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Cardiovascular risk in type 2 diabetes: Patients are often clueless
ORLANDO – What most people with type 2 diabetes don’t know about their cardiovascular risk could get them killed.
A national online survey revealed a surprising lack of awareness among patients with type 2 diabetes and their loved ones regarding the well-established significantly increased risk of cardiovascular mortality associated with the disease.
The same low rate of awareness was present in the general population, as represented by the 1,004 controls who didn’t have type 2 diabetes or know anyone who did, Jonathan Pak, PharmD, reported at the annual meeting of the American College of Cardiology.
“We thought patient awareness would be higher, but some who I think understand this space better are surprised it’s even this high,” Dr. Pak said in an interview.
Putting aside the widespread lack of awareness of cardiovascular disease as the leading cause of death in patients with type 2 diabetes, 52% of the patients with type 2 diabetes and a similar proportion of their loved ones were unaware that type 2 diabetes is associated with any increased risk of cardiovascular disease and other macrovascular events, noted Dr. Pak, director of metabolism at Boehringer Ingelheim in Ridgefield, Conn.
There was a strong whiff of denial in the patients’ attitudes. For example, only 24% of the group with type 2 diabetes rated themselves as “likely” to have an amputation in the future, yet they rated 42% of others with type 2 disease as likely to undergo amputation. The same attitude pertained to the prospect of having an acute MI: It’s the others who are at increased risk, not me.
Encouragingly though, more than 80% of the type 2 diabetes patients who hadn’t realized they were at increased cardiovascular risk indicated that if they truly are at increased risk, they would take preventive measures to reduce that risk, including dietary modification and a conversation with their healthcare provider. In addition, 80% said their motivation in doing so would be to improve their quality of life, and 73% cited a desire to live longer and spend more time with their family, Dr. Pak observed.
“The findings from this survey highlight a huge opportunity to educate and inform, and for patients and their loved ones to act on,” he said.
The For Your Sweetheart survey was supported by Boehringer Ingelheim, Eli Lilly, and the Company Diabetes Alliance.
SOURCE: Pak J. ACC 18.
ORLANDO – What most people with type 2 diabetes don’t know about their cardiovascular risk could get them killed.
A national online survey revealed a surprising lack of awareness among patients with type 2 diabetes and their loved ones regarding the well-established significantly increased risk of cardiovascular mortality associated with the disease.
The same low rate of awareness was present in the general population, as represented by the 1,004 controls who didn’t have type 2 diabetes or know anyone who did, Jonathan Pak, PharmD, reported at the annual meeting of the American College of Cardiology.
“We thought patient awareness would be higher, but some who I think understand this space better are surprised it’s even this high,” Dr. Pak said in an interview.
Putting aside the widespread lack of awareness of cardiovascular disease as the leading cause of death in patients with type 2 diabetes, 52% of the patients with type 2 diabetes and a similar proportion of their loved ones were unaware that type 2 diabetes is associated with any increased risk of cardiovascular disease and other macrovascular events, noted Dr. Pak, director of metabolism at Boehringer Ingelheim in Ridgefield, Conn.
There was a strong whiff of denial in the patients’ attitudes. For example, only 24% of the group with type 2 diabetes rated themselves as “likely” to have an amputation in the future, yet they rated 42% of others with type 2 disease as likely to undergo amputation. The same attitude pertained to the prospect of having an acute MI: It’s the others who are at increased risk, not me.
Encouragingly though, more than 80% of the type 2 diabetes patients who hadn’t realized they were at increased cardiovascular risk indicated that if they truly are at increased risk, they would take preventive measures to reduce that risk, including dietary modification and a conversation with their healthcare provider. In addition, 80% said their motivation in doing so would be to improve their quality of life, and 73% cited a desire to live longer and spend more time with their family, Dr. Pak observed.
“The findings from this survey highlight a huge opportunity to educate and inform, and for patients and their loved ones to act on,” he said.
The For Your Sweetheart survey was supported by Boehringer Ingelheim, Eli Lilly, and the Company Diabetes Alliance.
SOURCE: Pak J. ACC 18.
ORLANDO – What most people with type 2 diabetes don’t know about their cardiovascular risk could get them killed.
A national online survey revealed a surprising lack of awareness among patients with type 2 diabetes and their loved ones regarding the well-established significantly increased risk of cardiovascular mortality associated with the disease.
The same low rate of awareness was present in the general population, as represented by the 1,004 controls who didn’t have type 2 diabetes or know anyone who did, Jonathan Pak, PharmD, reported at the annual meeting of the American College of Cardiology.
“We thought patient awareness would be higher, but some who I think understand this space better are surprised it’s even this high,” Dr. Pak said in an interview.
Putting aside the widespread lack of awareness of cardiovascular disease as the leading cause of death in patients with type 2 diabetes, 52% of the patients with type 2 diabetes and a similar proportion of their loved ones were unaware that type 2 diabetes is associated with any increased risk of cardiovascular disease and other macrovascular events, noted Dr. Pak, director of metabolism at Boehringer Ingelheim in Ridgefield, Conn.
There was a strong whiff of denial in the patients’ attitudes. For example, only 24% of the group with type 2 diabetes rated themselves as “likely” to have an amputation in the future, yet they rated 42% of others with type 2 disease as likely to undergo amputation. The same attitude pertained to the prospect of having an acute MI: It’s the others who are at increased risk, not me.
Encouragingly though, more than 80% of the type 2 diabetes patients who hadn’t realized they were at increased cardiovascular risk indicated that if they truly are at increased risk, they would take preventive measures to reduce that risk, including dietary modification and a conversation with their healthcare provider. In addition, 80% said their motivation in doing so would be to improve their quality of life, and 73% cited a desire to live longer and spend more time with their family, Dr. Pak observed.
“The findings from this survey highlight a huge opportunity to educate and inform, and for patients and their loved ones to act on,” he said.
The For Your Sweetheart survey was supported by Boehringer Ingelheim, Eli Lilly, and the Company Diabetes Alliance.
SOURCE: Pak J. ACC 18.
REPORTING FROM ACC 2018
Key clinical point: What most people with type 2 diabetes don’t know about their cardiovascular risk could get them killed.
Major finding: More than half of patients with type 2 diabetes who participated in an online survey were unaware that their disease places them at increased cardiovascular risk.
Study details: This online, cross-sectional survey included 1,869 respondents.
Disclosures: The For Your Sweetheart survey was supported by Boehringer Ingelheim and Eli Lilly. The presenter is a Boehringer Ingelheim employee.
Source: Pak J. ACC 18.
Permanent His-bundle pacing superior to RV pacing
ORLANDO – Pacing at the bundle of His was associated with significantly reduced morbidity and mortality, compared with right ventricular pacing, over time in a large observational registry of patients needing a permanent pacemaker for bradycardia, Mohamed Abdelrahman, MD, reported at the annual meeting of the American College of Cardiology.
The superiority of His-bundle pacing (HBP) was concentrated in patients who required ventricular pacing more than 20% of the time. This finding is consistent with previous reports that even a modest utilization of ventricular pacing is sufficient to boost the risk of left ventricular dysfunction secondary to electrical and mechanical dyssynchrony, added Dr. Abdelrahman of the Geisinger Heart Institute in Danville, Pa.
The primary study endpoint was a composite of all-cause mortality, heart-failure hospitalization, and biventricular pacing upgrade. During a mean 2 years of follow-up, this endpoint was reached in 25% of the HBP group, compared with 32% of the RVP group, for a significant 29% relative risk reduction. In patients with a ventricular pacing burden greater than 20%, the primary endpoint occurred in 25% of the HBP group and 36% of patients with RVP, for a 35% relative risk reduction. However, in patients who required ventricular pacing less than 20% of the time, there was no significant difference in the primary outcome between the two groups.
Heart failure hospitalization occurred in 12.4% of the HBP group and 17.6% of the RVP patients, for a 37% relative risk reduction. In patients with ventricular pacing more than 20% of the time, the rates were 12.4% and 20.1%, for a 46% relative risk reduction in favor of HBP.
Among patients with a ventricular pacing burden of more than 20%, all-cause mortality occurred in 18% of the HBP group, compared with 23.7% of RVP-treated patients.
One patient in the HBP group required an upgrade to biventricular pacing, as did six patients in the RVP group. Lead revision was necessary in 14 patients in the HBP group, versus 2 in the RVP group. Pericardial effusion within the first month of pacemaker implantation occurred in three patients in the RVP group and did not occur in the HBP group.
Discussant Kristen K. Patton, MD, called the Geisinger work “a really wonderful study,” adding, “It’s incredibly difficult to overstate how excited we are in electrophysiology about His-bundle pacing and what a wonderfully elegant solution this is to the problem of pacing-induced dyssynchrony.
“Is there anything that gives you pause, any patients in whom the increased risk of revisions makes you think, ‘I shouldn’t do this in everyone?’ Because I can tell you, it’s hard not to want to do this in everyone,” said Dr. Patton, professor of medicine at the University of Washington, Seattle.
Dr. Abdelrahman replied that Geisinger electrophysiologists now utilize HBP in all patients who require a permanent pacemaker for bradycardia.
Session chair Martin B. Leon, MD, of Columbia University, New York, had a question: “This is such an important area. Why didn’t you do a randomized trial from the start?”
Dr. Abdelrahman’s senior coinvestigator, Pugazhendhi Vijayaraman, MD, explained: “His-bundle pacing has been around for the last 20 years. It’s had its ups and downs. In the last few years there’s been a groundswell of implanters doing His-bundle pacing. The number of implanters here and around the world is rapidly expanding. So we are ready for a randomized trial, and we’ve applied for funding from the National Institutes of Health. Industry support for this has not been forthcoming because His-bundle pacing does not seem to add to the value of a company’s portfolio, but more to better patient outcomes.”
He emphasized that, of the 14 patients in the HBP group who underwent lead revision, only 2 had absolute lead failure and loss of capture, underscoring the safety of this pacing strategy.
Dr. Abdelrahman reported having no financial conflicts of interest regarding the study.
SOURCE: Abdelrahman M. ACC 18.
ORLANDO – Pacing at the bundle of His was associated with significantly reduced morbidity and mortality, compared with right ventricular pacing, over time in a large observational registry of patients needing a permanent pacemaker for bradycardia, Mohamed Abdelrahman, MD, reported at the annual meeting of the American College of Cardiology.
The superiority of His-bundle pacing (HBP) was concentrated in patients who required ventricular pacing more than 20% of the time. This finding is consistent with previous reports that even a modest utilization of ventricular pacing is sufficient to boost the risk of left ventricular dysfunction secondary to electrical and mechanical dyssynchrony, added Dr. Abdelrahman of the Geisinger Heart Institute in Danville, Pa.
The primary study endpoint was a composite of all-cause mortality, heart-failure hospitalization, and biventricular pacing upgrade. During a mean 2 years of follow-up, this endpoint was reached in 25% of the HBP group, compared with 32% of the RVP group, for a significant 29% relative risk reduction. In patients with a ventricular pacing burden greater than 20%, the primary endpoint occurred in 25% of the HBP group and 36% of patients with RVP, for a 35% relative risk reduction. However, in patients who required ventricular pacing less than 20% of the time, there was no significant difference in the primary outcome between the two groups.
Heart failure hospitalization occurred in 12.4% of the HBP group and 17.6% of the RVP patients, for a 37% relative risk reduction. In patients with ventricular pacing more than 20% of the time, the rates were 12.4% and 20.1%, for a 46% relative risk reduction in favor of HBP.
Among patients with a ventricular pacing burden of more than 20%, all-cause mortality occurred in 18% of the HBP group, compared with 23.7% of RVP-treated patients.
One patient in the HBP group required an upgrade to biventricular pacing, as did six patients in the RVP group. Lead revision was necessary in 14 patients in the HBP group, versus 2 in the RVP group. Pericardial effusion within the first month of pacemaker implantation occurred in three patients in the RVP group and did not occur in the HBP group.
Discussant Kristen K. Patton, MD, called the Geisinger work “a really wonderful study,” adding, “It’s incredibly difficult to overstate how excited we are in electrophysiology about His-bundle pacing and what a wonderfully elegant solution this is to the problem of pacing-induced dyssynchrony.
“Is there anything that gives you pause, any patients in whom the increased risk of revisions makes you think, ‘I shouldn’t do this in everyone?’ Because I can tell you, it’s hard not to want to do this in everyone,” said Dr. Patton, professor of medicine at the University of Washington, Seattle.
Dr. Abdelrahman replied that Geisinger electrophysiologists now utilize HBP in all patients who require a permanent pacemaker for bradycardia.
Session chair Martin B. Leon, MD, of Columbia University, New York, had a question: “This is such an important area. Why didn’t you do a randomized trial from the start?”
Dr. Abdelrahman’s senior coinvestigator, Pugazhendhi Vijayaraman, MD, explained: “His-bundle pacing has been around for the last 20 years. It’s had its ups and downs. In the last few years there’s been a groundswell of implanters doing His-bundle pacing. The number of implanters here and around the world is rapidly expanding. So we are ready for a randomized trial, and we’ve applied for funding from the National Institutes of Health. Industry support for this has not been forthcoming because His-bundle pacing does not seem to add to the value of a company’s portfolio, but more to better patient outcomes.”
He emphasized that, of the 14 patients in the HBP group who underwent lead revision, only 2 had absolute lead failure and loss of capture, underscoring the safety of this pacing strategy.
Dr. Abdelrahman reported having no financial conflicts of interest regarding the study.
SOURCE: Abdelrahman M. ACC 18.
ORLANDO – Pacing at the bundle of His was associated with significantly reduced morbidity and mortality, compared with right ventricular pacing, over time in a large observational registry of patients needing a permanent pacemaker for bradycardia, Mohamed Abdelrahman, MD, reported at the annual meeting of the American College of Cardiology.
The superiority of His-bundle pacing (HBP) was concentrated in patients who required ventricular pacing more than 20% of the time. This finding is consistent with previous reports that even a modest utilization of ventricular pacing is sufficient to boost the risk of left ventricular dysfunction secondary to electrical and mechanical dyssynchrony, added Dr. Abdelrahman of the Geisinger Heart Institute in Danville, Pa.
The primary study endpoint was a composite of all-cause mortality, heart-failure hospitalization, and biventricular pacing upgrade. During a mean 2 years of follow-up, this endpoint was reached in 25% of the HBP group, compared with 32% of the RVP group, for a significant 29% relative risk reduction. In patients with a ventricular pacing burden greater than 20%, the primary endpoint occurred in 25% of the HBP group and 36% of patients with RVP, for a 35% relative risk reduction. However, in patients who required ventricular pacing less than 20% of the time, there was no significant difference in the primary outcome between the two groups.
Heart failure hospitalization occurred in 12.4% of the HBP group and 17.6% of the RVP patients, for a 37% relative risk reduction. In patients with ventricular pacing more than 20% of the time, the rates were 12.4% and 20.1%, for a 46% relative risk reduction in favor of HBP.
Among patients with a ventricular pacing burden of more than 20%, all-cause mortality occurred in 18% of the HBP group, compared with 23.7% of RVP-treated patients.
One patient in the HBP group required an upgrade to biventricular pacing, as did six patients in the RVP group. Lead revision was necessary in 14 patients in the HBP group, versus 2 in the RVP group. Pericardial effusion within the first month of pacemaker implantation occurred in three patients in the RVP group and did not occur in the HBP group.
Discussant Kristen K. Patton, MD, called the Geisinger work “a really wonderful study,” adding, “It’s incredibly difficult to overstate how excited we are in electrophysiology about His-bundle pacing and what a wonderfully elegant solution this is to the problem of pacing-induced dyssynchrony.
“Is there anything that gives you pause, any patients in whom the increased risk of revisions makes you think, ‘I shouldn’t do this in everyone?’ Because I can tell you, it’s hard not to want to do this in everyone,” said Dr. Patton, professor of medicine at the University of Washington, Seattle.
Dr. Abdelrahman replied that Geisinger electrophysiologists now utilize HBP in all patients who require a permanent pacemaker for bradycardia.
Session chair Martin B. Leon, MD, of Columbia University, New York, had a question: “This is such an important area. Why didn’t you do a randomized trial from the start?”
Dr. Abdelrahman’s senior coinvestigator, Pugazhendhi Vijayaraman, MD, explained: “His-bundle pacing has been around for the last 20 years. It’s had its ups and downs. In the last few years there’s been a groundswell of implanters doing His-bundle pacing. The number of implanters here and around the world is rapidly expanding. So we are ready for a randomized trial, and we’ve applied for funding from the National Institutes of Health. Industry support for this has not been forthcoming because His-bundle pacing does not seem to add to the value of a company’s portfolio, but more to better patient outcomes.”
He emphasized that, of the 14 patients in the HBP group who underwent lead revision, only 2 had absolute lead failure and loss of capture, underscoring the safety of this pacing strategy.
Dr. Abdelrahman reported having no financial conflicts of interest regarding the study.
SOURCE: Abdelrahman M. ACC 18.
REPORTING FROM ACC 18
Key clinical point:
Major finding: The combined rate of all-cause mortality, heart-failure hospitalization, and biventricular pacing upgrade during a mean 2 years of follow-up was 25% in patients with His-bundle pacing, compared with 32% with right ventricular pacing.
Study details: This observational registry included 765 consecutive patients who required an initial permanent pacemaker implantation. All those treated at one medical center underwent an attempt at His-bundle pacing, while all those at a closely allied sister medical center received right ventricular pacing.
Disclosures: The study presenter reported having no financial conflicts of interest.
Source: Abdelrahman M. ACC 18.
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.
Femoral artery endarterectomy still ‘gold standard’
CHICAGO – Additional higher quality supporting evidence is needed before , Jeffrey J. Siracuse, MD, FACS, asserted at a symposium on vascular surgery sponsored by Northwestern University.
“Open surgery in the CFA [common femoral artery] is probably still the gold standard in most cases,” said Dr. Siracuse, a vascular surgeon at Boston University.
He was quick to note that others would disagree. Stenting and other endovascular interventions in the CFA are booming in popularity, particularly among cardiologists, interventional radiologists, and the patients to whom the clinicians present the option in a favorable light. But this enthusiasm is based almost entirely on small, single-center, retrospective studies conducted in patients with heterogeneous profiles. The one prospective randomized multicenter trial of stenting versus surgery for CFA stenosis published to date – the French TECCO study – has a number of key limitations, flaws, and unanswered questions, which endovascular proponents have overlooked in their enthusiasm to promote an “endo-first” approach in the CFA, according to Dr. Siracuse.
“Everyone’s pretty much jumping on the bandwagon now. I think endovascular therapy of the CFA is here to stay. You’re going to see more people doing it, and potentially doing it incorrectly,” he predicted.
“The biggest thing I worry about with stenting is covering or jailing out the deep femoral artery. On multiple occasions – including a case just 2 weeks ago – I’ve taken out stents placed in the CFA by others that developed in-stent hyperplasia to the extent that the entire stent goes down, the DFA is covered, and now all of a sudden you’ve lost all flow to the leg. That’s my biggest concern with stenting,” he said.
Dr. Siracuse has other reservations as well. The CFA has traditionally been considered a “no-stent zone” because of the unique biomechanical stresses the artery is subjected to as a result of torsion, flexion, and extension at the hip joint. These forces render the area particularly vulnerable to neointimal hyperplasia, acute thrombosis, and stent fracture.
In addition, he noted, CFA endarterectomy for atherosclerotic lesions is a mature, well-established operation with an excellent track record for safety and durability. Dr. Siracuse’s review of procedural safety in 1,513 patients in the American College of Surgeons National Surgical Quality Improvement Project database during 2007-2010 showed a 30-day mortality of 1.5% and a 7.9% rate of major or minor complications (Vasc Endovascular Surg. 2014 Jan;48[1]:27-33).
In contrast, his review of 1,014 patients who underwent nonemergent endovascular CFA interventions for CFA stenosis without acute limb ischemia in the Vascular Quality Initiative registry demonstrated a 1-year patency rate of 85.3%, significantly lower than historically observed patency rates for endarterectomy. The 30-day mortality rate of 1.6% associated with endovascular interventions was essentially the same as in his earlier analysis of endarterectomy in the ACS NSQIP database, and the average 1.5-day hospital length of stay was shorter than with open surgery. Of considerable concern, however, stent implantation, which was performed in 35% of the endovascular interventions, was an independent predictor of amputation or death, with an associated 195% increased risk (J Vasc Surg. 2017 Apr;[4]:1039-46).
The travails of TECCO
The 17-center French TECCO study randomized 117 patients with de novo CFA atherosclerotic lesions to treatment via self-expanding stents or open surgery. A total of 98 participants were Rutherford stage 3, making TECCO primarily a study of claudicants. The primary outcome – the 30-day combined rate of morbidity and mortality – occurred in 26% of the surgical patients, a significantly higher rate than the 12.5% in the stent population. After a median follow-up of 24 months, the rates of primary patency, target lesion and extremity revascularization, and sustained clinical improvement were similar in the two groups (JACC Cardiovasc Interv. 2017 Jul 10;10[13]:1344-54).
The TECCO findings were hailed by endovascular therapy partisans as a big win. However, closer examination tells a different story, according to Dr. Siracuse.
There was no 30-day mortality in this rather small study. All 16 morbidity events occurring in the open surgery group within 30 days were relatively minor: 10 cases of delayed wound healing, 4 cases of postoperative paresthesia requiring medication, and 2 cases of lymphorrhea lasting longer than 3 days. In contrast, the seven morbidity events in the stent group included a complication requiring urgent open surgical repair at the time of stenting, one stent fracture, and a major amputation.
“The investigators didn’t elaborate on that major amputation, but I thought it was a little alarming because you should not have a major amputation with CFA interventions for claudicants,” the vascular surgeon commented. “Really, do people care about a lymphatic leak or do they care about amputation? I think more needs to be fleshed out about what really happened in that case.”
He was also puzzled by the hospital lengths of stay: a mean of 3.2 days in the stent group and 6.3 days in the open surgery group. “I think those lengths of stay are astounding. Very high and unusual,” he observed.
Dr. Siracuse predicted that much-needed high-quality data comparing treatments of the CFA will be provided by the BEST-CLI trial (Best Endovascular versus Surgical Treatment for Critical Limb Ischemia), which has been updated to include both open and endovascular interventions.
He reported having no financial conflicts of interest regarding his presentation.
CHICAGO – Additional higher quality supporting evidence is needed before , Jeffrey J. Siracuse, MD, FACS, asserted at a symposium on vascular surgery sponsored by Northwestern University.
“Open surgery in the CFA [common femoral artery] is probably still the gold standard in most cases,” said Dr. Siracuse, a vascular surgeon at Boston University.
He was quick to note that others would disagree. Stenting and other endovascular interventions in the CFA are booming in popularity, particularly among cardiologists, interventional radiologists, and the patients to whom the clinicians present the option in a favorable light. But this enthusiasm is based almost entirely on small, single-center, retrospective studies conducted in patients with heterogeneous profiles. The one prospective randomized multicenter trial of stenting versus surgery for CFA stenosis published to date – the French TECCO study – has a number of key limitations, flaws, and unanswered questions, which endovascular proponents have overlooked in their enthusiasm to promote an “endo-first” approach in the CFA, according to Dr. Siracuse.
“Everyone’s pretty much jumping on the bandwagon now. I think endovascular therapy of the CFA is here to stay. You’re going to see more people doing it, and potentially doing it incorrectly,” he predicted.
“The biggest thing I worry about with stenting is covering or jailing out the deep femoral artery. On multiple occasions – including a case just 2 weeks ago – I’ve taken out stents placed in the CFA by others that developed in-stent hyperplasia to the extent that the entire stent goes down, the DFA is covered, and now all of a sudden you’ve lost all flow to the leg. That’s my biggest concern with stenting,” he said.
Dr. Siracuse has other reservations as well. The CFA has traditionally been considered a “no-stent zone” because of the unique biomechanical stresses the artery is subjected to as a result of torsion, flexion, and extension at the hip joint. These forces render the area particularly vulnerable to neointimal hyperplasia, acute thrombosis, and stent fracture.
In addition, he noted, CFA endarterectomy for atherosclerotic lesions is a mature, well-established operation with an excellent track record for safety and durability. Dr. Siracuse’s review of procedural safety in 1,513 patients in the American College of Surgeons National Surgical Quality Improvement Project database during 2007-2010 showed a 30-day mortality of 1.5% and a 7.9% rate of major or minor complications (Vasc Endovascular Surg. 2014 Jan;48[1]:27-33).
In contrast, his review of 1,014 patients who underwent nonemergent endovascular CFA interventions for CFA stenosis without acute limb ischemia in the Vascular Quality Initiative registry demonstrated a 1-year patency rate of 85.3%, significantly lower than historically observed patency rates for endarterectomy. The 30-day mortality rate of 1.6% associated with endovascular interventions was essentially the same as in his earlier analysis of endarterectomy in the ACS NSQIP database, and the average 1.5-day hospital length of stay was shorter than with open surgery. Of considerable concern, however, stent implantation, which was performed in 35% of the endovascular interventions, was an independent predictor of amputation or death, with an associated 195% increased risk (J Vasc Surg. 2017 Apr;[4]:1039-46).
The travails of TECCO
The 17-center French TECCO study randomized 117 patients with de novo CFA atherosclerotic lesions to treatment via self-expanding stents or open surgery. A total of 98 participants were Rutherford stage 3, making TECCO primarily a study of claudicants. The primary outcome – the 30-day combined rate of morbidity and mortality – occurred in 26% of the surgical patients, a significantly higher rate than the 12.5% in the stent population. After a median follow-up of 24 months, the rates of primary patency, target lesion and extremity revascularization, and sustained clinical improvement were similar in the two groups (JACC Cardiovasc Interv. 2017 Jul 10;10[13]:1344-54).
The TECCO findings were hailed by endovascular therapy partisans as a big win. However, closer examination tells a different story, according to Dr. Siracuse.
There was no 30-day mortality in this rather small study. All 16 morbidity events occurring in the open surgery group within 30 days were relatively minor: 10 cases of delayed wound healing, 4 cases of postoperative paresthesia requiring medication, and 2 cases of lymphorrhea lasting longer than 3 days. In contrast, the seven morbidity events in the stent group included a complication requiring urgent open surgical repair at the time of stenting, one stent fracture, and a major amputation.
“The investigators didn’t elaborate on that major amputation, but I thought it was a little alarming because you should not have a major amputation with CFA interventions for claudicants,” the vascular surgeon commented. “Really, do people care about a lymphatic leak or do they care about amputation? I think more needs to be fleshed out about what really happened in that case.”
He was also puzzled by the hospital lengths of stay: a mean of 3.2 days in the stent group and 6.3 days in the open surgery group. “I think those lengths of stay are astounding. Very high and unusual,” he observed.
Dr. Siracuse predicted that much-needed high-quality data comparing treatments of the CFA will be provided by the BEST-CLI trial (Best Endovascular versus Surgical Treatment for Critical Limb Ischemia), which has been updated to include both open and endovascular interventions.
He reported having no financial conflicts of interest regarding his presentation.
CHICAGO – Additional higher quality supporting evidence is needed before , Jeffrey J. Siracuse, MD, FACS, asserted at a symposium on vascular surgery sponsored by Northwestern University.
“Open surgery in the CFA [common femoral artery] is probably still the gold standard in most cases,” said Dr. Siracuse, a vascular surgeon at Boston University.
He was quick to note that others would disagree. Stenting and other endovascular interventions in the CFA are booming in popularity, particularly among cardiologists, interventional radiologists, and the patients to whom the clinicians present the option in a favorable light. But this enthusiasm is based almost entirely on small, single-center, retrospective studies conducted in patients with heterogeneous profiles. The one prospective randomized multicenter trial of stenting versus surgery for CFA stenosis published to date – the French TECCO study – has a number of key limitations, flaws, and unanswered questions, which endovascular proponents have overlooked in their enthusiasm to promote an “endo-first” approach in the CFA, according to Dr. Siracuse.
“Everyone’s pretty much jumping on the bandwagon now. I think endovascular therapy of the CFA is here to stay. You’re going to see more people doing it, and potentially doing it incorrectly,” he predicted.
“The biggest thing I worry about with stenting is covering or jailing out the deep femoral artery. On multiple occasions – including a case just 2 weeks ago – I’ve taken out stents placed in the CFA by others that developed in-stent hyperplasia to the extent that the entire stent goes down, the DFA is covered, and now all of a sudden you’ve lost all flow to the leg. That’s my biggest concern with stenting,” he said.
Dr. Siracuse has other reservations as well. The CFA has traditionally been considered a “no-stent zone” because of the unique biomechanical stresses the artery is subjected to as a result of torsion, flexion, and extension at the hip joint. These forces render the area particularly vulnerable to neointimal hyperplasia, acute thrombosis, and stent fracture.
In addition, he noted, CFA endarterectomy for atherosclerotic lesions is a mature, well-established operation with an excellent track record for safety and durability. Dr. Siracuse’s review of procedural safety in 1,513 patients in the American College of Surgeons National Surgical Quality Improvement Project database during 2007-2010 showed a 30-day mortality of 1.5% and a 7.9% rate of major or minor complications (Vasc Endovascular Surg. 2014 Jan;48[1]:27-33).
In contrast, his review of 1,014 patients who underwent nonemergent endovascular CFA interventions for CFA stenosis without acute limb ischemia in the Vascular Quality Initiative registry demonstrated a 1-year patency rate of 85.3%, significantly lower than historically observed patency rates for endarterectomy. The 30-day mortality rate of 1.6% associated with endovascular interventions was essentially the same as in his earlier analysis of endarterectomy in the ACS NSQIP database, and the average 1.5-day hospital length of stay was shorter than with open surgery. Of considerable concern, however, stent implantation, which was performed in 35% of the endovascular interventions, was an independent predictor of amputation or death, with an associated 195% increased risk (J Vasc Surg. 2017 Apr;[4]:1039-46).
The travails of TECCO
The 17-center French TECCO study randomized 117 patients with de novo CFA atherosclerotic lesions to treatment via self-expanding stents or open surgery. A total of 98 participants were Rutherford stage 3, making TECCO primarily a study of claudicants. The primary outcome – the 30-day combined rate of morbidity and mortality – occurred in 26% of the surgical patients, a significantly higher rate than the 12.5% in the stent population. After a median follow-up of 24 months, the rates of primary patency, target lesion and extremity revascularization, and sustained clinical improvement were similar in the two groups (JACC Cardiovasc Interv. 2017 Jul 10;10[13]:1344-54).
The TECCO findings were hailed by endovascular therapy partisans as a big win. However, closer examination tells a different story, according to Dr. Siracuse.
There was no 30-day mortality in this rather small study. All 16 morbidity events occurring in the open surgery group within 30 days were relatively minor: 10 cases of delayed wound healing, 4 cases of postoperative paresthesia requiring medication, and 2 cases of lymphorrhea lasting longer than 3 days. In contrast, the seven morbidity events in the stent group included a complication requiring urgent open surgical repair at the time of stenting, one stent fracture, and a major amputation.
“The investigators didn’t elaborate on that major amputation, but I thought it was a little alarming because you should not have a major amputation with CFA interventions for claudicants,” the vascular surgeon commented. “Really, do people care about a lymphatic leak or do they care about amputation? I think more needs to be fleshed out about what really happened in that case.”
He was also puzzled by the hospital lengths of stay: a mean of 3.2 days in the stent group and 6.3 days in the open surgery group. “I think those lengths of stay are astounding. Very high and unusual,” he observed.
Dr. Siracuse predicted that much-needed high-quality data comparing treatments of the CFA will be provided by the BEST-CLI trial (Best Endovascular versus Surgical Treatment for Critical Limb Ischemia), which has been updated to include both open and endovascular interventions.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE NORTHWESTERN VASCULAR SYMPOSIUM
Major message: Most heart failure is preventable
SNOWMASS, COLO. – More than 960,000 new cases of heart failure will occur in the United States this year – and most of them could have been prevented, Gregg C. Fonarow, MD, asserted at the Annual Cardiovascular Conference at Snowmass.
Preventing heart failure doesn’t require heroic measures. It entails identifying high-risk individuals while they are still asymptomatic and free of structural heart disease – that is, patients who are stage A, pre–heart failure, in the American College of Cardiology/American Heart Association classification system for heart failure – and then addressing their modifiable risk factors via evidence-based, guideline-directed medical therapy, said Dr. Fonarow, professor of cardiovascular medicine and cochief of cardiology at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center.
A special word about obesity: A Framingham Heart Study analysis concluded that, after controlling for other cardiovascular risk factors, obese individuals had double the risk of new-onset heart failure, compared with normal weight subjects, during a mean follow-up of 14 years. For each one-unit increase in body mass index, the adjusted risk of heart failure climbed by 5% in men and 7% in women (N Engl J Med. 2002 Aug 1;347[5]:305-13). And that spells trouble down the line.
“You can imagine, with the marked increase in overweight and obesity status now affecting over half of U.S. adults, what this will mean for a potential rise in heart failure prevalence and incidence unless we do something further to modify this,” the cardiologist observed.
Dr. Fonarow is a member of the writing group for the ACC/AHA guidelines on management of heart failure. They recommend as a risk reduction strategy identification of patients with stage A pre–heart failure and addressing their risk factors: treating their hypertension and lipid disorders, gaining control over metabolic syndrome, discouraging heavy alcohol intake, and encouraging smoking cessation and regular exercise (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-239).
What kind of reduction in heart failure risk can be expected via these measures?
Antihypertensive therapy
More than a quarter century ago, the landmark SHEP trial (Systolic Hypertension in the Elderly Program) in more than 4,700 hypertensive seniors showed that treatment with diuretics and beta-blockers resulted in a 49% reduction in heart failure events, compared with placebo. And this has been a consistent finding in other studies: A meta-analysis of all 12 major randomized trials of antihypertensive therapy conducted over a 20-year period showed that treatment resulted in a whopping 52% reduction in the risk of heart failure (J Am Coll Cardiol. 1995 Apr; 27[5]:1214-8).
“If you ask most people why they’re on antihypertensive medication, they say, ‘Oh, to prevent heart attacks and stroke.’ But in fact the greatest relative risk reduction that we see is this remarkable reduction in the risk of developing heart failure with blood pressure treatment,” Dr. Fonarow said.
There has been some argument within medicine as to whether aggressive blood pressure lowering is appropriate in individuals over age 80. But in the HYVET trial (Hypertension in the Very Elderly Trial) conducted in that age group, the use of diuretics and/or ACE inhibitors to lower systolic blood pressure from roughly 155 mm Hg to 145 mm Hg resulted in a dramatic 64% reduction in the rate of new-onset heart failure (N Engl J Med. 2008 May 1;358[18]:1887-98).
How low to go with blood pressure reduction in order to maximize the heart failure risk reduction benefit? In the SPRINT trial (Systolic Blood Pressure Intervention Trial) of 9,361 hypertensive patients with a history of cardiovascular disease or multiple risk factors, participants randomized to a goal of less than 120 mm Hg enjoyed a 38% lower risk of heart failure events, compared with those whose target was less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16).
A secondary analysis from SPRINT showed that the risk of acute decompensated heart failure was 37% lower in patients treated to the target of less than 120 mm Hg. That finding takes on particular importance because SPRINT participants who developed acute decompensated heart failure had a 27-fold increase in cardiovascular death (Circ Heart Fail. 2017 Apr; doi: 10.1161/CIRCHEARTFAILURE.116.003613).
Lipid lowering
A meta-analysis of four major, randomized clinical trials of intensive versus moderate statin therapy in 27,546 patients with stable coronary artery disease or acute coronary syndrome concluded that intensive therapy resulted in a 27% reduction in the risk of hospitalization for heart failure (J Am Coll Cardiol. 2006 Jun 6;47[11]:2326-31).
SGLT-2 inhibition
Until the randomized EMPA-REG OUTCOME trial of the sodium-glucose transporter 2 (SGLT-2) inhibitor empagliflozin(Jardiance), no glucose-lowering drug available for treatment of type 2 diabetes had shown any benefit in terms of reducing diabetic patients’ elevated risk of heart failure. Neither had weight loss. Abundant evidence showed that glycemic control had no impact on the risk of heart failure events. So EMPA-REG OUTCOME was cause for celebration among heart failure specialists, with its demonstration of a 35% reduction in the risk of hospitalization for heart failure, compared with placebo in more than 7,000 randomized patients. The risk of death because of heart failure was chopped by 68%. Sharp reductions in other cardiovascular events were also seen with empagliflozin (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
Similar benefits were subsequently documented with another SGLT-2 inhibitor, canagliflozin(Invokana), in the CANVAS study program (N Engl J Med. 2017 Aug 17;377:644-57).
The reduction in cardiovascular mortality achieved with empagliflozin in EMPA-REG OUTCOME was actually bigger than seen with ACE inhibitors and angiotensin-receptor blockers (ARBs) in earlier landmark heart failure trials (Eur J Heart Fail. 2017 Jan;19[1]:43-53).
Dr. Fonarow views these data as “compelling.” These trials mark a huge step forward in the prevention of heart failure.
“We now for the first time in patients with diabetes have the ability to markedly prevent heart failure as well as cardiovascular death,” the cardiologist commented. “It is critical for cardiologists and heart failure specialists to play an active role in this [pharmacologic diabetes] management, as choice of therapy is a key determinant of outcomes, including survival.”
ACE inhibitors and ARBs
The ACC/AHA heart failure guidelines give a Class I recommendation to the routine use of ACE inhibitors or ARBs in patients at high risk for developing heart failure because of a history of diabetes, hypertension with associated cardiovascular risk factors, or any form of atherosclerotic vascular disease.
Lifestyle modification
Heavy drinking is known to raise the risk of heart failure. However, moderate alcohol consumption may be protective. In a classic prospective cohort study, individuals who reported consuming 1.5-4 drinks per day in the previous month had a 47% reduction in subsequent new-onset heart failure, compared with teetotalers in a multivariate analysis adjusted for conventional cardiovascular risk factors. Those who drank less than 1.5 drinks per day had a 21% reduction in heart failure risk, compared with the nondrinkers (JAMA. 2001 Apr 18;285[15]:1971-7).
In the prospective observational Physicians’ Health Study of nearly 21,000 men, adherence to six modifiable healthy lifestyle factors was associated with an incremental stepwise reduction in lifetime risk of developing heart failure. The six lifestyle factors – a forerunner of the AHA’s Life’s Simple 7 – were maintaining a normal body weight, stopping smoking, getting exercise, drinking alcohol in moderation, consuming breakfast cereals, and eating fruits and vegetables. Male physicians who shunned all six had a 21.2% lifetime risk of heart failure; those who followed at least four of the healthy lifestyle factors had a 10.1% risk (JAMA 2009 Jul 22;302[4]:394-400).
In a separate analysis from the Physicians’ Health Study, men who engaged in vigorous exercise to the point of breaking a sweat as little as one to three times per month had an 18% lower risk of developing heart failure during follow-up, compared with inactive men (Circulation 2009 Jan 6;119[1]:44-52).
What’s next in prevention of heart failure
Heart failure is one of the most expensive health care problems in the United States, and one of the deadliest. Today an estimated 6.5 million Americans have symptomatic heart failure. But that’s just the tip of the iceberg.
“Countless millions more are likely to manifest heart failure in the future,” Dr. Fonarow warned, noting the vast prevalence of identifiable risk factors.
It’s time for a high-visibility public health campaign designed to foster community education and engagement regarding heart failure prevention, he added.
“We have a lot of action and events around preventing atherosclerotic cardiovascular disease. But can you think of any campaign you’ve seen focusing specifically on heart failure? Heart failure isn’t one of the endpoints in the ACC/AHA Atherosclerotic Cardiovascular Disease Risk Calculator or even the new hypertension risk calculator, so we need to take this a whole lot more seriously,” the cardiologist said.
The 2017 focused update of the ACC/AHA heart failure guidelines endorsed a novel strategy of primary care–centered, biomarker-based screening of patients with cardiovascular risk factors as a means of triggering early intervention to prevent heart failure (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803). This strategy, which received a Class IIa recommendation, involves screening measurement of a natriuretic peptide biomarker.
The recommendation was based on evidence including the STOP-HF randomized trial (St. Vincent’s Screening to Prevent Heart Failure Study), in which 1,374 asymptomatic Irish patients with cardiovascular risk factors were randomized to routine primary care or primary care plus screening with brain-type natriuretic peptide testing. Patients with a brain-type natriuretic peptide level of 50 pg/mL or more were directed to team-based care involving a collaboration between their primary care physician and a specialist cardiovascular service focused on optimizing guideline-directed medical therapy. During a mean follow-up of 4.2 years, the primary endpoint of new-onset left ventricular dysfunction occurred in 5.3% of the intervention group and 8.7% of controls, for a 45% relative risk reduction (JAMA 2013 Jul 3;310[1]:66-74).
Dr. Fonarow reported receiving research grants from and serving as a consultant to the National Heart, Lung, and Blood Institute and a handful of medical companies.
SNOWMASS, COLO. – More than 960,000 new cases of heart failure will occur in the United States this year – and most of them could have been prevented, Gregg C. Fonarow, MD, asserted at the Annual Cardiovascular Conference at Snowmass.
Preventing heart failure doesn’t require heroic measures. It entails identifying high-risk individuals while they are still asymptomatic and free of structural heart disease – that is, patients who are stage A, pre–heart failure, in the American College of Cardiology/American Heart Association classification system for heart failure – and then addressing their modifiable risk factors via evidence-based, guideline-directed medical therapy, said Dr. Fonarow, professor of cardiovascular medicine and cochief of cardiology at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center.
A special word about obesity: A Framingham Heart Study analysis concluded that, after controlling for other cardiovascular risk factors, obese individuals had double the risk of new-onset heart failure, compared with normal weight subjects, during a mean follow-up of 14 years. For each one-unit increase in body mass index, the adjusted risk of heart failure climbed by 5% in men and 7% in women (N Engl J Med. 2002 Aug 1;347[5]:305-13). And that spells trouble down the line.
“You can imagine, with the marked increase in overweight and obesity status now affecting over half of U.S. adults, what this will mean for a potential rise in heart failure prevalence and incidence unless we do something further to modify this,” the cardiologist observed.
Dr. Fonarow is a member of the writing group for the ACC/AHA guidelines on management of heart failure. They recommend as a risk reduction strategy identification of patients with stage A pre–heart failure and addressing their risk factors: treating their hypertension and lipid disorders, gaining control over metabolic syndrome, discouraging heavy alcohol intake, and encouraging smoking cessation and regular exercise (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-239).
What kind of reduction in heart failure risk can be expected via these measures?
Antihypertensive therapy
More than a quarter century ago, the landmark SHEP trial (Systolic Hypertension in the Elderly Program) in more than 4,700 hypertensive seniors showed that treatment with diuretics and beta-blockers resulted in a 49% reduction in heart failure events, compared with placebo. And this has been a consistent finding in other studies: A meta-analysis of all 12 major randomized trials of antihypertensive therapy conducted over a 20-year period showed that treatment resulted in a whopping 52% reduction in the risk of heart failure (J Am Coll Cardiol. 1995 Apr; 27[5]:1214-8).
“If you ask most people why they’re on antihypertensive medication, they say, ‘Oh, to prevent heart attacks and stroke.’ But in fact the greatest relative risk reduction that we see is this remarkable reduction in the risk of developing heart failure with blood pressure treatment,” Dr. Fonarow said.
There has been some argument within medicine as to whether aggressive blood pressure lowering is appropriate in individuals over age 80. But in the HYVET trial (Hypertension in the Very Elderly Trial) conducted in that age group, the use of diuretics and/or ACE inhibitors to lower systolic blood pressure from roughly 155 mm Hg to 145 mm Hg resulted in a dramatic 64% reduction in the rate of new-onset heart failure (N Engl J Med. 2008 May 1;358[18]:1887-98).
How low to go with blood pressure reduction in order to maximize the heart failure risk reduction benefit? In the SPRINT trial (Systolic Blood Pressure Intervention Trial) of 9,361 hypertensive patients with a history of cardiovascular disease or multiple risk factors, participants randomized to a goal of less than 120 mm Hg enjoyed a 38% lower risk of heart failure events, compared with those whose target was less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16).
A secondary analysis from SPRINT showed that the risk of acute decompensated heart failure was 37% lower in patients treated to the target of less than 120 mm Hg. That finding takes on particular importance because SPRINT participants who developed acute decompensated heart failure had a 27-fold increase in cardiovascular death (Circ Heart Fail. 2017 Apr; doi: 10.1161/CIRCHEARTFAILURE.116.003613).
Lipid lowering
A meta-analysis of four major, randomized clinical trials of intensive versus moderate statin therapy in 27,546 patients with stable coronary artery disease or acute coronary syndrome concluded that intensive therapy resulted in a 27% reduction in the risk of hospitalization for heart failure (J Am Coll Cardiol. 2006 Jun 6;47[11]:2326-31).
SGLT-2 inhibition
Until the randomized EMPA-REG OUTCOME trial of the sodium-glucose transporter 2 (SGLT-2) inhibitor empagliflozin(Jardiance), no glucose-lowering drug available for treatment of type 2 diabetes had shown any benefit in terms of reducing diabetic patients’ elevated risk of heart failure. Neither had weight loss. Abundant evidence showed that glycemic control had no impact on the risk of heart failure events. So EMPA-REG OUTCOME was cause for celebration among heart failure specialists, with its demonstration of a 35% reduction in the risk of hospitalization for heart failure, compared with placebo in more than 7,000 randomized patients. The risk of death because of heart failure was chopped by 68%. Sharp reductions in other cardiovascular events were also seen with empagliflozin (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
Similar benefits were subsequently documented with another SGLT-2 inhibitor, canagliflozin(Invokana), in the CANVAS study program (N Engl J Med. 2017 Aug 17;377:644-57).
The reduction in cardiovascular mortality achieved with empagliflozin in EMPA-REG OUTCOME was actually bigger than seen with ACE inhibitors and angiotensin-receptor blockers (ARBs) in earlier landmark heart failure trials (Eur J Heart Fail. 2017 Jan;19[1]:43-53).
Dr. Fonarow views these data as “compelling.” These trials mark a huge step forward in the prevention of heart failure.
“We now for the first time in patients with diabetes have the ability to markedly prevent heart failure as well as cardiovascular death,” the cardiologist commented. “It is critical for cardiologists and heart failure specialists to play an active role in this [pharmacologic diabetes] management, as choice of therapy is a key determinant of outcomes, including survival.”
ACE inhibitors and ARBs
The ACC/AHA heart failure guidelines give a Class I recommendation to the routine use of ACE inhibitors or ARBs in patients at high risk for developing heart failure because of a history of diabetes, hypertension with associated cardiovascular risk factors, or any form of atherosclerotic vascular disease.
Lifestyle modification
Heavy drinking is known to raise the risk of heart failure. However, moderate alcohol consumption may be protective. In a classic prospective cohort study, individuals who reported consuming 1.5-4 drinks per day in the previous month had a 47% reduction in subsequent new-onset heart failure, compared with teetotalers in a multivariate analysis adjusted for conventional cardiovascular risk factors. Those who drank less than 1.5 drinks per day had a 21% reduction in heart failure risk, compared with the nondrinkers (JAMA. 2001 Apr 18;285[15]:1971-7).
In the prospective observational Physicians’ Health Study of nearly 21,000 men, adherence to six modifiable healthy lifestyle factors was associated with an incremental stepwise reduction in lifetime risk of developing heart failure. The six lifestyle factors – a forerunner of the AHA’s Life’s Simple 7 – were maintaining a normal body weight, stopping smoking, getting exercise, drinking alcohol in moderation, consuming breakfast cereals, and eating fruits and vegetables. Male physicians who shunned all six had a 21.2% lifetime risk of heart failure; those who followed at least four of the healthy lifestyle factors had a 10.1% risk (JAMA 2009 Jul 22;302[4]:394-400).
In a separate analysis from the Physicians’ Health Study, men who engaged in vigorous exercise to the point of breaking a sweat as little as one to three times per month had an 18% lower risk of developing heart failure during follow-up, compared with inactive men (Circulation 2009 Jan 6;119[1]:44-52).
What’s next in prevention of heart failure
Heart failure is one of the most expensive health care problems in the United States, and one of the deadliest. Today an estimated 6.5 million Americans have symptomatic heart failure. But that’s just the tip of the iceberg.
“Countless millions more are likely to manifest heart failure in the future,” Dr. Fonarow warned, noting the vast prevalence of identifiable risk factors.
It’s time for a high-visibility public health campaign designed to foster community education and engagement regarding heart failure prevention, he added.
“We have a lot of action and events around preventing atherosclerotic cardiovascular disease. But can you think of any campaign you’ve seen focusing specifically on heart failure? Heart failure isn’t one of the endpoints in the ACC/AHA Atherosclerotic Cardiovascular Disease Risk Calculator or even the new hypertension risk calculator, so we need to take this a whole lot more seriously,” the cardiologist said.
The 2017 focused update of the ACC/AHA heart failure guidelines endorsed a novel strategy of primary care–centered, biomarker-based screening of patients with cardiovascular risk factors as a means of triggering early intervention to prevent heart failure (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803). This strategy, which received a Class IIa recommendation, involves screening measurement of a natriuretic peptide biomarker.
The recommendation was based on evidence including the STOP-HF randomized trial (St. Vincent’s Screening to Prevent Heart Failure Study), in which 1,374 asymptomatic Irish patients with cardiovascular risk factors were randomized to routine primary care or primary care plus screening with brain-type natriuretic peptide testing. Patients with a brain-type natriuretic peptide level of 50 pg/mL or more were directed to team-based care involving a collaboration between their primary care physician and a specialist cardiovascular service focused on optimizing guideline-directed medical therapy. During a mean follow-up of 4.2 years, the primary endpoint of new-onset left ventricular dysfunction occurred in 5.3% of the intervention group and 8.7% of controls, for a 45% relative risk reduction (JAMA 2013 Jul 3;310[1]:66-74).
Dr. Fonarow reported receiving research grants from and serving as a consultant to the National Heart, Lung, and Blood Institute and a handful of medical companies.
SNOWMASS, COLO. – More than 960,000 new cases of heart failure will occur in the United States this year – and most of them could have been prevented, Gregg C. Fonarow, MD, asserted at the Annual Cardiovascular Conference at Snowmass.
Preventing heart failure doesn’t require heroic measures. It entails identifying high-risk individuals while they are still asymptomatic and free of structural heart disease – that is, patients who are stage A, pre–heart failure, in the American College of Cardiology/American Heart Association classification system for heart failure – and then addressing their modifiable risk factors via evidence-based, guideline-directed medical therapy, said Dr. Fonarow, professor of cardiovascular medicine and cochief of cardiology at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center.
A special word about obesity: A Framingham Heart Study analysis concluded that, after controlling for other cardiovascular risk factors, obese individuals had double the risk of new-onset heart failure, compared with normal weight subjects, during a mean follow-up of 14 years. For each one-unit increase in body mass index, the adjusted risk of heart failure climbed by 5% in men and 7% in women (N Engl J Med. 2002 Aug 1;347[5]:305-13). And that spells trouble down the line.
“You can imagine, with the marked increase in overweight and obesity status now affecting over half of U.S. adults, what this will mean for a potential rise in heart failure prevalence and incidence unless we do something further to modify this,” the cardiologist observed.
Dr. Fonarow is a member of the writing group for the ACC/AHA guidelines on management of heart failure. They recommend as a risk reduction strategy identification of patients with stage A pre–heart failure and addressing their risk factors: treating their hypertension and lipid disorders, gaining control over metabolic syndrome, discouraging heavy alcohol intake, and encouraging smoking cessation and regular exercise (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-239).
What kind of reduction in heart failure risk can be expected via these measures?
Antihypertensive therapy
More than a quarter century ago, the landmark SHEP trial (Systolic Hypertension in the Elderly Program) in more than 4,700 hypertensive seniors showed that treatment with diuretics and beta-blockers resulted in a 49% reduction in heart failure events, compared with placebo. And this has been a consistent finding in other studies: A meta-analysis of all 12 major randomized trials of antihypertensive therapy conducted over a 20-year period showed that treatment resulted in a whopping 52% reduction in the risk of heart failure (J Am Coll Cardiol. 1995 Apr; 27[5]:1214-8).
“If you ask most people why they’re on antihypertensive medication, they say, ‘Oh, to prevent heart attacks and stroke.’ But in fact the greatest relative risk reduction that we see is this remarkable reduction in the risk of developing heart failure with blood pressure treatment,” Dr. Fonarow said.
There has been some argument within medicine as to whether aggressive blood pressure lowering is appropriate in individuals over age 80. But in the HYVET trial (Hypertension in the Very Elderly Trial) conducted in that age group, the use of diuretics and/or ACE inhibitors to lower systolic blood pressure from roughly 155 mm Hg to 145 mm Hg resulted in a dramatic 64% reduction in the rate of new-onset heart failure (N Engl J Med. 2008 May 1;358[18]:1887-98).
How low to go with blood pressure reduction in order to maximize the heart failure risk reduction benefit? In the SPRINT trial (Systolic Blood Pressure Intervention Trial) of 9,361 hypertensive patients with a history of cardiovascular disease or multiple risk factors, participants randomized to a goal of less than 120 mm Hg enjoyed a 38% lower risk of heart failure events, compared with those whose target was less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16).
A secondary analysis from SPRINT showed that the risk of acute decompensated heart failure was 37% lower in patients treated to the target of less than 120 mm Hg. That finding takes on particular importance because SPRINT participants who developed acute decompensated heart failure had a 27-fold increase in cardiovascular death (Circ Heart Fail. 2017 Apr; doi: 10.1161/CIRCHEARTFAILURE.116.003613).
Lipid lowering
A meta-analysis of four major, randomized clinical trials of intensive versus moderate statin therapy in 27,546 patients with stable coronary artery disease or acute coronary syndrome concluded that intensive therapy resulted in a 27% reduction in the risk of hospitalization for heart failure (J Am Coll Cardiol. 2006 Jun 6;47[11]:2326-31).
SGLT-2 inhibition
Until the randomized EMPA-REG OUTCOME trial of the sodium-glucose transporter 2 (SGLT-2) inhibitor empagliflozin(Jardiance), no glucose-lowering drug available for treatment of type 2 diabetes had shown any benefit in terms of reducing diabetic patients’ elevated risk of heart failure. Neither had weight loss. Abundant evidence showed that glycemic control had no impact on the risk of heart failure events. So EMPA-REG OUTCOME was cause for celebration among heart failure specialists, with its demonstration of a 35% reduction in the risk of hospitalization for heart failure, compared with placebo in more than 7,000 randomized patients. The risk of death because of heart failure was chopped by 68%. Sharp reductions in other cardiovascular events were also seen with empagliflozin (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
Similar benefits were subsequently documented with another SGLT-2 inhibitor, canagliflozin(Invokana), in the CANVAS study program (N Engl J Med. 2017 Aug 17;377:644-57).
The reduction in cardiovascular mortality achieved with empagliflozin in EMPA-REG OUTCOME was actually bigger than seen with ACE inhibitors and angiotensin-receptor blockers (ARBs) in earlier landmark heart failure trials (Eur J Heart Fail. 2017 Jan;19[1]:43-53).
Dr. Fonarow views these data as “compelling.” These trials mark a huge step forward in the prevention of heart failure.
“We now for the first time in patients with diabetes have the ability to markedly prevent heart failure as well as cardiovascular death,” the cardiologist commented. “It is critical for cardiologists and heart failure specialists to play an active role in this [pharmacologic diabetes] management, as choice of therapy is a key determinant of outcomes, including survival.”
ACE inhibitors and ARBs
The ACC/AHA heart failure guidelines give a Class I recommendation to the routine use of ACE inhibitors or ARBs in patients at high risk for developing heart failure because of a history of diabetes, hypertension with associated cardiovascular risk factors, or any form of atherosclerotic vascular disease.
Lifestyle modification
Heavy drinking is known to raise the risk of heart failure. However, moderate alcohol consumption may be protective. In a classic prospective cohort study, individuals who reported consuming 1.5-4 drinks per day in the previous month had a 47% reduction in subsequent new-onset heart failure, compared with teetotalers in a multivariate analysis adjusted for conventional cardiovascular risk factors. Those who drank less than 1.5 drinks per day had a 21% reduction in heart failure risk, compared with the nondrinkers (JAMA. 2001 Apr 18;285[15]:1971-7).
In the prospective observational Physicians’ Health Study of nearly 21,000 men, adherence to six modifiable healthy lifestyle factors was associated with an incremental stepwise reduction in lifetime risk of developing heart failure. The six lifestyle factors – a forerunner of the AHA’s Life’s Simple 7 – were maintaining a normal body weight, stopping smoking, getting exercise, drinking alcohol in moderation, consuming breakfast cereals, and eating fruits and vegetables. Male physicians who shunned all six had a 21.2% lifetime risk of heart failure; those who followed at least four of the healthy lifestyle factors had a 10.1% risk (JAMA 2009 Jul 22;302[4]:394-400).
In a separate analysis from the Physicians’ Health Study, men who engaged in vigorous exercise to the point of breaking a sweat as little as one to three times per month had an 18% lower risk of developing heart failure during follow-up, compared with inactive men (Circulation 2009 Jan 6;119[1]:44-52).
What’s next in prevention of heart failure
Heart failure is one of the most expensive health care problems in the United States, and one of the deadliest. Today an estimated 6.5 million Americans have symptomatic heart failure. But that’s just the tip of the iceberg.
“Countless millions more are likely to manifest heart failure in the future,” Dr. Fonarow warned, noting the vast prevalence of identifiable risk factors.
It’s time for a high-visibility public health campaign designed to foster community education and engagement regarding heart failure prevention, he added.
“We have a lot of action and events around preventing atherosclerotic cardiovascular disease. But can you think of any campaign you’ve seen focusing specifically on heart failure? Heart failure isn’t one of the endpoints in the ACC/AHA Atherosclerotic Cardiovascular Disease Risk Calculator or even the new hypertension risk calculator, so we need to take this a whole lot more seriously,” the cardiologist said.
The 2017 focused update of the ACC/AHA heart failure guidelines endorsed a novel strategy of primary care–centered, biomarker-based screening of patients with cardiovascular risk factors as a means of triggering early intervention to prevent heart failure (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803). This strategy, which received a Class IIa recommendation, involves screening measurement of a natriuretic peptide biomarker.
The recommendation was based on evidence including the STOP-HF randomized trial (St. Vincent’s Screening to Prevent Heart Failure Study), in which 1,374 asymptomatic Irish patients with cardiovascular risk factors were randomized to routine primary care or primary care plus screening with brain-type natriuretic peptide testing. Patients with a brain-type natriuretic peptide level of 50 pg/mL or more were directed to team-based care involving a collaboration between their primary care physician and a specialist cardiovascular service focused on optimizing guideline-directed medical therapy. During a mean follow-up of 4.2 years, the primary endpoint of new-onset left ventricular dysfunction occurred in 5.3% of the intervention group and 8.7% of controls, for a 45% relative risk reduction (JAMA 2013 Jul 3;310[1]:66-74).
Dr. Fonarow reported receiving research grants from and serving as a consultant to the National Heart, Lung, and Blood Institute and a handful of medical companies.
EXPERT ANALYSIS FROM THE ANNUAL CARDIOVASCULAR CONFERENCE AT SNOWMASS
Think methotrexate for granulomatous mastitis
MAUI, HAWAII – Methotrexate is the most effective therapy for granulomatous mastitis, according to Anna Postolova, MD, a rheumatology fellow at Stanford (Calif.) University.
Granulomatous mastitis is a rare inflammatory disease of the breast of uncertain but possibly autoimmune etiology. The most common treatments – antibiotics, prednisone, and incision and drainage – are often ineffective and have a roughly 50% recurrence rate. That’s why Stanford rheumatologists began using methotrexate more than a decade ago with impressive results, she explained at the 2018 Rheumatology Winter Clinical Symposium.
Dr. Postolova presented a retrospective series of 19 women referred to Stanford for recurrent or refractory granulomatous mastitis. At diagnosis, they averaged 33.5 years of age with a 6-month history of symptoms prior to diagnosis. Of the 19 women, 11 were Hispanic, and only 2 were Caucasian. A total of 17 women were multiparous, with an average of two children, and 3 women were breastfeeding at symptom onset.
The women were placed on methotrexate at 15 mg/week. At 3 months, 17 of the 19 patients showed improvement, but none had disease resolution. At that point the dose was raised to 20 mg/week. After 3 months at the higher dose, 16 of 18 patients were improved and 4 had experienced resolution of their granulomatous mastitis. After 9 months on methotrexate – 6 at the higher dose – the granulomatous mastitis showed continued improvement in 13 of 15 women and resolution in 8. One woman experienced recurrent disease at 9 months of follow-up after her methotrexate was withheld because of liver test abnormalities and lack of birth control; however, she went into remission upon restarting therapy.
By 12 months, 12 of 15 women, or 80%, had experienced disease resolution. Their methotrexate was then slowly tapered over the course of 18-24 months without disease recurrence.
On the other hand, two women who had previously shown improvement were experiencing mild recurrences at the 12-month mark. They were switched to subcutaneous methotrexate. One responded favorably to the change, and the other had not yet returned for follow-up.
Dr. Postolova reported having no financial conflicts of interest regarding her presentation.
MAUI, HAWAII – Methotrexate is the most effective therapy for granulomatous mastitis, according to Anna Postolova, MD, a rheumatology fellow at Stanford (Calif.) University.
Granulomatous mastitis is a rare inflammatory disease of the breast of uncertain but possibly autoimmune etiology. The most common treatments – antibiotics, prednisone, and incision and drainage – are often ineffective and have a roughly 50% recurrence rate. That’s why Stanford rheumatologists began using methotrexate more than a decade ago with impressive results, she explained at the 2018 Rheumatology Winter Clinical Symposium.
Dr. Postolova presented a retrospective series of 19 women referred to Stanford for recurrent or refractory granulomatous mastitis. At diagnosis, they averaged 33.5 years of age with a 6-month history of symptoms prior to diagnosis. Of the 19 women, 11 were Hispanic, and only 2 were Caucasian. A total of 17 women were multiparous, with an average of two children, and 3 women were breastfeeding at symptom onset.
The women were placed on methotrexate at 15 mg/week. At 3 months, 17 of the 19 patients showed improvement, but none had disease resolution. At that point the dose was raised to 20 mg/week. After 3 months at the higher dose, 16 of 18 patients were improved and 4 had experienced resolution of their granulomatous mastitis. After 9 months on methotrexate – 6 at the higher dose – the granulomatous mastitis showed continued improvement in 13 of 15 women and resolution in 8. One woman experienced recurrent disease at 9 months of follow-up after her methotrexate was withheld because of liver test abnormalities and lack of birth control; however, she went into remission upon restarting therapy.
By 12 months, 12 of 15 women, or 80%, had experienced disease resolution. Their methotrexate was then slowly tapered over the course of 18-24 months without disease recurrence.
On the other hand, two women who had previously shown improvement were experiencing mild recurrences at the 12-month mark. They were switched to subcutaneous methotrexate. One responded favorably to the change, and the other had not yet returned for follow-up.
Dr. Postolova reported having no financial conflicts of interest regarding her presentation.
MAUI, HAWAII – Methotrexate is the most effective therapy for granulomatous mastitis, according to Anna Postolova, MD, a rheumatology fellow at Stanford (Calif.) University.
Granulomatous mastitis is a rare inflammatory disease of the breast of uncertain but possibly autoimmune etiology. The most common treatments – antibiotics, prednisone, and incision and drainage – are often ineffective and have a roughly 50% recurrence rate. That’s why Stanford rheumatologists began using methotrexate more than a decade ago with impressive results, she explained at the 2018 Rheumatology Winter Clinical Symposium.
Dr. Postolova presented a retrospective series of 19 women referred to Stanford for recurrent or refractory granulomatous mastitis. At diagnosis, they averaged 33.5 years of age with a 6-month history of symptoms prior to diagnosis. Of the 19 women, 11 were Hispanic, and only 2 were Caucasian. A total of 17 women were multiparous, with an average of two children, and 3 women were breastfeeding at symptom onset.
The women were placed on methotrexate at 15 mg/week. At 3 months, 17 of the 19 patients showed improvement, but none had disease resolution. At that point the dose was raised to 20 mg/week. After 3 months at the higher dose, 16 of 18 patients were improved and 4 had experienced resolution of their granulomatous mastitis. After 9 months on methotrexate – 6 at the higher dose – the granulomatous mastitis showed continued improvement in 13 of 15 women and resolution in 8. One woman experienced recurrent disease at 9 months of follow-up after her methotrexate was withheld because of liver test abnormalities and lack of birth control; however, she went into remission upon restarting therapy.
By 12 months, 12 of 15 women, or 80%, had experienced disease resolution. Their methotrexate was then slowly tapered over the course of 18-24 months without disease recurrence.
On the other hand, two women who had previously shown improvement were experiencing mild recurrences at the 12-month mark. They were switched to subcutaneous methotrexate. One responded favorably to the change, and the other had not yet returned for follow-up.
Dr. Postolova reported having no financial conflicts of interest regarding her presentation.
EXPERT ANALYSIS FROM RWCS 2018
Key clinical point:
Major finding: At 3 months, 17 of 19 patients showed improvement on methotrexate at 15 mg/week, and at 12 months, 12 of 15 had experienced disease resolution on 20 mg/week.
Study details: A single-center retrospective review of 19 patients with granulomatous mastitis.
Disclosures: The presenter reported having no financial conflicts of interest regarding her presentation.
Maternal biologic therapy does not affect infant vaccine responses
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
EXPERT ANALYSIS FROM RWCS 2018
Putting IBD medication risks into perspective
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
EXPERT ANALYSIS FROM GUILD 2018
Management of IBD in older patients
MAUI, HAWAII – Misconceptions abound regarding inflammatory bowel disease (IBD) in the elderly, Uma Mahadevan, MD, said at the Gastroenterology, IBD, Liver Disease meeting.
In addition to dispelling these notions, she outlined her favored treatment strategies in older IBD patients.
IBD in older individuals is actually very common
A Swedish national registry study of all 27,834 patients diagnosed with IBD in that country during 2006-2013 showed that 23% were first diagnosed at age 60 or older, with an incidence rate of 35 per 100,000 person-years for Crohn’s disease and 19 per 100,000 person-years for ulcerative colitis (Gastroenterology. 2018 Feb;154[3]:518-528e15.
“One in four to one in five of your new IBD patients are going to be over the age of 60. That’s pretty impressive,” Dr. Mahadevan said.
Genetics is less important in the pathophysiology of older-onset IBD. In one study, a positive family history of Crohn’s disease was present in 16% of affected patients under age 17 but in only 7% of those with disease onset after age 60. Similarly, a positive family history was present in 13% of ulcerative colitis patients under age 17 but in just 3% of those with onset after 60.
If genetics plays a minimal role in elderly-onset IBD, then what are the drivers? Two contributors are immunosenescence and age-related changes in the gut microbiota. Aging is accompanied by diminished T-cell responses marked by impaired memory T cells and a reduction in naive T-cell precursors.
“As the rest of you starts to age and sag, so do your T cells,” the gastroenterologist quipped.
Aging also brings physiologic alterations in gastrointestinal motility and transit. Together with changes in diet and an increase in comorbid conditions, with consequent need for a raft of medications, the end result is reduced abundance and diversity of anaerobes in the microbiota. This has immunologic implications.
Elderly IBD isn’t less severe
During a median of 4.2 years of follow-up in the Swedish national study, patients diagnosed with IBD after age 60 had more IBD-related hospitalizations and overall health care utilization than those diagnosed at ages 18-59. The incidence of extraintestinal disease manifestations was similar in the elderly and younger-adult patients; however, bowel surgery was significantly more common in the elderly patients, with a 13% rate after 5 years versus 10% in patients diagnosed as younger adults.
Moreover, elderly patients were less likely to use biologic agents and received much more systemic corticosteroid therapy than younger adults. These findings suggest that the reason elderly patients aren’t using biologics isn’t because their disease is milder, but rather because their physicians are afraid of using biologics. Due to their overconcern about risks of malignancy and serious infections, many physicians opt instead for repeated courses of corticosteroids, which is an inappropriate treatment strategy, Dr. Mahadevan said.
A cross-sectional U.S. study utilizing data from the National Inpatient Sample demonstrated that 25% of all patients hospitalized for IBD were above age 65. The study by investigators at the Medical College of Wisconsin, Milwaukee, found that age greater than 65 was an independent risk factor for in-hospital mortality. Indeed, even after adjustment for comorbidity in a multivariate logistic regression analysis, IBD patients above age 65 had a sobering 3.9-fold greater risk of in-hospital mortality (Inflamm Bowel Dis. 2009 Feb;15[2]182-9).
Another piece of evidence that elderly-onset IBD isn’t less severe comes from a Canadian cohort study of all newly diagnosed cases of IBD in Ontario during 1999-2008. The elderly-onset ulcerative colitis patients were one-third more likely to undergo IBD-related surgery than those diagnosed at ages 18-40. Older-onset Crohn’s disease patients weren’t more likely to have IBD-related operations than younger-onset patients; however, IBD-specific mortality was significantly greater in elderly-onset Crohn’s disease patients than in those diagnosed in middle age or as young adults, by a margin of 33.1 cases to 5.6 cases to 1.0 case per 10,000 person-years (Inflamm Bowel Dis. 2017 Feb;23[2]:218-23).
Treatment of IBD in the elderly
Dr. Mahadevan emphasized that, if elderly patients need biologic therapy because their disease isn’t being adequately controlled with more conservative management strategies, then they should get it. The higher rates of IBD-related surgery and in-hospital mortality in elderly IBD patients argue in favor of that strategy in order to keep them out of the hospital and optimize quality of life.
Her go-to biologics in elderly IBD patients are vedolizumab (Entyvio) and ustekinumab (Stelara): “In my older patients I reach for these two first.”
This is because of the well-documented, excellent safety profiles of those two biologics, which are particularly relevant in an elderly population at increased background risk for lymphoma and serious infections. A pooled analysis of three clinical trials of ustekinumab in induction therapy for Crohn’s disease showed an adverse event risk no different from placebo (J Comp Eff Res. 2017 Oct;6[7]:601-12). Vedolizumab, like ustekinumab, doesn’t carry a black box warning for lymphoma, and the biologic had no increase in any infections in an analysis of six clinical trials entailing more than 4,800 person-years of vedolizumab exposure (Gut. 2017 May;66[5]:839-51).
She provided three illustrative clinical scenarios, each involving a 62-year-old fit and active patient. If that patient had newly diagnosed moderate to severe ulcerative colitis, had failed on 5-aminosalicylic acid, and had good symptomatic control on prednisone, that’s someone who needs a steroid-sparing drug, and she would choose vedolizumab based upon its track record. If that active 62-year-old had moderate to severe ileal and perianal Crohn’s disease, she would opt for ustekinumab or a tumor necrosis factor inhibitor. But if that older patient was hospitalized with newly diagnosed severe ulcerative colitis that was only partially responsive to intravenous steroids, she would eschew vedolizumab and ustekinumab and turn to infliximab (Remicade).
“That patient should get infliximab just like a 32-year-old would. You need to give this patient the best shot [at avoiding colectomy], and to this day the data still supports infliximab in that population,” Dr. Mahadevan said.
Complicating management in the elderly are the commonly encountered challenges posed by polypharmacy, frailty, history of skin cancer or solid organ tumors, and heart failure. In one study, older patients with Crohn’s disease were on an average of 10 medications, ulcerative colitis patients on nine. Forty percent of the patients had potential drug-drug interactions involving their IBD medications (Inflamm Bowel Dis. 2015 Jun;21[6]:1392-400). These are situations that require individually tailored immunosuppressive decision-making.
Dr. Mahadevan reported receiving research support from the Crohn’s and Colitis Foundation, Celgene, and Pfizer and serving as a consultant to those pharmaceutical companies as well as AbbVie, Janssen, and Takeda.
MAUI, HAWAII – Misconceptions abound regarding inflammatory bowel disease (IBD) in the elderly, Uma Mahadevan, MD, said at the Gastroenterology, IBD, Liver Disease meeting.
In addition to dispelling these notions, she outlined her favored treatment strategies in older IBD patients.
IBD in older individuals is actually very common
A Swedish national registry study of all 27,834 patients diagnosed with IBD in that country during 2006-2013 showed that 23% were first diagnosed at age 60 or older, with an incidence rate of 35 per 100,000 person-years for Crohn’s disease and 19 per 100,000 person-years for ulcerative colitis (Gastroenterology. 2018 Feb;154[3]:518-528e15.
“One in four to one in five of your new IBD patients are going to be over the age of 60. That’s pretty impressive,” Dr. Mahadevan said.
Genetics is less important in the pathophysiology of older-onset IBD. In one study, a positive family history of Crohn’s disease was present in 16% of affected patients under age 17 but in only 7% of those with disease onset after age 60. Similarly, a positive family history was present in 13% of ulcerative colitis patients under age 17 but in just 3% of those with onset after 60.
If genetics plays a minimal role in elderly-onset IBD, then what are the drivers? Two contributors are immunosenescence and age-related changes in the gut microbiota. Aging is accompanied by diminished T-cell responses marked by impaired memory T cells and a reduction in naive T-cell precursors.
“As the rest of you starts to age and sag, so do your T cells,” the gastroenterologist quipped.
Aging also brings physiologic alterations in gastrointestinal motility and transit. Together with changes in diet and an increase in comorbid conditions, with consequent need for a raft of medications, the end result is reduced abundance and diversity of anaerobes in the microbiota. This has immunologic implications.
Elderly IBD isn’t less severe
During a median of 4.2 years of follow-up in the Swedish national study, patients diagnosed with IBD after age 60 had more IBD-related hospitalizations and overall health care utilization than those diagnosed at ages 18-59. The incidence of extraintestinal disease manifestations was similar in the elderly and younger-adult patients; however, bowel surgery was significantly more common in the elderly patients, with a 13% rate after 5 years versus 10% in patients diagnosed as younger adults.
Moreover, elderly patients were less likely to use biologic agents and received much more systemic corticosteroid therapy than younger adults. These findings suggest that the reason elderly patients aren’t using biologics isn’t because their disease is milder, but rather because their physicians are afraid of using biologics. Due to their overconcern about risks of malignancy and serious infections, many physicians opt instead for repeated courses of corticosteroids, which is an inappropriate treatment strategy, Dr. Mahadevan said.
A cross-sectional U.S. study utilizing data from the National Inpatient Sample demonstrated that 25% of all patients hospitalized for IBD were above age 65. The study by investigators at the Medical College of Wisconsin, Milwaukee, found that age greater than 65 was an independent risk factor for in-hospital mortality. Indeed, even after adjustment for comorbidity in a multivariate logistic regression analysis, IBD patients above age 65 had a sobering 3.9-fold greater risk of in-hospital mortality (Inflamm Bowel Dis. 2009 Feb;15[2]182-9).
Another piece of evidence that elderly-onset IBD isn’t less severe comes from a Canadian cohort study of all newly diagnosed cases of IBD in Ontario during 1999-2008. The elderly-onset ulcerative colitis patients were one-third more likely to undergo IBD-related surgery than those diagnosed at ages 18-40. Older-onset Crohn’s disease patients weren’t more likely to have IBD-related operations than younger-onset patients; however, IBD-specific mortality was significantly greater in elderly-onset Crohn’s disease patients than in those diagnosed in middle age or as young adults, by a margin of 33.1 cases to 5.6 cases to 1.0 case per 10,000 person-years (Inflamm Bowel Dis. 2017 Feb;23[2]:218-23).
Treatment of IBD in the elderly
Dr. Mahadevan emphasized that, if elderly patients need biologic therapy because their disease isn’t being adequately controlled with more conservative management strategies, then they should get it. The higher rates of IBD-related surgery and in-hospital mortality in elderly IBD patients argue in favor of that strategy in order to keep them out of the hospital and optimize quality of life.
Her go-to biologics in elderly IBD patients are vedolizumab (Entyvio) and ustekinumab (Stelara): “In my older patients I reach for these two first.”
This is because of the well-documented, excellent safety profiles of those two biologics, which are particularly relevant in an elderly population at increased background risk for lymphoma and serious infections. A pooled analysis of three clinical trials of ustekinumab in induction therapy for Crohn’s disease showed an adverse event risk no different from placebo (J Comp Eff Res. 2017 Oct;6[7]:601-12). Vedolizumab, like ustekinumab, doesn’t carry a black box warning for lymphoma, and the biologic had no increase in any infections in an analysis of six clinical trials entailing more than 4,800 person-years of vedolizumab exposure (Gut. 2017 May;66[5]:839-51).
She provided three illustrative clinical scenarios, each involving a 62-year-old fit and active patient. If that patient had newly diagnosed moderate to severe ulcerative colitis, had failed on 5-aminosalicylic acid, and had good symptomatic control on prednisone, that’s someone who needs a steroid-sparing drug, and she would choose vedolizumab based upon its track record. If that active 62-year-old had moderate to severe ileal and perianal Crohn’s disease, she would opt for ustekinumab or a tumor necrosis factor inhibitor. But if that older patient was hospitalized with newly diagnosed severe ulcerative colitis that was only partially responsive to intravenous steroids, she would eschew vedolizumab and ustekinumab and turn to infliximab (Remicade).
“That patient should get infliximab just like a 32-year-old would. You need to give this patient the best shot [at avoiding colectomy], and to this day the data still supports infliximab in that population,” Dr. Mahadevan said.
Complicating management in the elderly are the commonly encountered challenges posed by polypharmacy, frailty, history of skin cancer or solid organ tumors, and heart failure. In one study, older patients with Crohn’s disease were on an average of 10 medications, ulcerative colitis patients on nine. Forty percent of the patients had potential drug-drug interactions involving their IBD medications (Inflamm Bowel Dis. 2015 Jun;21[6]:1392-400). These are situations that require individually tailored immunosuppressive decision-making.
Dr. Mahadevan reported receiving research support from the Crohn’s and Colitis Foundation, Celgene, and Pfizer and serving as a consultant to those pharmaceutical companies as well as AbbVie, Janssen, and Takeda.
MAUI, HAWAII – Misconceptions abound regarding inflammatory bowel disease (IBD) in the elderly, Uma Mahadevan, MD, said at the Gastroenterology, IBD, Liver Disease meeting.
In addition to dispelling these notions, she outlined her favored treatment strategies in older IBD patients.
IBD in older individuals is actually very common
A Swedish national registry study of all 27,834 patients diagnosed with IBD in that country during 2006-2013 showed that 23% were first diagnosed at age 60 or older, with an incidence rate of 35 per 100,000 person-years for Crohn’s disease and 19 per 100,000 person-years for ulcerative colitis (Gastroenterology. 2018 Feb;154[3]:518-528e15.
“One in four to one in five of your new IBD patients are going to be over the age of 60. That’s pretty impressive,” Dr. Mahadevan said.
Genetics is less important in the pathophysiology of older-onset IBD. In one study, a positive family history of Crohn’s disease was present in 16% of affected patients under age 17 but in only 7% of those with disease onset after age 60. Similarly, a positive family history was present in 13% of ulcerative colitis patients under age 17 but in just 3% of those with onset after 60.
If genetics plays a minimal role in elderly-onset IBD, then what are the drivers? Two contributors are immunosenescence and age-related changes in the gut microbiota. Aging is accompanied by diminished T-cell responses marked by impaired memory T cells and a reduction in naive T-cell precursors.
“As the rest of you starts to age and sag, so do your T cells,” the gastroenterologist quipped.
Aging also brings physiologic alterations in gastrointestinal motility and transit. Together with changes in diet and an increase in comorbid conditions, with consequent need for a raft of medications, the end result is reduced abundance and diversity of anaerobes in the microbiota. This has immunologic implications.
Elderly IBD isn’t less severe
During a median of 4.2 years of follow-up in the Swedish national study, patients diagnosed with IBD after age 60 had more IBD-related hospitalizations and overall health care utilization than those diagnosed at ages 18-59. The incidence of extraintestinal disease manifestations was similar in the elderly and younger-adult patients; however, bowel surgery was significantly more common in the elderly patients, with a 13% rate after 5 years versus 10% in patients diagnosed as younger adults.
Moreover, elderly patients were less likely to use biologic agents and received much more systemic corticosteroid therapy than younger adults. These findings suggest that the reason elderly patients aren’t using biologics isn’t because their disease is milder, but rather because their physicians are afraid of using biologics. Due to their overconcern about risks of malignancy and serious infections, many physicians opt instead for repeated courses of corticosteroids, which is an inappropriate treatment strategy, Dr. Mahadevan said.
A cross-sectional U.S. study utilizing data from the National Inpatient Sample demonstrated that 25% of all patients hospitalized for IBD were above age 65. The study by investigators at the Medical College of Wisconsin, Milwaukee, found that age greater than 65 was an independent risk factor for in-hospital mortality. Indeed, even after adjustment for comorbidity in a multivariate logistic regression analysis, IBD patients above age 65 had a sobering 3.9-fold greater risk of in-hospital mortality (Inflamm Bowel Dis. 2009 Feb;15[2]182-9).
Another piece of evidence that elderly-onset IBD isn’t less severe comes from a Canadian cohort study of all newly diagnosed cases of IBD in Ontario during 1999-2008. The elderly-onset ulcerative colitis patients were one-third more likely to undergo IBD-related surgery than those diagnosed at ages 18-40. Older-onset Crohn’s disease patients weren’t more likely to have IBD-related operations than younger-onset patients; however, IBD-specific mortality was significantly greater in elderly-onset Crohn’s disease patients than in those diagnosed in middle age or as young adults, by a margin of 33.1 cases to 5.6 cases to 1.0 case per 10,000 person-years (Inflamm Bowel Dis. 2017 Feb;23[2]:218-23).
Treatment of IBD in the elderly
Dr. Mahadevan emphasized that, if elderly patients need biologic therapy because their disease isn’t being adequately controlled with more conservative management strategies, then they should get it. The higher rates of IBD-related surgery and in-hospital mortality in elderly IBD patients argue in favor of that strategy in order to keep them out of the hospital and optimize quality of life.
Her go-to biologics in elderly IBD patients are vedolizumab (Entyvio) and ustekinumab (Stelara): “In my older patients I reach for these two first.”
This is because of the well-documented, excellent safety profiles of those two biologics, which are particularly relevant in an elderly population at increased background risk for lymphoma and serious infections. A pooled analysis of three clinical trials of ustekinumab in induction therapy for Crohn’s disease showed an adverse event risk no different from placebo (J Comp Eff Res. 2017 Oct;6[7]:601-12). Vedolizumab, like ustekinumab, doesn’t carry a black box warning for lymphoma, and the biologic had no increase in any infections in an analysis of six clinical trials entailing more than 4,800 person-years of vedolizumab exposure (Gut. 2017 May;66[5]:839-51).
She provided three illustrative clinical scenarios, each involving a 62-year-old fit and active patient. If that patient had newly diagnosed moderate to severe ulcerative colitis, had failed on 5-aminosalicylic acid, and had good symptomatic control on prednisone, that’s someone who needs a steroid-sparing drug, and she would choose vedolizumab based upon its track record. If that active 62-year-old had moderate to severe ileal and perianal Crohn’s disease, she would opt for ustekinumab or a tumor necrosis factor inhibitor. But if that older patient was hospitalized with newly diagnosed severe ulcerative colitis that was only partially responsive to intravenous steroids, she would eschew vedolizumab and ustekinumab and turn to infliximab (Remicade).
“That patient should get infliximab just like a 32-year-old would. You need to give this patient the best shot [at avoiding colectomy], and to this day the data still supports infliximab in that population,” Dr. Mahadevan said.
Complicating management in the elderly are the commonly encountered challenges posed by polypharmacy, frailty, history of skin cancer or solid organ tumors, and heart failure. In one study, older patients with Crohn’s disease were on an average of 10 medications, ulcerative colitis patients on nine. Forty percent of the patients had potential drug-drug interactions involving their IBD medications (Inflamm Bowel Dis. 2015 Jun;21[6]:1392-400). These are situations that require individually tailored immunosuppressive decision-making.
Dr. Mahadevan reported receiving research support from the Crohn’s and Colitis Foundation, Celgene, and Pfizer and serving as a consultant to those pharmaceutical companies as well as AbbVie, Janssen, and Takeda.
EXPERT ANALYSIS FROM GUILD 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.