroll 288 patients to achieve strong statistical power, the study’s data safety monitoring committee recommended on the basis of an interim analysis that the trial be halted early. The reasoning was that the experience of the first 200 enrollees made it clear that the noninvasive-imaging-first strategy would achieve the goal of reducing the volume of referrals to invasive angiography for suspected NSTEMI.
Session cochair Stefan D. Anker, MD, was irked by the trial’s early termination, which weakened the strength of the conclusions, especially with regard to the safety of the novel strategy.
“I agree that this imaging-first strategy reduces procedures, but the use of the word ‘safely’ is premature,” said Dr. Anker, professor of homeostasis and cachexia at Charite Medical School in Berlin.
“I totally agree with you,” Dr. Smulders replied. “We need a bigger trial to confirm our results – preferably a multicenter trial.”
“How can you do a bigger trial when your data safety monitoring board didn’t allow you to complete even this trial? They killed your trial. That’s the way I see it,” Dr. Anker said.
The CARMENTA trial was funded by the Dutch Heart Foundation. Dr. Smulders reported having no financial conflicts of interest.
SOURCE: Smulders M. ACC 18.
ORLANDO – A novel diagnostic strategy of performing CT angiography or cardiovascular MRI first in patients with suspected non-ST-elevation MI safely improved appropriate selection for invasive coronary angiography in the Dutch randomized CARMENTA trial.
The strategy of using noninvasive imaging first significantly cut down on the high proportion of diagnostic invasive angiography procedures that end up showing no significant obstructive coronary artery disease in the current era of high-sensitivity cardiac troponin assays, Martijn W. Smulders, MD, reported at the annual meeting of the American College of Cardiology.
CARMENTA (Cardiovascular Magnetic Resonance Imaging and Computed Tomography Angiography) was a single-center, prospective, randomized trial including 207 patients with suspected NSTEMI on the basis of acute chest pain, an elevated high-sensitivity cardiac troponin level, and an inconclusive ECG. They were randomized to one of three diagnostic strategies: a routine invasive strategy in which they were sent straight to the cardiac catheterization lab for invasive coronary angiography, or either CTA- or CMR-first as gatekeeper strategies in which referral for invasive angiography was reserved for only those patients whose noninvasive imaging demonstrated myocardial ischemia, infarction, or obstructive CAD with at least a 70% stenosis.
The impetus for the trial was the investigators’ concern that widespread embrace of high-sensitivity cardiac troponin assays has resulted in a serious clinical problem: Although these assays offer very high sensitivity for rapid detection of acute MI, their positive predictive value is only 56%, compared with 76% for the older troponin assays.
“That means almost one out of two patients with acute chest pain and an elevated high-sensitivity troponin level does not have a type 1 MI. We see a twofold higher incidence of elevated troponin levels with these assays, so there has been a significant increase in referrals for invasive angiography – and up to one-third of these patients with suspected NSTEMI don’t have an obstructive stenosis. We need a strategy to improve patient selection,” explained Dr. Smulders of Maastricht (the Netherlands) University.
The CARMENTA strategy worked. The primary outcome – the proportion of patients with suspected NSTEMI who underwent invasive coronary angiography during their initial hospitalization – was 65% in the CTA-first group and 77% in the CMR group, compared with 100% in the routine invasive-strategy control group. Moreover, fully 38% of patients in the control group turned out not to have obstructive CAD, compared with 15% who were sent for invasive angiography only after CTA and 31% who first had CMR.
Procedure-related complications, a secondary outcome, occurred in 12% of the CMR-first group, 13% of the CTA-first group, and 16% of patients in the routine invasive strategy control group. Major adverse cardiac events during 1 year of follow-up, which was the other secondary outcome, occurred in 9% of the CMR group, 6% of the CTA group, and 9% of the control group.
A limitation of the CARMENTA trial was that, even though it was scheduled to enroll 288 patients to achieve strong statistical power, the study’s data safety monitoring committee recommended on the basis of an interim analysis that the trial be halted early. The reasoning was that the experience of the first 200 enrollees made it clear that the noninvasive-imaging-first strategy would achieve the goal of reducing the volume of referrals to invasive angiography for suspected NSTEMI.
Session cochair Stefan D. Anker, MD, was irked by the trial’s early termination, which weakened the strength of the conclusions, especially with regard to the safety of the novel strategy.
“I agree that this imaging-first strategy reduces procedures, but the use of the word ‘safely’ is premature,” said Dr. Anker, professor of homeostasis and cachexia at Charite Medical School in Berlin.
“I totally agree with you,” Dr. Smulders replied. “We need a bigger trial to confirm our results – preferably a multicenter trial.”
“How can you do a bigger trial when your data safety monitoring board didn’t allow you to complete even this trial? They killed your trial. That’s the way I see it,” Dr. Anker said.
The CARMENTA trial was funded by the Dutch Heart Foundation. Dr. Smulders reported having no financial conflicts of interest.
SOURCE: Smulders M. ACC 18.
ORLANDO – A novel diagnostic strategy of performing CT angiography or cardiovascular MRI first in patients with suspected non-ST-elevation MI safely improved appropriate selection for invasive coronary angiography in the Dutch randomized CARMENTA trial.
The strategy of using noninvasive imaging first significantly cut down on the high proportion of diagnostic invasive angiography procedures that end up showing no significant obstructive coronary artery disease in the current era of high-sensitivity cardiac troponin assays, Martijn W. Smulders, MD, reported at the annual meeting of the American College of Cardiology.
CARMENTA (Cardiovascular Magnetic Resonance Imaging and Computed Tomography Angiography) was a single-center, prospective, randomized trial including 207 patients with suspected NSTEMI on the basis of acute chest pain, an elevated high-sensitivity cardiac troponin level, and an inconclusive ECG. They were randomized to one of three diagnostic strategies: a routine invasive strategy in which they were sent straight to the cardiac catheterization lab for invasive coronary angiography, or either CTA- or CMR-first as gatekeeper strategies in which referral for invasive angiography was reserved for only those patients whose noninvasive imaging demonstrated myocardial ischemia, infarction, or obstructive CAD with at least a 70% stenosis.
The impetus for the trial was the investigators’ concern that widespread embrace of high-sensitivity cardiac troponin assays has resulted in a serious clinical problem: Although these assays offer very high sensitivity for rapid detection of acute MI, their positive predictive value is only 56%, compared with 76% for the older troponin assays.
“That means almost one out of two patients with acute chest pain and an elevated high-sensitivity troponin level does not have a type 1 MI. We see a twofold higher incidence of elevated troponin levels with these assays, so there has been a significant increase in referrals for invasive angiography – and up to one-third of these patients with suspected NSTEMI don’t have an obstructive stenosis. We need a strategy to improve patient selection,” explained Dr. Smulders of Maastricht (the Netherlands) University.
The CARMENTA strategy worked. The primary outcome – the proportion of patients with suspected NSTEMI who underwent invasive coronary angiography during their initial hospitalization – was 65% in the CTA-first group and 77% in the CMR group, compared with 100% in the routine invasive-strategy control group. Moreover, fully 38% of patients in the control group turned out not to have obstructive CAD, compared with 15% who were sent for invasive angiography only after CTA and 31% who first had CMR.
Procedure-related complications, a secondary outcome, occurred in 12% of the CMR-first group, 13% of the CTA-first group, and 16% of patients in the routine invasive strategy control group. Major adverse cardiac events during 1 year of follow-up, which was the other secondary outcome, occurred in 9% of the CMR group, 6% of the CTA group, and 9% of the control group.
A limitation of the CARMENTA trial was that, even though it was scheduled to enroll 288 patients to achieve strong statistical power, the study’s data safety monitoring committee recommended on the basis of an interim analysis that the trial be halted early. The reasoning was that the experience of the first 200 enrollees made it clear that the noninvasive-imaging-first strategy would achieve the goal of reducing the volume of referrals to invasive angiography for suspected NSTEMI.
Session cochair Stefan D. Anker, MD, was irked by the trial’s early termination, which weakened the strength of the conclusions, especially with regard to the safety of the novel strategy.
“I agree that this imaging-first strategy reduces procedures, but the use of the word ‘safely’ is premature,” said Dr. Anker, professor of homeostasis and cachexia at Charite Medical School in Berlin.
“I totally agree with you,” Dr. Smulders replied. “We need a bigger trial to confirm our results – preferably a multicenter trial.”
“How can you do a bigger trial when your data safety monitoring board didn’t allow you to complete even this trial? They killed your trial. That’s the way I see it,” Dr. Anker said.
The CARMENTA trial was funded by the Dutch Heart Foundation. Dr. Smulders reported having no financial conflicts of interest.
SOURCE: Smulders M. ACC 18.
REPORTING FROM ACC 18
Key clinical point: Dutch cardiologists have come up with a novel way to reduce the high rate of negative diagnostic coronary angiography in patients with suspected NSTEMI.
Major finding: Reserving invasive coronary angiography for only those patients with suspected NSTEMI who first showed positive findings on noninvasive CT angiography reduced invasive angiography volume by 35%.
Study details: This single-center, randomized, prospective, three-arm clinical trial included 207 patients with suspected NSTEMI.
Disclosures: The CARMENTA trial was funded by the Dutch Heart Foundation. The presenter reported having no financial conflicts of interest.
Source: Smulders M. ACC 18.
Top hospital heart failure performance translates to longer survival
ORLANDO – Hospitals in the first quartile of short-term performance in treating heart failure patients had higher long-term survival rates for those patients, based on data from 317 hospitals that participated in a voluntary quality improvement program.
The burden of heart failure remains substantial in the United States, and health policies are increasingly focused on improving care for heart failure patients, said Ambarish Pandey, MD, of the University of Texas, Dallas, in a presentation at the annual meeting of the American College of Cardiology.
The researchers assessed hospital performance based on 30-day risk-standardized mortality rates (RSMR) in hospitals participating in the Get With the Guidelines–Heart Failure (GWTG-HF) registry, using a hierarchical, logistic regression model to calculate hospital-specific 30-day RSMRs.
Get With the Guidelines is a voluntary, observational quality improvement program that has been linked with CMS to capture long-term follow-up data, Dr. Pandey explained.
The study included 106,304 heart failure patients older than 65 years at 317 GWTG hospitals across the United States during 2005-2013. The hospitals were divided into performance quartiles based on 30-day RSMR. The 30-day RSMRs were 8.6%, 9.4%, 9.9%, and 10.7% in the first, second, third, and fourth quartiles, respectively.
There was a strong association between the top-performing hospitals and long-term survival rates for the patients that persisted beyond 30 days, said Dr. Pandey. The mortality rates after 5 years were 75.6%, 76.2%, 76.9%, and 79.6%, in the first, second, third, and fourth quartiles, respectively.
The hospitals in the first quartile were more likely than those in the fourth quartile to have primary percutaneous coronary intervention capabilities (80% vs. 73%), in-house cardiac surgery (66% vs. 57%), and a heart transplant center (13% vs. 2%).
In addition, the hospitals in the highest quartile had higher rates of adherence than those in the lowest quartile to guideline-directed heart failure therapies, including evidence-based beta-blocker use, ACE inhibitor and angiotensin receptor blocker use, postdischarge heart failure follow-up, implantable cardioverter defibrillator placement prior to discharge, and cardiac resynchronization therapy prior to discharge.The study was limited by a possible lack of generalizability to hospitals not participating in the GWTG program, Dr. Pandey said. In addition, “we cannot establish causation between hospital performance based on 30-day RSMR and long-term survival.”
However, the long-term survival advantage for heart failure patients treated at hospitals with the highest measures of short-term performance suggests that the 30-day RSMR could be used as an incentive for quality care and the improvement of long-term outcomes, he said.
Dr. Pandey had no financial conflicts to disclose. The Get With the Guidelines–Heart Failure program is supported by the American Heart Association, and has been previously funded by Medtronic, GlaxoSmithKline, Ortho-McNeil, and the AHA Pharmaceutical Roundtable. The findings were published simultaneously in JAMA Cardiology (2018 Mar 12. doi:10.1001/jamacardio.2018.0579).
SOURCE: Pandy A. ACC 2018.
ORLANDO – Hospitals in the first quartile of short-term performance in treating heart failure patients had higher long-term survival rates for those patients, based on data from 317 hospitals that participated in a voluntary quality improvement program.
The burden of heart failure remains substantial in the United States, and health policies are increasingly focused on improving care for heart failure patients, said Ambarish Pandey, MD, of the University of Texas, Dallas, in a presentation at the annual meeting of the American College of Cardiology.
The researchers assessed hospital performance based on 30-day risk-standardized mortality rates (RSMR) in hospitals participating in the Get With the Guidelines–Heart Failure (GWTG-HF) registry, using a hierarchical, logistic regression model to calculate hospital-specific 30-day RSMRs.
Get With the Guidelines is a voluntary, observational quality improvement program that has been linked with CMS to capture long-term follow-up data, Dr. Pandey explained.
The study included 106,304 heart failure patients older than 65 years at 317 GWTG hospitals across the United States during 2005-2013. The hospitals were divided into performance quartiles based on 30-day RSMR. The 30-day RSMRs were 8.6%, 9.4%, 9.9%, and 10.7% in the first, second, third, and fourth quartiles, respectively.
There was a strong association between the top-performing hospitals and long-term survival rates for the patients that persisted beyond 30 days, said Dr. Pandey. The mortality rates after 5 years were 75.6%, 76.2%, 76.9%, and 79.6%, in the first, second, third, and fourth quartiles, respectively.
The hospitals in the first quartile were more likely than those in the fourth quartile to have primary percutaneous coronary intervention capabilities (80% vs. 73%), in-house cardiac surgery (66% vs. 57%), and a heart transplant center (13% vs. 2%).
In addition, the hospitals in the highest quartile had higher rates of adherence than those in the lowest quartile to guideline-directed heart failure therapies, including evidence-based beta-blocker use, ACE inhibitor and angiotensin receptor blocker use, postdischarge heart failure follow-up, implantable cardioverter defibrillator placement prior to discharge, and cardiac resynchronization therapy prior to discharge.The study was limited by a possible lack of generalizability to hospitals not participating in the GWTG program, Dr. Pandey said. In addition, “we cannot establish causation between hospital performance based on 30-day RSMR and long-term survival.”
However, the long-term survival advantage for heart failure patients treated at hospitals with the highest measures of short-term performance suggests that the 30-day RSMR could be used as an incentive for quality care and the improvement of long-term outcomes, he said.
Dr. Pandey had no financial conflicts to disclose. The Get With the Guidelines–Heart Failure program is supported by the American Heart Association, and has been previously funded by Medtronic, GlaxoSmithKline, Ortho-McNeil, and the AHA Pharmaceutical Roundtable. The findings were published simultaneously in JAMA Cardiology (2018 Mar 12. doi:10.1001/jamacardio.2018.0579).
SOURCE: Pandy A. ACC 2018.
ORLANDO – Hospitals in the first quartile of short-term performance in treating heart failure patients had higher long-term survival rates for those patients, based on data from 317 hospitals that participated in a voluntary quality improvement program.
The burden of heart failure remains substantial in the United States, and health policies are increasingly focused on improving care for heart failure patients, said Ambarish Pandey, MD, of the University of Texas, Dallas, in a presentation at the annual meeting of the American College of Cardiology.
The researchers assessed hospital performance based on 30-day risk-standardized mortality rates (RSMR) in hospitals participating in the Get With the Guidelines–Heart Failure (GWTG-HF) registry, using a hierarchical, logistic regression model to calculate hospital-specific 30-day RSMRs.
Get With the Guidelines is a voluntary, observational quality improvement program that has been linked with CMS to capture long-term follow-up data, Dr. Pandey explained.
The study included 106,304 heart failure patients older than 65 years at 317 GWTG hospitals across the United States during 2005-2013. The hospitals were divided into performance quartiles based on 30-day RSMR. The 30-day RSMRs were 8.6%, 9.4%, 9.9%, and 10.7% in the first, second, third, and fourth quartiles, respectively.
There was a strong association between the top-performing hospitals and long-term survival rates for the patients that persisted beyond 30 days, said Dr. Pandey. The mortality rates after 5 years were 75.6%, 76.2%, 76.9%, and 79.6%, in the first, second, third, and fourth quartiles, respectively.
The hospitals in the first quartile were more likely than those in the fourth quartile to have primary percutaneous coronary intervention capabilities (80% vs. 73%), in-house cardiac surgery (66% vs. 57%), and a heart transplant center (13% vs. 2%).
In addition, the hospitals in the highest quartile had higher rates of adherence than those in the lowest quartile to guideline-directed heart failure therapies, including evidence-based beta-blocker use, ACE inhibitor and angiotensin receptor blocker use, postdischarge heart failure follow-up, implantable cardioverter defibrillator placement prior to discharge, and cardiac resynchronization therapy prior to discharge.The study was limited by a possible lack of generalizability to hospitals not participating in the GWTG program, Dr. Pandey said. In addition, “we cannot establish causation between hospital performance based on 30-day RSMR and long-term survival.”
However, the long-term survival advantage for heart failure patients treated at hospitals with the highest measures of short-term performance suggests that the 30-day RSMR could be used as an incentive for quality care and the improvement of long-term outcomes, he said.
Dr. Pandey had no financial conflicts to disclose. The Get With the Guidelines–Heart Failure program is supported by the American Heart Association, and has been previously funded by Medtronic, GlaxoSmithKline, Ortho-McNeil, and the AHA Pharmaceutical Roundtable. The findings were published simultaneously in JAMA Cardiology (2018 Mar 12. doi:10.1001/jamacardio.2018.0579).
SOURCE: Pandy A. ACC 2018.
REPORTING FROM ACC 2018
Key clinical point:
Major finding: Hospitals in the lowest quartile had a 22% higher 5-year mortality rate for heart failure patients compared with the highest quartile hospitals.
Study details: The data come from 106,304 heart failure patients admitted to 317 hospitals participating in a voluntary quality improvement program.
Disclosures: Dr. Pandey had no financial conflicts to disclose. The Get With the Guidelines–Heart Failure program is supported by the American Heart Association, and has been previously funded by Medtronic, GlaxoSmithKline, Ortho-McNeil, and the AHA Pharmaceutical Roundtable.
Source: Pandey A. ACC 2018.
VIDEO: PFO closure device 100% effective against future strokes
ORLANDO – Closing a patent foramen ovale reduced the incidence of stroke and other adverse events in patients at increased risk the DEFENSE-PRO trial.
“The potential association between patent foramen ovale [PFO] and cryptogenic stroke has been a controversial issue for decades,” Jae Kwan Song, MD, of Asan Medical Center in Seoul, South Korea, said in an interview at the annual meeting of the American College of Cardiology.
In this study, 60 patients with high-risk PFOs (at least 2 mm) were randomized to receive anticoagulant or antiplatelet medications alone, and 60 were randomized to medication plus implantation of the Amplatzer PFO closure device.
The device implantation was successful for all patients in the device group. The primary endpoint was a combination of stroke, vascular death, and major bleeding within 2 years of follow-up after the procedure.
After an average follow-up of 2.8 years, none of the patients in the device group and six (10%) of patients in the medication-only group experienced a primary endpoint event. The events in the medication-only group included five cases of ischemic stroke, two cases of TIMI-defined major bleeding, one cerebral hemorrhage, and one transient ischemic attack.
Nonfatal procedural complications included two cases of atrial fibrillation, one case of pericardial effusion, and one pseudoaneurysm.
The average age of the patients was 54 years in the medication-only group and 49 years in the device group, and roughly one-third of the patients in each group were male. The baseline clinical characteristics, including the presence of hypertension, diabetes, smoking, and high cholesterol, were similar between the groups.
“We should consider two things before clinical decision of device closure,” Dr. Song said. First, exclude other causes of cryptogenic stroke; and second, conduct a comprehensive evaluation of the PFO to determine which patients are at highest risk and would be most likely to benefit from the procedure, he said.
To better determine which patients would benefit from the device implantation, Dr. Song and his colleagues used imaging to review data on the size and features of the PFO; patients with evidence of an atrial septal aneurysm or hypermobility (defined as a septal excursion 10 mm or larger) were deemed at especially high risk.
Dr. Song said that the next steps for research on management of PFOs include determining which medications are most effective in patients treated with medication alone, as well as clarifying the process of patient selection for device use based on PFO morphology.
The study was terminated early because of several factors, including low patient recruitment and the decision not to deny patients the closure treatment because of its demonstrated effectiveness, Dr. Song noted.
The study was supported by the Cardiovascular Research Foundation in Seoul, South Korea. Dr. Song had no financial conflicts to disclose. The findings were published simultaneously in the Journal of the American College of Cardiology (doi: 10.1016/j.jacc.2018.02.046).
SOURCE: Song J. ACC 2018.
ORLANDO – Closing a patent foramen ovale reduced the incidence of stroke and other adverse events in patients at increased risk the DEFENSE-PRO trial.
“The potential association between patent foramen ovale [PFO] and cryptogenic stroke has been a controversial issue for decades,” Jae Kwan Song, MD, of Asan Medical Center in Seoul, South Korea, said in an interview at the annual meeting of the American College of Cardiology.
In this study, 60 patients with high-risk PFOs (at least 2 mm) were randomized to receive anticoagulant or antiplatelet medications alone, and 60 were randomized to medication plus implantation of the Amplatzer PFO closure device.
The device implantation was successful for all patients in the device group. The primary endpoint was a combination of stroke, vascular death, and major bleeding within 2 years of follow-up after the procedure.
After an average follow-up of 2.8 years, none of the patients in the device group and six (10%) of patients in the medication-only group experienced a primary endpoint event. The events in the medication-only group included five cases of ischemic stroke, two cases of TIMI-defined major bleeding, one cerebral hemorrhage, and one transient ischemic attack.
Nonfatal procedural complications included two cases of atrial fibrillation, one case of pericardial effusion, and one pseudoaneurysm.
The average age of the patients was 54 years in the medication-only group and 49 years in the device group, and roughly one-third of the patients in each group were male. The baseline clinical characteristics, including the presence of hypertension, diabetes, smoking, and high cholesterol, were similar between the groups.
“We should consider two things before clinical decision of device closure,” Dr. Song said. First, exclude other causes of cryptogenic stroke; and second, conduct a comprehensive evaluation of the PFO to determine which patients are at highest risk and would be most likely to benefit from the procedure, he said.
To better determine which patients would benefit from the device implantation, Dr. Song and his colleagues used imaging to review data on the size and features of the PFO; patients with evidence of an atrial septal aneurysm or hypermobility (defined as a septal excursion 10 mm or larger) were deemed at especially high risk.
Dr. Song said that the next steps for research on management of PFOs include determining which medications are most effective in patients treated with medication alone, as well as clarifying the process of patient selection for device use based on PFO morphology.
The study was terminated early because of several factors, including low patient recruitment and the decision not to deny patients the closure treatment because of its demonstrated effectiveness, Dr. Song noted.
The study was supported by the Cardiovascular Research Foundation in Seoul, South Korea. Dr. Song had no financial conflicts to disclose. The findings were published simultaneously in the Journal of the American College of Cardiology (doi: 10.1016/j.jacc.2018.02.046).
SOURCE: Song J. ACC 2018.
ORLANDO – Closing a patent foramen ovale reduced the incidence of stroke and other adverse events in patients at increased risk the DEFENSE-PRO trial.
“The potential association between patent foramen ovale [PFO] and cryptogenic stroke has been a controversial issue for decades,” Jae Kwan Song, MD, of Asan Medical Center in Seoul, South Korea, said in an interview at the annual meeting of the American College of Cardiology.
In this study, 60 patients with high-risk PFOs (at least 2 mm) were randomized to receive anticoagulant or antiplatelet medications alone, and 60 were randomized to medication plus implantation of the Amplatzer PFO closure device.
The device implantation was successful for all patients in the device group. The primary endpoint was a combination of stroke, vascular death, and major bleeding within 2 years of follow-up after the procedure.
After an average follow-up of 2.8 years, none of the patients in the device group and six (10%) of patients in the medication-only group experienced a primary endpoint event. The events in the medication-only group included five cases of ischemic stroke, two cases of TIMI-defined major bleeding, one cerebral hemorrhage, and one transient ischemic attack.
Nonfatal procedural complications included two cases of atrial fibrillation, one case of pericardial effusion, and one pseudoaneurysm.
The average age of the patients was 54 years in the medication-only group and 49 years in the device group, and roughly one-third of the patients in each group were male. The baseline clinical characteristics, including the presence of hypertension, diabetes, smoking, and high cholesterol, were similar between the groups.
“We should consider two things before clinical decision of device closure,” Dr. Song said. First, exclude other causes of cryptogenic stroke; and second, conduct a comprehensive evaluation of the PFO to determine which patients are at highest risk and would be most likely to benefit from the procedure, he said.
To better determine which patients would benefit from the device implantation, Dr. Song and his colleagues used imaging to review data on the size and features of the PFO; patients with evidence of an atrial septal aneurysm or hypermobility (defined as a septal excursion 10 mm or larger) were deemed at especially high risk.
Dr. Song said that the next steps for research on management of PFOs include determining which medications are most effective in patients treated with medication alone, as well as clarifying the process of patient selection for device use based on PFO morphology.
The study was terminated early because of several factors, including low patient recruitment and the decision not to deny patients the closure treatment because of its demonstrated effectiveness, Dr. Song noted.
The study was supported by the Cardiovascular Research Foundation in Seoul, South Korea. Dr. Song had no financial conflicts to disclose. The findings were published simultaneously in the Journal of the American College of Cardiology (doi: 10.1016/j.jacc.2018.02.046).
SOURCE: Song J. ACC 2018.
REPORTING FROM ACC 18
Key clinical point: Closure of patent foramen ovale resulted in no adverse events or recurrent strokes during 2 years’ follow-up.
Major finding: No adverse event or strokes occurred in the device-plus-medication group, compared with six events in the medication-only group.
Study details: The data come from DEFENSE-PFO, a randomized trial of 120 adults with a history of cryptogenic stroke and high-risk PFO.
Disclosures: DEFENSE-PFO was supported by the Cardiovascular Research Foundation in Seoul, South Korea. Dr. Song had no financial conflicts to disclose.
Source: Song J. ACC 2018.
VIDEO: Case for rivaroxaban & aspirin for PAD gets stronger
ORLANDO – Combination treatment with aspirin and a low dosage of the anticoagulant rivaroxaban had a broader benefit for reducing adverse events in patients with peripheral artery disease than initially reported from the COMPASS trial, which included more than 7,000 patients whose primary diagnosis at study entry was stable PAD.
Secondary analysis of data from the PAD patients enrolled in the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial showed that, compared with aspirin alone, treatment with 100 mg aspirin daily plus a low dosage of the anticoagulant rivaroxaban (2.5 mg b.i.d.) resulted in a statistically significant, 24% relative cut in the combined rate of vascular interventions: acute or chronic limb ischemia, vascular amputations, peripheral vascular bypass or percutaneous intervention, and vascular hospitalizations, Sonia S. Anand, MD, said at the annual meeting of the American College of Cardiology.
This finding plus the results in a prior report from COMPASS that rivaroxaban plus aspirin cut major adverse limb events (MALE) by 33%, compared with aspirin alone (Lancet. 2018 Jan 20;391:219-9), together show that rivaroxaban plus aspirin represent a new, effective regimen for a majority of PAD patients (in addition to treating with a statin and an ACE inhibitor) to cut adverse outcomes in a high-risk but historically undertreated patient population, Dr. Anand said in a video interview.
Additional analysis that Dr. Anand reported in her talk showed that patients with PAD who had an index MALE during follow-up had a very high rate of subsequent events. Among the 128 PAD patients in COMPASS who had an index MALE (major vascular amputation or severe limb ischemia that resulted in an intervention) and, compared with the PAD patients who did not have a MALE, the rate of subsequent death was more than three times higher, the rate of hospitalization increased more than 7-fold, and the rate of amputation increased nearly 200-fold.
Concurrently with Dr. Anand’s report at the meeting the results appeared in an article online in the Journal of the American College of Cardiology.
The analysis of post-MALE outcomes, as well as the expanded vascular-outcomes analysis, focused on 6,391 of the COMPASS patients who had lower-extremity PAD and were randomized to either 100 mg aspirin daily or the low-dosage rivaroxaban plus aspirin regimen. COMPASS also randomized patients to a higher-dosage rivaroxaban-only regimen administered at 5 mg b.i.d., but this arm did not perform as well as the lower-dosage regimen, with an efficacy that equaled aspirin only and with more bleeding. The primary efficacy and safety data from COMPASS for all 27,395 enrolled patients, which included many patients with stable coronary artery disease and without diagnosed PAD, appeared in 2017 (N Engl J Med. Oct 5;377[14]:1319-30).
Dr. Anand also reported on a comparison of the clinical and demographic profiles of the 128 PAD patients who developed MALE during follow-up and the 6,263 who did not, a 2% incidence during almost 2 years.
Multivariate analysis identified four significant factors that closely linked with MALE incidence: a history of peripheral surgery or angioplasty, prior limb amputation, baseline Fontaine classification of stage III or IV, and treatment in COMPASS with aspirin alone and not with rivaroxaban plus aspirin.
The new, additional analyses Dr. Anand reported also showed total peripheral vascular outcomes during follow-up in COMPASS in 8.0% of patients on aspirin only and 6.2% of patients on aspirin plus low-dosage rivaroxaban, a 24% relative risk reduction, and vascular interventions in 7.1% of aspirin-only patients and in 5.5% of the combined-regimen patients, also a 24% relative risk reduction. MALE occurred in 2.6% of the aspirin-only patients and in 1.5% of patients on both drugs, a 33% relative risk reduction. All three of these relative risk reductions were statistically significant, said Dr. Anand, a cardiologist and professor of medicine at McMaster University in Hamilton, Ont.
She estimated that about two-thirds of the PAD patients she sees in routine practice would qualify for treatment with aspirin plus low-dosage rivaroxaban once the 2.5 mg formulation becomes approved by regulators. The companies that jointly market rivaroxaban (Xarelto)have an application pending with the Food and Drug Administration to market a 2.5-mg pill based on the COMPASS results. Patients with stable PAD who are not good candidates for the COMPASS regimen are those with a history of a major bleed, those who require full-dose anticoagulation for a comorbidity such as atrial fibrillation or a mechanical heart valve, and patients with newly diagnosed, stable PAD without concurrent coronary artery disease who might receive adequate protection from aspirin alone, Dr. Anand said.
COMPASS was sponsored by Bayer, the company that along with Janssen markets rivaroxaban. Dr. Anand has been a consultant to Bayer and Novartis. Dr. Beckman has been a consultant to Janssen and other pharmaceutical companies.
SOURCE: Anand SS et al. J Amer Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.008.
ORLANDO – Combination treatment with aspirin and a low dosage of the anticoagulant rivaroxaban had a broader benefit for reducing adverse events in patients with peripheral artery disease than initially reported from the COMPASS trial, which included more than 7,000 patients whose primary diagnosis at study entry was stable PAD.
Secondary analysis of data from the PAD patients enrolled in the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial showed that, compared with aspirin alone, treatment with 100 mg aspirin daily plus a low dosage of the anticoagulant rivaroxaban (2.5 mg b.i.d.) resulted in a statistically significant, 24% relative cut in the combined rate of vascular interventions: acute or chronic limb ischemia, vascular amputations, peripheral vascular bypass or percutaneous intervention, and vascular hospitalizations, Sonia S. Anand, MD, said at the annual meeting of the American College of Cardiology.
This finding plus the results in a prior report from COMPASS that rivaroxaban plus aspirin cut major adverse limb events (MALE) by 33%, compared with aspirin alone (Lancet. 2018 Jan 20;391:219-9), together show that rivaroxaban plus aspirin represent a new, effective regimen for a majority of PAD patients (in addition to treating with a statin and an ACE inhibitor) to cut adverse outcomes in a high-risk but historically undertreated patient population, Dr. Anand said in a video interview.
Additional analysis that Dr. Anand reported in her talk showed that patients with PAD who had an index MALE during follow-up had a very high rate of subsequent events. Among the 128 PAD patients in COMPASS who had an index MALE (major vascular amputation or severe limb ischemia that resulted in an intervention) and, compared with the PAD patients who did not have a MALE, the rate of subsequent death was more than three times higher, the rate of hospitalization increased more than 7-fold, and the rate of amputation increased nearly 200-fold.
Concurrently with Dr. Anand’s report at the meeting the results appeared in an article online in the Journal of the American College of Cardiology.
The analysis of post-MALE outcomes, as well as the expanded vascular-outcomes analysis, focused on 6,391 of the COMPASS patients who had lower-extremity PAD and were randomized to either 100 mg aspirin daily or the low-dosage rivaroxaban plus aspirin regimen. COMPASS also randomized patients to a higher-dosage rivaroxaban-only regimen administered at 5 mg b.i.d., but this arm did not perform as well as the lower-dosage regimen, with an efficacy that equaled aspirin only and with more bleeding. The primary efficacy and safety data from COMPASS for all 27,395 enrolled patients, which included many patients with stable coronary artery disease and without diagnosed PAD, appeared in 2017 (N Engl J Med. Oct 5;377[14]:1319-30).
Dr. Anand also reported on a comparison of the clinical and demographic profiles of the 128 PAD patients who developed MALE during follow-up and the 6,263 who did not, a 2% incidence during almost 2 years.
Multivariate analysis identified four significant factors that closely linked with MALE incidence: a history of peripheral surgery or angioplasty, prior limb amputation, baseline Fontaine classification of stage III or IV, and treatment in COMPASS with aspirin alone and not with rivaroxaban plus aspirin.
The new, additional analyses Dr. Anand reported also showed total peripheral vascular outcomes during follow-up in COMPASS in 8.0% of patients on aspirin only and 6.2% of patients on aspirin plus low-dosage rivaroxaban, a 24% relative risk reduction, and vascular interventions in 7.1% of aspirin-only patients and in 5.5% of the combined-regimen patients, also a 24% relative risk reduction. MALE occurred in 2.6% of the aspirin-only patients and in 1.5% of patients on both drugs, a 33% relative risk reduction. All three of these relative risk reductions were statistically significant, said Dr. Anand, a cardiologist and professor of medicine at McMaster University in Hamilton, Ont.
She estimated that about two-thirds of the PAD patients she sees in routine practice would qualify for treatment with aspirin plus low-dosage rivaroxaban once the 2.5 mg formulation becomes approved by regulators. The companies that jointly market rivaroxaban (Xarelto)have an application pending with the Food and Drug Administration to market a 2.5-mg pill based on the COMPASS results. Patients with stable PAD who are not good candidates for the COMPASS regimen are those with a history of a major bleed, those who require full-dose anticoagulation for a comorbidity such as atrial fibrillation or a mechanical heart valve, and patients with newly diagnosed, stable PAD without concurrent coronary artery disease who might receive adequate protection from aspirin alone, Dr. Anand said.
COMPASS was sponsored by Bayer, the company that along with Janssen markets rivaroxaban. Dr. Anand has been a consultant to Bayer and Novartis. Dr. Beckman has been a consultant to Janssen and other pharmaceutical companies.
SOURCE: Anand SS et al. J Amer Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.008.
ORLANDO – Combination treatment with aspirin and a low dosage of the anticoagulant rivaroxaban had a broader benefit for reducing adverse events in patients with peripheral artery disease than initially reported from the COMPASS trial, which included more than 7,000 patients whose primary diagnosis at study entry was stable PAD.
Secondary analysis of data from the PAD patients enrolled in the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial showed that, compared with aspirin alone, treatment with 100 mg aspirin daily plus a low dosage of the anticoagulant rivaroxaban (2.5 mg b.i.d.) resulted in a statistically significant, 24% relative cut in the combined rate of vascular interventions: acute or chronic limb ischemia, vascular amputations, peripheral vascular bypass or percutaneous intervention, and vascular hospitalizations, Sonia S. Anand, MD, said at the annual meeting of the American College of Cardiology.
This finding plus the results in a prior report from COMPASS that rivaroxaban plus aspirin cut major adverse limb events (MALE) by 33%, compared with aspirin alone (Lancet. 2018 Jan 20;391:219-9), together show that rivaroxaban plus aspirin represent a new, effective regimen for a majority of PAD patients (in addition to treating with a statin and an ACE inhibitor) to cut adverse outcomes in a high-risk but historically undertreated patient population, Dr. Anand said in a video interview.
Additional analysis that Dr. Anand reported in her talk showed that patients with PAD who had an index MALE during follow-up had a very high rate of subsequent events. Among the 128 PAD patients in COMPASS who had an index MALE (major vascular amputation or severe limb ischemia that resulted in an intervention) and, compared with the PAD patients who did not have a MALE, the rate of subsequent death was more than three times higher, the rate of hospitalization increased more than 7-fold, and the rate of amputation increased nearly 200-fold.
Concurrently with Dr. Anand’s report at the meeting the results appeared in an article online in the Journal of the American College of Cardiology.
The analysis of post-MALE outcomes, as well as the expanded vascular-outcomes analysis, focused on 6,391 of the COMPASS patients who had lower-extremity PAD and were randomized to either 100 mg aspirin daily or the low-dosage rivaroxaban plus aspirin regimen. COMPASS also randomized patients to a higher-dosage rivaroxaban-only regimen administered at 5 mg b.i.d., but this arm did not perform as well as the lower-dosage regimen, with an efficacy that equaled aspirin only and with more bleeding. The primary efficacy and safety data from COMPASS for all 27,395 enrolled patients, which included many patients with stable coronary artery disease and without diagnosed PAD, appeared in 2017 (N Engl J Med. Oct 5;377[14]:1319-30).
Dr. Anand also reported on a comparison of the clinical and demographic profiles of the 128 PAD patients who developed MALE during follow-up and the 6,263 who did not, a 2% incidence during almost 2 years.
Multivariate analysis identified four significant factors that closely linked with MALE incidence: a history of peripheral surgery or angioplasty, prior limb amputation, baseline Fontaine classification of stage III or IV, and treatment in COMPASS with aspirin alone and not with rivaroxaban plus aspirin.
The new, additional analyses Dr. Anand reported also showed total peripheral vascular outcomes during follow-up in COMPASS in 8.0% of patients on aspirin only and 6.2% of patients on aspirin plus low-dosage rivaroxaban, a 24% relative risk reduction, and vascular interventions in 7.1% of aspirin-only patients and in 5.5% of the combined-regimen patients, also a 24% relative risk reduction. MALE occurred in 2.6% of the aspirin-only patients and in 1.5% of patients on both drugs, a 33% relative risk reduction. All three of these relative risk reductions were statistically significant, said Dr. Anand, a cardiologist and professor of medicine at McMaster University in Hamilton, Ont.
She estimated that about two-thirds of the PAD patients she sees in routine practice would qualify for treatment with aspirin plus low-dosage rivaroxaban once the 2.5 mg formulation becomes approved by regulators. The companies that jointly market rivaroxaban (Xarelto)have an application pending with the Food and Drug Administration to market a 2.5-mg pill based on the COMPASS results. Patients with stable PAD who are not good candidates for the COMPASS regimen are those with a history of a major bleed, those who require full-dose anticoagulation for a comorbidity such as atrial fibrillation or a mechanical heart valve, and patients with newly diagnosed, stable PAD without concurrent coronary artery disease who might receive adequate protection from aspirin alone, Dr. Anand said.
COMPASS was sponsored by Bayer, the company that along with Janssen markets rivaroxaban. Dr. Anand has been a consultant to Bayer and Novartis. Dr. Beckman has been a consultant to Janssen and other pharmaceutical companies.
SOURCE: Anand SS et al. J Amer Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.008.
REPORTING FROM ACC 18
Key clinical point: PAD patients on rivaroxaban plus aspirin had significantly fewer adverse peripheral vascular outcomes.
Major finding: Dual therapy cut total adverse peripheral vascular outcomes by a relative 24%, compared with aspirin alone, during 23-month follow-up.
Study details: Secondary analysis of data from COMPASS, a multicenter, randomized trial with 6,391 patients in the new analysis.
Disclosures: COMPASS was sponsored by Bayer, the company that, along with Janssen markets rivaroxaban. Dr. Anand has been a consultant to Bayer and Novartis. Dr. Beckman has been a consultant to Janssen and other pharmaceutical companies.
Source: Anand SS et al. J Amer Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.008.
VIDEO: Andexanet alfa effectively reverses factor Xa anticoagulant
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
REPORTING FROM ACC 18
Key clinical point:
Major finding: Hemostatic efficacy of andexanet alfa was 83%, and thrombotic events occurred in 11%.
Study details: ANNEXA-4, a single arm cohort study with 227 patients.
Disclosures: ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis.
Source: Connolly S. ACC 2018.
SGLT2 inhibitors cut cardiovascular outcomes regardless of region
ORLANDO – Cardiovascular outcomes were significantly more favorable with sodium glucose cotransporter-2 inhibitors compared with other glucose-lowering drugs, according to data from more than 400,000 type 2 diabetes patients in the Middle East, Asia Pacific, and North America.
Data on cardiovascular outcomes from diabetes treatments in patients outside the United States and Europe are limited, said Mikhail Kosiborod, MD, of Saint Luke’s Mid-America Heart Institute and University of Missouri–Kansas City.
In fact, most patients with type 2 diabetes reside in the Asia-Pacific and the Middle East, he said in a presentation at the annual meeting of the American College of Cardiology.
Dr. Kosiborod was involved in a previous large pharmaco-epidemiologic study known as the Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), that showed SGLT2 inhibitor effects in a broad population of type 2 diabetes patients, but that study included only patients from Europe and North America, and focused on just two outcomes: all-cause mortality and hospitalization for heart failure.
The study population included adults aged 18 years and older diagnosed with type 2 diabetes; a total of 235,064 treated with SGLT2 inhibitors and 235,064 treated with other GLDs. The participants were selected from national databases in Australia, Canada, Israel, Japan, Singapore, and South Korea. Individuals with type 1 diabetes or gestational diabetes were excluded from the study.
Outcomes comparing SGLT2 inhibitors and other GLDs included all-cause death, all-cause death or hospitalization for heart failure, hospitalization for heart failure, myocardial infarction, and stroke. Baseline patient characteristics were similar between the two treatment groups. Exposure time for patients in the SGLT2-inhibitor group was highest by far for dapagliflozin (75%), followed by empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin at 9%, 8%, 4%, 3%, and 1%, respectively. (Ipragliflozin, tofogliflozin, and luseogliflozin are approved only in Japan.)
The researchers identified 5,216 deaths from any cause. Overall, treatment with an SGLT2 inhibitor was associated with significantly lower risks of death (hazard ratio, 0.51), hospitalization for heart failure (HR, 0.64), death or hospitalization for heart failure (HR, 0.60), myocardial infarction (HR, 0.81), and stroke (HR, 0.68).
The findings remained consistent across countries and patient subgroups, and in patients with and without cardiovascular disease, Dr. Kosiborod noted.
The results were limited by several factors, including the observational nature of the study and incomplete mortality data, Dr. Kosiborod said. However, the results suggest that the SGLT2 inhibitors’ impacts on cardiovascular outcomes persist across categories of ethnicity, geography, and cardiovascular disease.
AstraZeneca supported the study. Dr. Kosiborod disclosed relationships with multiple companies including AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, Glytec, and ZS Pharma. The findings were simultaneously published online (J Am Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.009).
SOURCE: Kosiborod M. ACC 2018.
ORLANDO – Cardiovascular outcomes were significantly more favorable with sodium glucose cotransporter-2 inhibitors compared with other glucose-lowering drugs, according to data from more than 400,000 type 2 diabetes patients in the Middle East, Asia Pacific, and North America.
Data on cardiovascular outcomes from diabetes treatments in patients outside the United States and Europe are limited, said Mikhail Kosiborod, MD, of Saint Luke’s Mid-America Heart Institute and University of Missouri–Kansas City.
In fact, most patients with type 2 diabetes reside in the Asia-Pacific and the Middle East, he said in a presentation at the annual meeting of the American College of Cardiology.
Dr. Kosiborod was involved in a previous large pharmaco-epidemiologic study known as the Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), that showed SGLT2 inhibitor effects in a broad population of type 2 diabetes patients, but that study included only patients from Europe and North America, and focused on just two outcomes: all-cause mortality and hospitalization for heart failure.
The study population included adults aged 18 years and older diagnosed with type 2 diabetes; a total of 235,064 treated with SGLT2 inhibitors and 235,064 treated with other GLDs. The participants were selected from national databases in Australia, Canada, Israel, Japan, Singapore, and South Korea. Individuals with type 1 diabetes or gestational diabetes were excluded from the study.
Outcomes comparing SGLT2 inhibitors and other GLDs included all-cause death, all-cause death or hospitalization for heart failure, hospitalization for heart failure, myocardial infarction, and stroke. Baseline patient characteristics were similar between the two treatment groups. Exposure time for patients in the SGLT2-inhibitor group was highest by far for dapagliflozin (75%), followed by empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin at 9%, 8%, 4%, 3%, and 1%, respectively. (Ipragliflozin, tofogliflozin, and luseogliflozin are approved only in Japan.)
The researchers identified 5,216 deaths from any cause. Overall, treatment with an SGLT2 inhibitor was associated with significantly lower risks of death (hazard ratio, 0.51), hospitalization for heart failure (HR, 0.64), death or hospitalization for heart failure (HR, 0.60), myocardial infarction (HR, 0.81), and stroke (HR, 0.68).
The findings remained consistent across countries and patient subgroups, and in patients with and without cardiovascular disease, Dr. Kosiborod noted.
The results were limited by several factors, including the observational nature of the study and incomplete mortality data, Dr. Kosiborod said. However, the results suggest that the SGLT2 inhibitors’ impacts on cardiovascular outcomes persist across categories of ethnicity, geography, and cardiovascular disease.
AstraZeneca supported the study. Dr. Kosiborod disclosed relationships with multiple companies including AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, Glytec, and ZS Pharma. The findings were simultaneously published online (J Am Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.009).
SOURCE: Kosiborod M. ACC 2018.
ORLANDO – Cardiovascular outcomes were significantly more favorable with sodium glucose cotransporter-2 inhibitors compared with other glucose-lowering drugs, according to data from more than 400,000 type 2 diabetes patients in the Middle East, Asia Pacific, and North America.
Data on cardiovascular outcomes from diabetes treatments in patients outside the United States and Europe are limited, said Mikhail Kosiborod, MD, of Saint Luke’s Mid-America Heart Institute and University of Missouri–Kansas City.
In fact, most patients with type 2 diabetes reside in the Asia-Pacific and the Middle East, he said in a presentation at the annual meeting of the American College of Cardiology.
Dr. Kosiborod was involved in a previous large pharmaco-epidemiologic study known as the Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), that showed SGLT2 inhibitor effects in a broad population of type 2 diabetes patients, but that study included only patients from Europe and North America, and focused on just two outcomes: all-cause mortality and hospitalization for heart failure.
The study population included adults aged 18 years and older diagnosed with type 2 diabetes; a total of 235,064 treated with SGLT2 inhibitors and 235,064 treated with other GLDs. The participants were selected from national databases in Australia, Canada, Israel, Japan, Singapore, and South Korea. Individuals with type 1 diabetes or gestational diabetes were excluded from the study.
Outcomes comparing SGLT2 inhibitors and other GLDs included all-cause death, all-cause death or hospitalization for heart failure, hospitalization for heart failure, myocardial infarction, and stroke. Baseline patient characteristics were similar between the two treatment groups. Exposure time for patients in the SGLT2-inhibitor group was highest by far for dapagliflozin (75%), followed by empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin at 9%, 8%, 4%, 3%, and 1%, respectively. (Ipragliflozin, tofogliflozin, and luseogliflozin are approved only in Japan.)
The researchers identified 5,216 deaths from any cause. Overall, treatment with an SGLT2 inhibitor was associated with significantly lower risks of death (hazard ratio, 0.51), hospitalization for heart failure (HR, 0.64), death or hospitalization for heart failure (HR, 0.60), myocardial infarction (HR, 0.81), and stroke (HR, 0.68).
The findings remained consistent across countries and patient subgroups, and in patients with and without cardiovascular disease, Dr. Kosiborod noted.
The results were limited by several factors, including the observational nature of the study and incomplete mortality data, Dr. Kosiborod said. However, the results suggest that the SGLT2 inhibitors’ impacts on cardiovascular outcomes persist across categories of ethnicity, geography, and cardiovascular disease.
AstraZeneca supported the study. Dr. Kosiborod disclosed relationships with multiple companies including AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, Glytec, and ZS Pharma. The findings were simultaneously published online (J Am Coll Cardiol. 2018 Mar 11. doi: 10.1016/j.jacc.2018.03.009).
SOURCE: Kosiborod M. ACC 2018.
REPORTING FROM ACC 18
Key clinical point: SGLT2 inhibitor use was linked to a lower risk of all-cause death, hospitalization for heart failure, myocardial infarction, and stroke in a large, multinational study of adults with type 2 diabetes.
Major finding: All-cause mortality was significantly lower in patients treated with an SGLT2 inhibitor compared with other glucose lowering drugs (HR 0.51).
Study details: The data come from more than 400,000 adults with type 2 diabetes via databases in the Middle East, Asia Pacific, and North America.
Disclosures: AstraZeneca supported the study. Dr. Kosiborod disclosed relationships with AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, Glytec, and ZS Pharma.
Source: Kosiborod M. ACC 2018.
Febuxostat increases cardiovascular mortality in CARES trial
ORLANDO – Long-term treatment with febuxostat in gout patients with comorbid cardiovascular disease conferred significantly higher risks of both cardiovascular death and all-cause mortality, compared with allopurinol, in the Food and Drug Administration–mandated postmarketing CARES trial, William B. White, MD, reported at the annual meeting of the American College of Cardiology.
CARES (Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout and Cardiovascular Disease) was a prospective, double-blind, 320-center North American clinical trial in which 6,190 patients were randomized to febuxostat (Uloric) at 40-80 mg once daily or 200-600 mg of allopurinol once daily. The postmarketing safety study was required by the FDA as a condition of marketing approval for febuxostat in light of preapproval evidence suggestive of a possible increased risk of cardiovascular events, explained Dr. White, professor of medicine and chief of the division of hypertension and clinical pharmacology at the University of Connecticut, Farmington.
The warning klaxon sounded when investigators scrutinized the individual components of the primary endpoint. They found that the 4.3% cardiovascular death rate in the febuxostat group was significantly higher than the 3.2% rate in the allopurinol group, representing a statistically significant 34% increase in relative risk. The event curves began to separate roughly 30 months into the trial. Moreover, all-cause mortality was also significantly increased in the febuxostat group, by a margin of 7.8% to 6.4%, for a 22% increase in risk.
The increased cardiovascular mortality in the febuxostat group was driven by a higher adjudicated sudden cardiac death rate: 2.7%, compared with 1.8% in the allopurinol group.
In a prespecified per protocol analysis of cardiovascular events occurring while patients were actually on treatment or within 1 month after discontinuation, the key findings remained unchanged: no between-group difference in the primary composite endpoint, but a 49% increase in the relative risk of cardiovascular death in the febuxostat-treated patients.
A hefty 45% of participants stopped taking their assigned drug early. Dr. White said this isn’t unusual; high dropout rates are common in clinical trials of patients with painful conditions. Because of the high lost-to-follow-up rate, however, the investigators hired a private investigator to scour the country looking for missed deaths among enrollees. This turned up an extra 199 deaths. When those were added to the total, all-cause mortality in the febuxostat group was no longer significantly higher than for allopurinol.
The puzzle over nonfatal events
A puzzling key study finding was that except for cardiovascular death, the other components of the primary composite endpoint – that is, nonfatal MI, nonfatal stroke, and urgent revascularization due to unstable angina – were all either neutral or numerically favored febuxostat.
“That’s been the biggest challenge in the trial: The nonfatal events didn’t go in the same direction as the fatal events. And we don’t have a real mechanism to explain why,” Dr. White told a panel of discussants.
“I scanned the medical literature over the last 4 decades, and I did not see another prospective, randomized, double-blind trial in which mortality was increased when none of the nonfatal events were increased. The finding is unique. Statistically there is only a 4% chance that the mortality finding is wrong,” the cardiologist said.
The CARES leadership included rheumatologists and nephrologists as well as cardiologists. Dr. White said he and the others were at a loss to come up with an explanation for the findings.
Patients in the febuxostat arm were significantly more likely to achieve serum urate levels below 6 and 5 mg/dL. Their flare rate was 0.68 events per person-year, similar to the 0.63 per person-year rate in the allopurinol group.
Among the pieces of the study puzzle: The majority of cardiovascular deaths occurred in patients who were no longer on therapy, yet investigators could find no evidence of a legacy effect. The mortality risk was 2.3-fold greater with febuxostat than with allopurinol among patients on NSAID therapy, but there was no significant between-group difference among patients not taking NSAIDs. There was a trend for more cardiovascular deaths with febuxostat than allopurinol among patients not on low-dose aspirin. And the cardiovascular mortality was 2.2-fold greater in the febuxostat arm than with allopurinol in patients on colchicine during the study.
Notably, prior to febuxostat’s marketing approval there were extensive studies of the drug’s potential effect on left ventricular function, thrombotic potential, possible arrhythmogenic effects, and impact upon atherosclerosis. Among these investigations was a QT-interval study conducted using febuxostat doses four times higher than the maximum therapeutic dose, which was prescient given the increased sudden cardiac death rate in the subsequent CARES trial. Yet no concerning signals were seen in any of this work, he continued.
“We’re still looking at some correlates that might have an impact. For example, my rheumatologist colleagues feel very strongly that we need to look really extensively at gout flares, even though rates were not that different between the two treatment groups. Gout flares are known to increase oxidative stress and perhaps cause temporary increases in endothelial dysfunction and possibly vasomotor abnormalities,” Dr. White said.
One would think, though, that if gout flares figured in the increase in cardiovascular mortality they would also have been associated with more urgent revascularization for unstable angina, when in fact the rate was actually numerically lower in the febuxostat group, he noted.
Discussant Athena Poppas, MD, director of the Lifespan Cardiovascular Institute at Rhode Island Hospital, Providence, said she couldn’t determine how much of the increased cardiovascular mortality in the febuxostat patients was due to the drug and how much resulted from the suboptimal use of guideline-directed medical therapy across both study arms. At baseline, only 60% of study participants – all by definition at high cardiovascular risk – were on aspirin, just under 75% were on lipid-lowering therapy, 58% were on a beta blocker, and 70% were on a renin-angiotensin system blocker, even though the majority of subjects had stage 3 chronic kidney disease.
Implications of findings and FDA’s next steps
Another discussant, C. Noel Bairey Merz, MD, called the CARES findings “curious.” But despite the lack of a plausible mechanistic explanation for the results, she said, the implications are clear.
“I would conclude that because your modified intention-to-treat as well as your per protocol analyses were consistent for the death endpoint, then despite the high dropout rate, that finding is relatively robust and probably should be used to inform policy,” said Dr. Merz, director of the Women’s Heart Center and the Preventive and Rehabilitative Cardiac Center in the Cedars-Sinai Heart Institute and professor of medicine at the University of California, Los Angeles.
At a press conference, Dr. White said the FDA will spend several months poring over the CARES results and that it would be premature to speculate on what action the agency might take on febuxostat. The drug is prescribed far less frequently than allopurinol for the nation’s estimated 8.2 million gout patients.
“I would certainly be concerned about our findings. However, rheumatologists take care of very ill patients and all the drugs they use have morbidity. So if they’re having substantial efficacy and the person has been on febuxostat for 8 years, I suspect they’re going to continue to give that drug to him,” he said.
Simultaneously with Dr. White’s presentation at ACC 2018, the CARES results were published in the New England Journal of Medicine (N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895).
The CARES trial was funded by Takeda. Dr. White reported serving as a consultant to that company and Novartis and receiving research funding from the National Institutes of Health.
SOURCE: White W et al. ACC 18.
ORLANDO – Long-term treatment with febuxostat in gout patients with comorbid cardiovascular disease conferred significantly higher risks of both cardiovascular death and all-cause mortality, compared with allopurinol, in the Food and Drug Administration–mandated postmarketing CARES trial, William B. White, MD, reported at the annual meeting of the American College of Cardiology.
CARES (Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout and Cardiovascular Disease) was a prospective, double-blind, 320-center North American clinical trial in which 6,190 patients were randomized to febuxostat (Uloric) at 40-80 mg once daily or 200-600 mg of allopurinol once daily. The postmarketing safety study was required by the FDA as a condition of marketing approval for febuxostat in light of preapproval evidence suggestive of a possible increased risk of cardiovascular events, explained Dr. White, professor of medicine and chief of the division of hypertension and clinical pharmacology at the University of Connecticut, Farmington.
The warning klaxon sounded when investigators scrutinized the individual components of the primary endpoint. They found that the 4.3% cardiovascular death rate in the febuxostat group was significantly higher than the 3.2% rate in the allopurinol group, representing a statistically significant 34% increase in relative risk. The event curves began to separate roughly 30 months into the trial. Moreover, all-cause mortality was also significantly increased in the febuxostat group, by a margin of 7.8% to 6.4%, for a 22% increase in risk.
The increased cardiovascular mortality in the febuxostat group was driven by a higher adjudicated sudden cardiac death rate: 2.7%, compared with 1.8% in the allopurinol group.
In a prespecified per protocol analysis of cardiovascular events occurring while patients were actually on treatment or within 1 month after discontinuation, the key findings remained unchanged: no between-group difference in the primary composite endpoint, but a 49% increase in the relative risk of cardiovascular death in the febuxostat-treated patients.
A hefty 45% of participants stopped taking their assigned drug early. Dr. White said this isn’t unusual; high dropout rates are common in clinical trials of patients with painful conditions. Because of the high lost-to-follow-up rate, however, the investigators hired a private investigator to scour the country looking for missed deaths among enrollees. This turned up an extra 199 deaths. When those were added to the total, all-cause mortality in the febuxostat group was no longer significantly higher than for allopurinol.
The puzzle over nonfatal events
A puzzling key study finding was that except for cardiovascular death, the other components of the primary composite endpoint – that is, nonfatal MI, nonfatal stroke, and urgent revascularization due to unstable angina – were all either neutral or numerically favored febuxostat.
“That’s been the biggest challenge in the trial: The nonfatal events didn’t go in the same direction as the fatal events. And we don’t have a real mechanism to explain why,” Dr. White told a panel of discussants.
“I scanned the medical literature over the last 4 decades, and I did not see another prospective, randomized, double-blind trial in which mortality was increased when none of the nonfatal events were increased. The finding is unique. Statistically there is only a 4% chance that the mortality finding is wrong,” the cardiologist said.
The CARES leadership included rheumatologists and nephrologists as well as cardiologists. Dr. White said he and the others were at a loss to come up with an explanation for the findings.
Patients in the febuxostat arm were significantly more likely to achieve serum urate levels below 6 and 5 mg/dL. Their flare rate was 0.68 events per person-year, similar to the 0.63 per person-year rate in the allopurinol group.
Among the pieces of the study puzzle: The majority of cardiovascular deaths occurred in patients who were no longer on therapy, yet investigators could find no evidence of a legacy effect. The mortality risk was 2.3-fold greater with febuxostat than with allopurinol among patients on NSAID therapy, but there was no significant between-group difference among patients not taking NSAIDs. There was a trend for more cardiovascular deaths with febuxostat than allopurinol among patients not on low-dose aspirin. And the cardiovascular mortality was 2.2-fold greater in the febuxostat arm than with allopurinol in patients on colchicine during the study.
Notably, prior to febuxostat’s marketing approval there were extensive studies of the drug’s potential effect on left ventricular function, thrombotic potential, possible arrhythmogenic effects, and impact upon atherosclerosis. Among these investigations was a QT-interval study conducted using febuxostat doses four times higher than the maximum therapeutic dose, which was prescient given the increased sudden cardiac death rate in the subsequent CARES trial. Yet no concerning signals were seen in any of this work, he continued.
“We’re still looking at some correlates that might have an impact. For example, my rheumatologist colleagues feel very strongly that we need to look really extensively at gout flares, even though rates were not that different between the two treatment groups. Gout flares are known to increase oxidative stress and perhaps cause temporary increases in endothelial dysfunction and possibly vasomotor abnormalities,” Dr. White said.
One would think, though, that if gout flares figured in the increase in cardiovascular mortality they would also have been associated with more urgent revascularization for unstable angina, when in fact the rate was actually numerically lower in the febuxostat group, he noted.
Discussant Athena Poppas, MD, director of the Lifespan Cardiovascular Institute at Rhode Island Hospital, Providence, said she couldn’t determine how much of the increased cardiovascular mortality in the febuxostat patients was due to the drug and how much resulted from the suboptimal use of guideline-directed medical therapy across both study arms. At baseline, only 60% of study participants – all by definition at high cardiovascular risk – were on aspirin, just under 75% were on lipid-lowering therapy, 58% were on a beta blocker, and 70% were on a renin-angiotensin system blocker, even though the majority of subjects had stage 3 chronic kidney disease.
Implications of findings and FDA’s next steps
Another discussant, C. Noel Bairey Merz, MD, called the CARES findings “curious.” But despite the lack of a plausible mechanistic explanation for the results, she said, the implications are clear.
“I would conclude that because your modified intention-to-treat as well as your per protocol analyses were consistent for the death endpoint, then despite the high dropout rate, that finding is relatively robust and probably should be used to inform policy,” said Dr. Merz, director of the Women’s Heart Center and the Preventive and Rehabilitative Cardiac Center in the Cedars-Sinai Heart Institute and professor of medicine at the University of California, Los Angeles.
At a press conference, Dr. White said the FDA will spend several months poring over the CARES results and that it would be premature to speculate on what action the agency might take on febuxostat. The drug is prescribed far less frequently than allopurinol for the nation’s estimated 8.2 million gout patients.
“I would certainly be concerned about our findings. However, rheumatologists take care of very ill patients and all the drugs they use have morbidity. So if they’re having substantial efficacy and the person has been on febuxostat for 8 years, I suspect they’re going to continue to give that drug to him,” he said.
Simultaneously with Dr. White’s presentation at ACC 2018, the CARES results were published in the New England Journal of Medicine (N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895).
The CARES trial was funded by Takeda. Dr. White reported serving as a consultant to that company and Novartis and receiving research funding from the National Institutes of Health.
SOURCE: White W et al. ACC 18.
ORLANDO – Long-term treatment with febuxostat in gout patients with comorbid cardiovascular disease conferred significantly higher risks of both cardiovascular death and all-cause mortality, compared with allopurinol, in the Food and Drug Administration–mandated postmarketing CARES trial, William B. White, MD, reported at the annual meeting of the American College of Cardiology.
CARES (Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout and Cardiovascular Disease) was a prospective, double-blind, 320-center North American clinical trial in which 6,190 patients were randomized to febuxostat (Uloric) at 40-80 mg once daily or 200-600 mg of allopurinol once daily. The postmarketing safety study was required by the FDA as a condition of marketing approval for febuxostat in light of preapproval evidence suggestive of a possible increased risk of cardiovascular events, explained Dr. White, professor of medicine and chief of the division of hypertension and clinical pharmacology at the University of Connecticut, Farmington.
The warning klaxon sounded when investigators scrutinized the individual components of the primary endpoint. They found that the 4.3% cardiovascular death rate in the febuxostat group was significantly higher than the 3.2% rate in the allopurinol group, representing a statistically significant 34% increase in relative risk. The event curves began to separate roughly 30 months into the trial. Moreover, all-cause mortality was also significantly increased in the febuxostat group, by a margin of 7.8% to 6.4%, for a 22% increase in risk.
The increased cardiovascular mortality in the febuxostat group was driven by a higher adjudicated sudden cardiac death rate: 2.7%, compared with 1.8% in the allopurinol group.
In a prespecified per protocol analysis of cardiovascular events occurring while patients were actually on treatment or within 1 month after discontinuation, the key findings remained unchanged: no between-group difference in the primary composite endpoint, but a 49% increase in the relative risk of cardiovascular death in the febuxostat-treated patients.
A hefty 45% of participants stopped taking their assigned drug early. Dr. White said this isn’t unusual; high dropout rates are common in clinical trials of patients with painful conditions. Because of the high lost-to-follow-up rate, however, the investigators hired a private investigator to scour the country looking for missed deaths among enrollees. This turned up an extra 199 deaths. When those were added to the total, all-cause mortality in the febuxostat group was no longer significantly higher than for allopurinol.
The puzzle over nonfatal events
A puzzling key study finding was that except for cardiovascular death, the other components of the primary composite endpoint – that is, nonfatal MI, nonfatal stroke, and urgent revascularization due to unstable angina – were all either neutral or numerically favored febuxostat.
“That’s been the biggest challenge in the trial: The nonfatal events didn’t go in the same direction as the fatal events. And we don’t have a real mechanism to explain why,” Dr. White told a panel of discussants.
“I scanned the medical literature over the last 4 decades, and I did not see another prospective, randomized, double-blind trial in which mortality was increased when none of the nonfatal events were increased. The finding is unique. Statistically there is only a 4% chance that the mortality finding is wrong,” the cardiologist said.
The CARES leadership included rheumatologists and nephrologists as well as cardiologists. Dr. White said he and the others were at a loss to come up with an explanation for the findings.
Patients in the febuxostat arm were significantly more likely to achieve serum urate levels below 6 and 5 mg/dL. Their flare rate was 0.68 events per person-year, similar to the 0.63 per person-year rate in the allopurinol group.
Among the pieces of the study puzzle: The majority of cardiovascular deaths occurred in patients who were no longer on therapy, yet investigators could find no evidence of a legacy effect. The mortality risk was 2.3-fold greater with febuxostat than with allopurinol among patients on NSAID therapy, but there was no significant between-group difference among patients not taking NSAIDs. There was a trend for more cardiovascular deaths with febuxostat than allopurinol among patients not on low-dose aspirin. And the cardiovascular mortality was 2.2-fold greater in the febuxostat arm than with allopurinol in patients on colchicine during the study.
Notably, prior to febuxostat’s marketing approval there were extensive studies of the drug’s potential effect on left ventricular function, thrombotic potential, possible arrhythmogenic effects, and impact upon atherosclerosis. Among these investigations was a QT-interval study conducted using febuxostat doses four times higher than the maximum therapeutic dose, which was prescient given the increased sudden cardiac death rate in the subsequent CARES trial. Yet no concerning signals were seen in any of this work, he continued.
“We’re still looking at some correlates that might have an impact. For example, my rheumatologist colleagues feel very strongly that we need to look really extensively at gout flares, even though rates were not that different between the two treatment groups. Gout flares are known to increase oxidative stress and perhaps cause temporary increases in endothelial dysfunction and possibly vasomotor abnormalities,” Dr. White said.
One would think, though, that if gout flares figured in the increase in cardiovascular mortality they would also have been associated with more urgent revascularization for unstable angina, when in fact the rate was actually numerically lower in the febuxostat group, he noted.
Discussant Athena Poppas, MD, director of the Lifespan Cardiovascular Institute at Rhode Island Hospital, Providence, said she couldn’t determine how much of the increased cardiovascular mortality in the febuxostat patients was due to the drug and how much resulted from the suboptimal use of guideline-directed medical therapy across both study arms. At baseline, only 60% of study participants – all by definition at high cardiovascular risk – were on aspirin, just under 75% were on lipid-lowering therapy, 58% were on a beta blocker, and 70% were on a renin-angiotensin system blocker, even though the majority of subjects had stage 3 chronic kidney disease.
Implications of findings and FDA’s next steps
Another discussant, C. Noel Bairey Merz, MD, called the CARES findings “curious.” But despite the lack of a plausible mechanistic explanation for the results, she said, the implications are clear.
“I would conclude that because your modified intention-to-treat as well as your per protocol analyses were consistent for the death endpoint, then despite the high dropout rate, that finding is relatively robust and probably should be used to inform policy,” said Dr. Merz, director of the Women’s Heart Center and the Preventive and Rehabilitative Cardiac Center in the Cedars-Sinai Heart Institute and professor of medicine at the University of California, Los Angeles.
At a press conference, Dr. White said the FDA will spend several months poring over the CARES results and that it would be premature to speculate on what action the agency might take on febuxostat. The drug is prescribed far less frequently than allopurinol for the nation’s estimated 8.2 million gout patients.
“I would certainly be concerned about our findings. However, rheumatologists take care of very ill patients and all the drugs they use have morbidity. So if they’re having substantial efficacy and the person has been on febuxostat for 8 years, I suspect they’re going to continue to give that drug to him,” he said.
Simultaneously with Dr. White’s presentation at ACC 2018, the CARES results were published in the New England Journal of Medicine (N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895).
The CARES trial was funded by Takeda. Dr. White reported serving as a consultant to that company and Novartis and receiving research funding from the National Institutes of Health.
SOURCE: White W et al. ACC 18.
REPORTING FROM ACC 18
Key clinical point: Gout patients on febuxostat were 34% more likely to die of cardiovascular causes than were those on allopurinol.
Major finding: Death due to cardiovascular causes occurred in 4.3% of febuxostat-treated patients and 3.2% assigned to allopurinol.
Study details: This prospective, randomized, double-blind, 320-center clinical trial included nearly 6,200 gout patients with comorbid cardiovascular disease.
Disclosures: The FDA-mandated CARES trial was sponsored by Takeda. The study presenter is a consultant to the company.
Source: White W et al. ACC 18.
VIDEO: Patient vouchers prompt physicians to prescribe top antiplatelet drugs
ORLANDO – Patients who received vouchers to cover copayments were more likely to receive prescriptions for more effective antiplatelet medication, according to data from a multicenter, randomized trial.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“We know that guidelines are very clear; we need to treat patients with antiplatelet therapy for 12 months,” and that the most potent drug, ticagrelor, should be used, Tracy Wang, MD, of Duke University, Durham, N.C., said in a video interview at the annual meeting of the American College of Cardiology. However, in the United States, clopidogrel, though less effective, is prescribed much more often, and many patients discontinue their P2Y12 inhibitor therapy within the first year because of cost, she added.
“We hypothesized that, by reducing the out of pocket costs, treatment would be more evidence driven, rather than driven by what patients could afford,” she said.
The Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS) included 11,001 MI patients at 301 hospitals across the United States. Patients in the treatment hospital group received a voucher to use at a pharmacy or through a mail-order pharmacy to reduce out of pocket costs. Randomization occurred at the hospital level, and hospital characteristics were similar between the groups.
Overall, patients in the treatment group were significantly more likely to receive a prescription for ticagrelor than clopidogrel (60% vs. 36%); 55% and 32% of patients in the usual care group were prescribed ticagrelor and clopidogrel, respectively. Nonpersistence, defined as a gap in P2Y12-inhibitor use of at least 30 days within 1 year, was significantly lower in the treatment group than it was in the usual care group based on patient reported analysis (13% vs. 16%).
However, the incidence of major adverse cardiac events was roughly 10% in both groups. The similar outcomes may stem from the fact that 28% of patients with vouchers did not fill their prescriptions for reasons that the study did not explore, said Dr. Wang.
All patients had health insurance: 64% private, 42% Medicare, 9% Medicaid. The average age of the patients was 62 years, and 31% were women. Patient demographics and clinical characteristics were similar between the groups.
The vouchers affected choice of treatment but didn’t help clinical outcomes, which suggests that copayment reduction should be part of a broader strategy to help patients with adherence over time, said Dr. Wang.
Next steps for research include taking a subset of patients who are more likely to be nonadherent and at high risk for adverse events and targeting them for additional intervention, she noted.
Discussant Craig J. Beavers, PharmD, of the University of Kentucky College of Pharmacy, Lexington, agreed that a multipronged approach is needed to get patients to take their medicines. “We have to figure out what other barriers there are,” he said. “The real trick is, even if you lead a horse to water, how to get them to drink it,” he said.
The study was funded by AstraZeneca. Dr. Wang disclosed relationships with companies including Gilead Sciences, Merck, and Sanofi Pasteur. Dr. Beavers had no financial conflicts to disclose.
SOURCE: Wang T. ACC 18.
ORLANDO – Patients who received vouchers to cover copayments were more likely to receive prescriptions for more effective antiplatelet medication, according to data from a multicenter, randomized trial.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“We know that guidelines are very clear; we need to treat patients with antiplatelet therapy for 12 months,” and that the most potent drug, ticagrelor, should be used, Tracy Wang, MD, of Duke University, Durham, N.C., said in a video interview at the annual meeting of the American College of Cardiology. However, in the United States, clopidogrel, though less effective, is prescribed much more often, and many patients discontinue their P2Y12 inhibitor therapy within the first year because of cost, she added.
“We hypothesized that, by reducing the out of pocket costs, treatment would be more evidence driven, rather than driven by what patients could afford,” she said.
The Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS) included 11,001 MI patients at 301 hospitals across the United States. Patients in the treatment hospital group received a voucher to use at a pharmacy or through a mail-order pharmacy to reduce out of pocket costs. Randomization occurred at the hospital level, and hospital characteristics were similar between the groups.
Overall, patients in the treatment group were significantly more likely to receive a prescription for ticagrelor than clopidogrel (60% vs. 36%); 55% and 32% of patients in the usual care group were prescribed ticagrelor and clopidogrel, respectively. Nonpersistence, defined as a gap in P2Y12-inhibitor use of at least 30 days within 1 year, was significantly lower in the treatment group than it was in the usual care group based on patient reported analysis (13% vs. 16%).
However, the incidence of major adverse cardiac events was roughly 10% in both groups. The similar outcomes may stem from the fact that 28% of patients with vouchers did not fill their prescriptions for reasons that the study did not explore, said Dr. Wang.
All patients had health insurance: 64% private, 42% Medicare, 9% Medicaid. The average age of the patients was 62 years, and 31% were women. Patient demographics and clinical characteristics were similar between the groups.
The vouchers affected choice of treatment but didn’t help clinical outcomes, which suggests that copayment reduction should be part of a broader strategy to help patients with adherence over time, said Dr. Wang.
Next steps for research include taking a subset of patients who are more likely to be nonadherent and at high risk for adverse events and targeting them for additional intervention, she noted.
Discussant Craig J. Beavers, PharmD, of the University of Kentucky College of Pharmacy, Lexington, agreed that a multipronged approach is needed to get patients to take their medicines. “We have to figure out what other barriers there are,” he said. “The real trick is, even if you lead a horse to water, how to get them to drink it,” he said.
The study was funded by AstraZeneca. Dr. Wang disclosed relationships with companies including Gilead Sciences, Merck, and Sanofi Pasteur. Dr. Beavers had no financial conflicts to disclose.
SOURCE: Wang T. ACC 18.
ORLANDO – Patients who received vouchers to cover copayments were more likely to receive prescriptions for more effective antiplatelet medication, according to data from a multicenter, randomized trial.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“We know that guidelines are very clear; we need to treat patients with antiplatelet therapy for 12 months,” and that the most potent drug, ticagrelor, should be used, Tracy Wang, MD, of Duke University, Durham, N.C., said in a video interview at the annual meeting of the American College of Cardiology. However, in the United States, clopidogrel, though less effective, is prescribed much more often, and many patients discontinue their P2Y12 inhibitor therapy within the first year because of cost, she added.
“We hypothesized that, by reducing the out of pocket costs, treatment would be more evidence driven, rather than driven by what patients could afford,” she said.
The Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS) included 11,001 MI patients at 301 hospitals across the United States. Patients in the treatment hospital group received a voucher to use at a pharmacy or through a mail-order pharmacy to reduce out of pocket costs. Randomization occurred at the hospital level, and hospital characteristics were similar between the groups.
Overall, patients in the treatment group were significantly more likely to receive a prescription for ticagrelor than clopidogrel (60% vs. 36%); 55% and 32% of patients in the usual care group were prescribed ticagrelor and clopidogrel, respectively. Nonpersistence, defined as a gap in P2Y12-inhibitor use of at least 30 days within 1 year, was significantly lower in the treatment group than it was in the usual care group based on patient reported analysis (13% vs. 16%).
However, the incidence of major adverse cardiac events was roughly 10% in both groups. The similar outcomes may stem from the fact that 28% of patients with vouchers did not fill their prescriptions for reasons that the study did not explore, said Dr. Wang.
All patients had health insurance: 64% private, 42% Medicare, 9% Medicaid. The average age of the patients was 62 years, and 31% were women. Patient demographics and clinical characteristics were similar between the groups.
The vouchers affected choice of treatment but didn’t help clinical outcomes, which suggests that copayment reduction should be part of a broader strategy to help patients with adherence over time, said Dr. Wang.
Next steps for research include taking a subset of patients who are more likely to be nonadherent and at high risk for adverse events and targeting them for additional intervention, she noted.
Discussant Craig J. Beavers, PharmD, of the University of Kentucky College of Pharmacy, Lexington, agreed that a multipronged approach is needed to get patients to take their medicines. “We have to figure out what other barriers there are,” he said. “The real trick is, even if you lead a horse to water, how to get them to drink it,” he said.
The study was funded by AstraZeneca. Dr. Wang disclosed relationships with companies including Gilead Sciences, Merck, and Sanofi Pasteur. Dr. Beavers had no financial conflicts to disclose.
SOURCE: Wang T. ACC 18.
REPORTING FROM ACC 18
Key clinical point: Physicians were more likely to prescribe ticagrelor after an MI when patients received vouchers.
Major finding: Patients with vouchers received prescriptions for ticagrelor significantly more than clopidogrel (60% vs. 36%).
Study details: The data come from a randomized trial of 301 hospitals in the United States and included 11,001 MI patients.
Disclosures: ARTEMIS was funded by AstraZeneca. Dr. Wang disclosed relationships with companies including Gilead Sciences, Merck, and Sanofi Pasteur. Dr. Beavers had no financial conflicts to disclose.
Source: Wang T. ACC 2018.
Barbershop intervention cuts blood pressure in black men
ORLANDO – Black men who received a pharmacist-led intervention in their local barbershops showed significantly improved blood pressure after 6 months, compared with controls, in a randomized trial of 319 individuals.
“Non-Hispanic black men still have the highest hypertension death rate of any group in the country. Something like 60% of black men have blood pressure of 140/90 or higher,” but they have relatively low rates of physician interaction for blood pressure management, compared with other groups, Ronald G. Victor, MD, of Cedars-Sinai Medical Center, Los Angeles, said in a video interview at the annual meeting of the American College of Cardiology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Health outreach to barbershops has been well established in the lay press, but they only scratch the surface in terms of a scientific evaluation, and that’s what we did,” he noted.
The primary outcome was a change in systolic blood pressure at 6 months. The average decrease was 27.0 mm Hg in the intervention group, compared with 9.3 mm Hg in the control group.
Dr. Victor and colleagues identified a study population of non-Hispanic black men aged 35-79 years with a baseline blood pressure of at least 140 mm Hg who were regular patrons of their local barbershops. Of these, 139 were randomized to a pharmacist-led intervention in 28 barbershops, and 180 served as controls in 24 barbershops.
The intervention included monthly checkups with a pharmacist in the barbershop setting, along with blood pressure readings, medication management, electrolyte monitoring, and progress notes sent to each man’s primary care provider. In addition, the barbers encouraged blood pressure management and a healthy lifestyle during the men’s regular haircut visits, occurring about every 2 weeks. The control group received encouragement from their barbers and usual care from their primary care providers.
The average baseline systolic blood pressure was 152.8 mm Hg in the intervention group, which dropped to 125.8 mm Hg at 6 months. The controls’ average systolic blood pressure was 154.6 mm Hg at baseline and 145.4 at 6 months.
Dr. Victor said he was thrilled with the results, and that the intervention group’s improvement was roughly three times that seen in many blood pressure intervention studies. “We lost very few men to follow-up,” Dr. Victor said. “I can’t underestimate how important the buy-in of the barbers was,” he emphasized. The primary analysis included 132 intervention men and 171 controls with complete 6 months data.
The between-group difference for the primary outcome was 21.6 mm Hg in favor of the intervention,” Dr. Victor said. As a secondary outcome, the between-group difference in diastolic blood pressure was 14.9 mm Hg in favor of the intervention.
In addition, 64% and 12% of the intervention and control groups, respectively, achieved the blood pressure target of 130/80.
“We think the intervention effect is multifaceted,” said Dr. Victor. The pharmacists were doctorate level with specialty training, and prescribed more intense therapy than did a community clinic. In addition, the convenience and comfort of the community barbershop setting, and the endorsement by the barbers, who are significant figures in the community, contributed to the success of the study, he said.
“We think the whole package was important,” he emphasized.
The intervention was safe and well tolerated, with no adverse events. A total of three cases of reversible acute kidney injury occurred in the intervention group that were related to indapamide and resolved when it was discontinued.
“This [study] is a home run,” discussant Eileen Handberg, MD, said in a press conference, “This is taking care where patients live; this is ‘high-touch’ medicine,” she said. Also, the 9-mm Hg improvement in the control group was comparable with improvements in many previous blood pressure control trials, she noted.
Dr. Victor said he plans to expand the study by establishing similar protocols in other communities. Additional next steps for research include extending the current study for another 6 months, expanding the research criteria to include men with mild hypertension, and conducting a cost analysis, he said.
The study was funded by the National Heart, Lung, and Blood Institute and others. Dr. Victor had no financial conflicts to disclose. Dr. Handberg disclosed relationships with multiple companies including Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Gilead Sciences, Ionis, and Relypsa.
The findings were published online simultaneously with Dr. Victor’s report (N Engl J Med. 2018 Mar 11; doi: 10.1056/NEJMoa1717250).
SOURCE: Victor R et al. ACC 2018.
ORLANDO – Black men who received a pharmacist-led intervention in their local barbershops showed significantly improved blood pressure after 6 months, compared with controls, in a randomized trial of 319 individuals.
“Non-Hispanic black men still have the highest hypertension death rate of any group in the country. Something like 60% of black men have blood pressure of 140/90 or higher,” but they have relatively low rates of physician interaction for blood pressure management, compared with other groups, Ronald G. Victor, MD, of Cedars-Sinai Medical Center, Los Angeles, said in a video interview at the annual meeting of the American College of Cardiology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Health outreach to barbershops has been well established in the lay press, but they only scratch the surface in terms of a scientific evaluation, and that’s what we did,” he noted.
The primary outcome was a change in systolic blood pressure at 6 months. The average decrease was 27.0 mm Hg in the intervention group, compared with 9.3 mm Hg in the control group.
Dr. Victor and colleagues identified a study population of non-Hispanic black men aged 35-79 years with a baseline blood pressure of at least 140 mm Hg who were regular patrons of their local barbershops. Of these, 139 were randomized to a pharmacist-led intervention in 28 barbershops, and 180 served as controls in 24 barbershops.
The intervention included monthly checkups with a pharmacist in the barbershop setting, along with blood pressure readings, medication management, electrolyte monitoring, and progress notes sent to each man’s primary care provider. In addition, the barbers encouraged blood pressure management and a healthy lifestyle during the men’s regular haircut visits, occurring about every 2 weeks. The control group received encouragement from their barbers and usual care from their primary care providers.
The average baseline systolic blood pressure was 152.8 mm Hg in the intervention group, which dropped to 125.8 mm Hg at 6 months. The controls’ average systolic blood pressure was 154.6 mm Hg at baseline and 145.4 at 6 months.
Dr. Victor said he was thrilled with the results, and that the intervention group’s improvement was roughly three times that seen in many blood pressure intervention studies. “We lost very few men to follow-up,” Dr. Victor said. “I can’t underestimate how important the buy-in of the barbers was,” he emphasized. The primary analysis included 132 intervention men and 171 controls with complete 6 months data.
The between-group difference for the primary outcome was 21.6 mm Hg in favor of the intervention,” Dr. Victor said. As a secondary outcome, the between-group difference in diastolic blood pressure was 14.9 mm Hg in favor of the intervention.
In addition, 64% and 12% of the intervention and control groups, respectively, achieved the blood pressure target of 130/80.
“We think the intervention effect is multifaceted,” said Dr. Victor. The pharmacists were doctorate level with specialty training, and prescribed more intense therapy than did a community clinic. In addition, the convenience and comfort of the community barbershop setting, and the endorsement by the barbers, who are significant figures in the community, contributed to the success of the study, he said.
“We think the whole package was important,” he emphasized.
The intervention was safe and well tolerated, with no adverse events. A total of three cases of reversible acute kidney injury occurred in the intervention group that were related to indapamide and resolved when it was discontinued.
“This [study] is a home run,” discussant Eileen Handberg, MD, said in a press conference, “This is taking care where patients live; this is ‘high-touch’ medicine,” she said. Also, the 9-mm Hg improvement in the control group was comparable with improvements in many previous blood pressure control trials, she noted.
Dr. Victor said he plans to expand the study by establishing similar protocols in other communities. Additional next steps for research include extending the current study for another 6 months, expanding the research criteria to include men with mild hypertension, and conducting a cost analysis, he said.
The study was funded by the National Heart, Lung, and Blood Institute and others. Dr. Victor had no financial conflicts to disclose. Dr. Handberg disclosed relationships with multiple companies including Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Gilead Sciences, Ionis, and Relypsa.
The findings were published online simultaneously with Dr. Victor’s report (N Engl J Med. 2018 Mar 11; doi: 10.1056/NEJMoa1717250).
SOURCE: Victor R et al. ACC 2018.
ORLANDO – Black men who received a pharmacist-led intervention in their local barbershops showed significantly improved blood pressure after 6 months, compared with controls, in a randomized trial of 319 individuals.
“Non-Hispanic black men still have the highest hypertension death rate of any group in the country. Something like 60% of black men have blood pressure of 140/90 or higher,” but they have relatively low rates of physician interaction for blood pressure management, compared with other groups, Ronald G. Victor, MD, of Cedars-Sinai Medical Center, Los Angeles, said in a video interview at the annual meeting of the American College of Cardiology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Health outreach to barbershops has been well established in the lay press, but they only scratch the surface in terms of a scientific evaluation, and that’s what we did,” he noted.
The primary outcome was a change in systolic blood pressure at 6 months. The average decrease was 27.0 mm Hg in the intervention group, compared with 9.3 mm Hg in the control group.
Dr. Victor and colleagues identified a study population of non-Hispanic black men aged 35-79 years with a baseline blood pressure of at least 140 mm Hg who were regular patrons of their local barbershops. Of these, 139 were randomized to a pharmacist-led intervention in 28 barbershops, and 180 served as controls in 24 barbershops.
The intervention included monthly checkups with a pharmacist in the barbershop setting, along with blood pressure readings, medication management, electrolyte monitoring, and progress notes sent to each man’s primary care provider. In addition, the barbers encouraged blood pressure management and a healthy lifestyle during the men’s regular haircut visits, occurring about every 2 weeks. The control group received encouragement from their barbers and usual care from their primary care providers.
The average baseline systolic blood pressure was 152.8 mm Hg in the intervention group, which dropped to 125.8 mm Hg at 6 months. The controls’ average systolic blood pressure was 154.6 mm Hg at baseline and 145.4 at 6 months.
Dr. Victor said he was thrilled with the results, and that the intervention group’s improvement was roughly three times that seen in many blood pressure intervention studies. “We lost very few men to follow-up,” Dr. Victor said. “I can’t underestimate how important the buy-in of the barbers was,” he emphasized. The primary analysis included 132 intervention men and 171 controls with complete 6 months data.
The between-group difference for the primary outcome was 21.6 mm Hg in favor of the intervention,” Dr. Victor said. As a secondary outcome, the between-group difference in diastolic blood pressure was 14.9 mm Hg in favor of the intervention.
In addition, 64% and 12% of the intervention and control groups, respectively, achieved the blood pressure target of 130/80.
“We think the intervention effect is multifaceted,” said Dr. Victor. The pharmacists were doctorate level with specialty training, and prescribed more intense therapy than did a community clinic. In addition, the convenience and comfort of the community barbershop setting, and the endorsement by the barbers, who are significant figures in the community, contributed to the success of the study, he said.
“We think the whole package was important,” he emphasized.
The intervention was safe and well tolerated, with no adverse events. A total of three cases of reversible acute kidney injury occurred in the intervention group that were related to indapamide and resolved when it was discontinued.
“This [study] is a home run,” discussant Eileen Handberg, MD, said in a press conference, “This is taking care where patients live; this is ‘high-touch’ medicine,” she said. Also, the 9-mm Hg improvement in the control group was comparable with improvements in many previous blood pressure control trials, she noted.
Dr. Victor said he plans to expand the study by establishing similar protocols in other communities. Additional next steps for research include extending the current study for another 6 months, expanding the research criteria to include men with mild hypertension, and conducting a cost analysis, he said.
The study was funded by the National Heart, Lung, and Blood Institute and others. Dr. Victor had no financial conflicts to disclose. Dr. Handberg disclosed relationships with multiple companies including Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Gilead Sciences, Ionis, and Relypsa.
The findings were published online simultaneously with Dr. Victor’s report (N Engl J Med. 2018 Mar 11; doi: 10.1056/NEJMoa1717250).
SOURCE: Victor R et al. ACC 2018.
REPORTING FROM ACC 18
Key clinical point: Major finding: After 6 months, mean systolic blood pressure among men who received intervention dropped an average of 27 mm Hg, compared with 9 mm Hg in controls.
Study details: The data come from a cluster randomized trial including 319 black men who visited 52 barbershops.
Disclosures: The study was funded by the National Heart, Lung, and Blood Institute and others.
Source: Victor R et al. ACC 2018.
VIDEO: Dabigatran effective for myocardial injury after noncardiac surgery
ORLANDO – Treating patients who developed myocardial injury after noncardiac surgery with the anticoagulant dabigatran significantly cut the rate of subsequent major vascular complications in a randomized, multicenter trial with 1,754 patients, a result that gives surgeons and physicians the first evidence-based intervention for treating a common postsurgical condition.
“Because we have not systematically followed noncardiac surgery patients, it’s easy to presume that everyone is okay, but all the epidemiology data show that these patients [who develop myocardial injury after noncardiac surgery] don’t do okay. We need to be aggressive with secondary prophylaxis,” P.J. Devereaux, MD, said at the annual meeting of the American College of Cardiology. “The unfortunate thing is that right now, we don’t do much for these patients,” said Dr. Devereaux, professor of medicine and director of cardiology at McMaster University in Hamilton, Ont.
Results from prior epidemiology studies have shown that, among the roughly 200 million patients who undergo noncardiac surgery worldwide each year, 8% will develop MINS (myocardial injury after noncardiac surgery) (Anesthesiology. 2014 March;120[3]:564-78). The myocardial injury that defines MINS is identified by either an overt MI that meets the universal definition, or an otherwise unexplained rise in serum troponin levels from baseline in the first couple of days after surgery. In the new study, Dr. Devereaux and his associates identified 80% of MINS by a troponin rise and 20% by a diagnosed MI.
The challenge in diagnosing MINS and then administering dabigatran will be implementation of this strategy into routine practice, commented Erin A. Bohula May, MD, a cardiologist at Brigham and Women’s Hospital in Boston. “The problem is, troponin is not routinely measured in postoperative patients. It will be hard to change practice,” she noted.
Dr. Devereaux agreed that a significant barrier is convincing clinicians, especially surgeons, to routinely measure a patient’s troponin levels just before and immediately after surgery. “People are lulled into a false sense of security because patients [who develop MINS] usually don’t have chest pain,” he said in a video interview. “When we first showed that patients with MINS have bad outcomes, that convinced some [surgeons] to measure troponin after surgery. “Showing we can do something about it” is another important step toward fostering more awareness of and interest in diagnosing and treating MINS.
The Management of Myocardial Injury After Noncardiac Surgery Trial (MANAGE) enrolled 1,754 patients at 82 centers in 19 countries. Researchers randomized patients to treatment with either 110 mg dabigatran b.i.d. or placebo. A majority of patients in both arms also received aspirin and a statin, treatments that Dr. Devereaux should be used along with dabigatran in routine practice, based on observational findings, although the efficacy of these drugs for MINS patients has not been tested in randomized studies. The study’s primary endpoint was the incidence of major vascular complications, a composite that included vascular mortality, nonfatal MI, nonfatal and nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, or symptomatic venous thromboembolism.
After an average follow-up of 16 months, the primary endpoint occurred in 11% of the dabigatran-treated patients and in 15% of controls, which represented a 28% risk reduction that was statistically significant. The study’s primary safety endpoint was a composite of life-threatening, major, and critical organ bleeds, which occurred in 3% of the dabigatran-treated patients and in 4% of controls, a nonsignificant difference. The dabigatran-treated patients showed a significant excess of both minor bleeds – 15% compared with 10% in controls – and “nonsignificant” lower gastrointestinal bleeds, 4% with dabigatran and 1% in the controls. The dabigatran-treated patients also had a significantly higher incidence of dyspepsia.
MANAGE was funded by the Population Health Research Institute and had no commercial funding. Dr. Devereaux has received research support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics. Dr. May has been a consultant to Daiichi Sankyo, Merck, and Servier and has received research funding from Eisai.
SOURCE: Devereaux P et al. ACC 18.
Dr. Devereaux and his associates are to be congratulated on identifying a new disease entity, MINS (myocardial injury after noncardiac surgery), and now giving us a way to treat it. MINS is extremely common and quite morbid, and there had never before been a trial that studied its treatment. Identifying patients with MINS is extremely important. These are very-high-risk patients, and they are very hard to find. The results from MANAGE give us a way to do something about MINS and an opportunity to improve patient outcomes.
Pamela S. Douglas, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. She had no disclosures. She made these comments as a discussant for MANAGE and in an interview.
Dr. Devereaux and his associates are to be congratulated on identifying a new disease entity, MINS (myocardial injury after noncardiac surgery), and now giving us a way to treat it. MINS is extremely common and quite morbid, and there had never before been a trial that studied its treatment. Identifying patients with MINS is extremely important. These are very-high-risk patients, and they are very hard to find. The results from MANAGE give us a way to do something about MINS and an opportunity to improve patient outcomes.
Pamela S. Douglas, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. She had no disclosures. She made these comments as a discussant for MANAGE and in an interview.
Dr. Devereaux and his associates are to be congratulated on identifying a new disease entity, MINS (myocardial injury after noncardiac surgery), and now giving us a way to treat it. MINS is extremely common and quite morbid, and there had never before been a trial that studied its treatment. Identifying patients with MINS is extremely important. These are very-high-risk patients, and they are very hard to find. The results from MANAGE give us a way to do something about MINS and an opportunity to improve patient outcomes.
Pamela S. Douglas, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. She had no disclosures. She made these comments as a discussant for MANAGE and in an interview.
ORLANDO – Treating patients who developed myocardial injury after noncardiac surgery with the anticoagulant dabigatran significantly cut the rate of subsequent major vascular complications in a randomized, multicenter trial with 1,754 patients, a result that gives surgeons and physicians the first evidence-based intervention for treating a common postsurgical condition.
“Because we have not systematically followed noncardiac surgery patients, it’s easy to presume that everyone is okay, but all the epidemiology data show that these patients [who develop myocardial injury after noncardiac surgery] don’t do okay. We need to be aggressive with secondary prophylaxis,” P.J. Devereaux, MD, said at the annual meeting of the American College of Cardiology. “The unfortunate thing is that right now, we don’t do much for these patients,” said Dr. Devereaux, professor of medicine and director of cardiology at McMaster University in Hamilton, Ont.
Results from prior epidemiology studies have shown that, among the roughly 200 million patients who undergo noncardiac surgery worldwide each year, 8% will develop MINS (myocardial injury after noncardiac surgery) (Anesthesiology. 2014 March;120[3]:564-78). The myocardial injury that defines MINS is identified by either an overt MI that meets the universal definition, or an otherwise unexplained rise in serum troponin levels from baseline in the first couple of days after surgery. In the new study, Dr. Devereaux and his associates identified 80% of MINS by a troponin rise and 20% by a diagnosed MI.
The challenge in diagnosing MINS and then administering dabigatran will be implementation of this strategy into routine practice, commented Erin A. Bohula May, MD, a cardiologist at Brigham and Women’s Hospital in Boston. “The problem is, troponin is not routinely measured in postoperative patients. It will be hard to change practice,” she noted.
Dr. Devereaux agreed that a significant barrier is convincing clinicians, especially surgeons, to routinely measure a patient’s troponin levels just before and immediately after surgery. “People are lulled into a false sense of security because patients [who develop MINS] usually don’t have chest pain,” he said in a video interview. “When we first showed that patients with MINS have bad outcomes, that convinced some [surgeons] to measure troponin after surgery. “Showing we can do something about it” is another important step toward fostering more awareness of and interest in diagnosing and treating MINS.
The Management of Myocardial Injury After Noncardiac Surgery Trial (MANAGE) enrolled 1,754 patients at 82 centers in 19 countries. Researchers randomized patients to treatment with either 110 mg dabigatran b.i.d. or placebo. A majority of patients in both arms also received aspirin and a statin, treatments that Dr. Devereaux should be used along with dabigatran in routine practice, based on observational findings, although the efficacy of these drugs for MINS patients has not been tested in randomized studies. The study’s primary endpoint was the incidence of major vascular complications, a composite that included vascular mortality, nonfatal MI, nonfatal and nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, or symptomatic venous thromboembolism.
After an average follow-up of 16 months, the primary endpoint occurred in 11% of the dabigatran-treated patients and in 15% of controls, which represented a 28% risk reduction that was statistically significant. The study’s primary safety endpoint was a composite of life-threatening, major, and critical organ bleeds, which occurred in 3% of the dabigatran-treated patients and in 4% of controls, a nonsignificant difference. The dabigatran-treated patients showed a significant excess of both minor bleeds – 15% compared with 10% in controls – and “nonsignificant” lower gastrointestinal bleeds, 4% with dabigatran and 1% in the controls. The dabigatran-treated patients also had a significantly higher incidence of dyspepsia.
MANAGE was funded by the Population Health Research Institute and had no commercial funding. Dr. Devereaux has received research support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics. Dr. May has been a consultant to Daiichi Sankyo, Merck, and Servier and has received research funding from Eisai.
SOURCE: Devereaux P et al. ACC 18.
ORLANDO – Treating patients who developed myocardial injury after noncardiac surgery with the anticoagulant dabigatran significantly cut the rate of subsequent major vascular complications in a randomized, multicenter trial with 1,754 patients, a result that gives surgeons and physicians the first evidence-based intervention for treating a common postsurgical condition.
“Because we have not systematically followed noncardiac surgery patients, it’s easy to presume that everyone is okay, but all the epidemiology data show that these patients [who develop myocardial injury after noncardiac surgery] don’t do okay. We need to be aggressive with secondary prophylaxis,” P.J. Devereaux, MD, said at the annual meeting of the American College of Cardiology. “The unfortunate thing is that right now, we don’t do much for these patients,” said Dr. Devereaux, professor of medicine and director of cardiology at McMaster University in Hamilton, Ont.
Results from prior epidemiology studies have shown that, among the roughly 200 million patients who undergo noncardiac surgery worldwide each year, 8% will develop MINS (myocardial injury after noncardiac surgery) (Anesthesiology. 2014 March;120[3]:564-78). The myocardial injury that defines MINS is identified by either an overt MI that meets the universal definition, or an otherwise unexplained rise in serum troponin levels from baseline in the first couple of days after surgery. In the new study, Dr. Devereaux and his associates identified 80% of MINS by a troponin rise and 20% by a diagnosed MI.
The challenge in diagnosing MINS and then administering dabigatran will be implementation of this strategy into routine practice, commented Erin A. Bohula May, MD, a cardiologist at Brigham and Women’s Hospital in Boston. “The problem is, troponin is not routinely measured in postoperative patients. It will be hard to change practice,” she noted.
Dr. Devereaux agreed that a significant barrier is convincing clinicians, especially surgeons, to routinely measure a patient’s troponin levels just before and immediately after surgery. “People are lulled into a false sense of security because patients [who develop MINS] usually don’t have chest pain,” he said in a video interview. “When we first showed that patients with MINS have bad outcomes, that convinced some [surgeons] to measure troponin after surgery. “Showing we can do something about it” is another important step toward fostering more awareness of and interest in diagnosing and treating MINS.
The Management of Myocardial Injury After Noncardiac Surgery Trial (MANAGE) enrolled 1,754 patients at 82 centers in 19 countries. Researchers randomized patients to treatment with either 110 mg dabigatran b.i.d. or placebo. A majority of patients in both arms also received aspirin and a statin, treatments that Dr. Devereaux should be used along with dabigatran in routine practice, based on observational findings, although the efficacy of these drugs for MINS patients has not been tested in randomized studies. The study’s primary endpoint was the incidence of major vascular complications, a composite that included vascular mortality, nonfatal MI, nonfatal and nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, or symptomatic venous thromboembolism.
After an average follow-up of 16 months, the primary endpoint occurred in 11% of the dabigatran-treated patients and in 15% of controls, which represented a 28% risk reduction that was statistically significant. The study’s primary safety endpoint was a composite of life-threatening, major, and critical organ bleeds, which occurred in 3% of the dabigatran-treated patients and in 4% of controls, a nonsignificant difference. The dabigatran-treated patients showed a significant excess of both minor bleeds – 15% compared with 10% in controls – and “nonsignificant” lower gastrointestinal bleeds, 4% with dabigatran and 1% in the controls. The dabigatran-treated patients also had a significantly higher incidence of dyspepsia.
MANAGE was funded by the Population Health Research Institute and had no commercial funding. Dr. Devereaux has received research support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics. Dr. May has been a consultant to Daiichi Sankyo, Merck, and Servier and has received research funding from Eisai.
SOURCE: Devereaux P et al. ACC 18.
REPORTING FROM ACC 18
Key clinical point: Dabigatran is the first intervention proven to benefit patients with MINS.
Major finding: Major vascular complications occurred in 11% of patients on dabigatran and 15% on placebo.
Study details: MANAGE, a multicenter, randomized trial with 1,754 patients.
Disclosures: MANAGE was funded by the Population Health Research Institute and had no commercial funding. Dr. Devereaux has received research support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics. Dr. May has been a consultant to Daiichi Sankyo, Merck, and Servier and has received research funding from Eisai.
Source: Devereaux P et al. ACC 18.
