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CardioMEMS shows real-world success as use expands
DALLAS – Management of outpatients with advanced heart failure using an implanted pulmonary artery pressure monitor continues to show real-world efficacy and safety at least as impressive as in the pivotal trial for the device.
Data from the first waves of patients to receive the CardioMEMS implanted pulmonary artery pressure (PAP) monitor since it got Food and Drug Administration marketing approval in May 2014 also showed steady uptake of this fluid volume management strategy for patients with advanced heart failure, despite Medicare reimbursement issues in some U.S. regions, J. Thomas Heywood, MD, said at the at the annual scientific meeting of the Heart Failure Society of America. He estimated that more than 6,000 U.S. heart failure patients have now had a CardioMEMS PAP monitor implanted.
“The clinicians using CardioMEMS now have a lot more experience” than they had during the trial, he said in an interview. “They have more experience using the device, they know what treatments to use to lower PAP more effectively, and they are now convinced that patients will benefit from reducing diastolic PAP.”
Dr. Heywood estimated that tens of thousands more U.S. heart failure patients with New York Heart Association class III disease and a recent history of at least one heart failure hospitalization are eligible to receive an implanted PAP monitor, dwarfing the more than 6,000 patients who received a device so far.
The postapproval study
The newest efficacy data come from the first 300 patients enrolled in the CardioMEMS HF System Post Approval Study, a registry of patients receiving an implanted PAP monitor funded by the device’s manufacturer and scheduled to include a total of 1,200 patients. Dr. Heywood said full enrollment was on track for completion by the end of October 2017.
The first 300 patients enrolled in the postapproval study were older than the CHAMPION cohort; they averaged about 69 years of age, compared with about 62 years in CHAMPION, were more often women (38% vs. 28% in CHAMPION), and were more likely to have heart failure with preserved ejection fraction (41% vs. about 22%).
A similar pattern existed for the 6-month cumulative tally of PAP area under the curve, which showed an average rise of 42 mm Hg/day in the CHAMPION control patients, an average drop of 160 mm Hg/day in the CHAMPION patients managed using their CardioMEMS data, and a drop of 281 mm Hg/day in the 300 postapproval study patients.
“We’re now using the implanted sensor in a broader population of patients, and one wonders whether the effect will be diluted. What we see is at least as good as in the CHAMPION trial. This is just an early snapshot, but it is exciting that we see no erosion of the benefit. It’s a great indication that the correct patients are receiving it,” Dr. Raval said while presenting a poster at the meeting.
Further scrutiny of the same 300 patients showed another feature of the impact of PAP monitoring on patient outcomes: The first 90 days with the PAP monitor in place led to a greater number of tweaks in patient treatment and a steady fall in PAP. During days 91-180, PAP tended to level off, the number of medication adjustments dropped, and heart failure hospitalizations fell even more than in the first 90 days, Joanna M. Joly, MD, reported in a separate poster at the meeting.
The data showed “effective reduction” of PAP during the second half of the study despite fewer medication adjustments. How was that possible? Patients who transmit data on their PAPs undergo “modeling of their behavior” based on the feedback they receive from the device, Dr. Joly suggested. Regular measurement of their PAP and seeing how the number relates to their clinical status helps patients “understand the impact of their nonadherence to diet and their medications.” Another factor could be the growing familiarity clinicians develop over time with PAP fluctuations that individual patients display repeatedly that are usually self-correcting. Also, patients may undergo “hemodynamic remodeling” that results in improved self-correction of minor shifts in fluid volume and vascular tone, she said.
This pattern of a reduced need for interventions after the first 90 days with a PAP implant suggests that many patients managed this way may be able to transition to care largely delivered by local providers, or even play a greater role in their own self-care once their PAP and clinical state stabilizes, Dr. Joly said.
The findings imply that by the end of the first 90 days, “patients accept the device and manage themselves better. It becomes basically a behavioral device” that helps patients better optimize their diet and behavior, Dr. Raval observed.
Safety holds steady
Continued real-world use of PAP monitoring has also resulted in new safety insights. During the first 3 years when the CardioMEMS device was on the U.S. market, May 2014–May 2017, the FDA’s adverse event reporting system for devices, the Manufacturer and User Facility Device Experience (MAUDE) received reports on 177 unique adverse events in 155 patients implanted with a PAP monitor, Muthiah Vaduganathan, MD, reported at the meeting. During the same 3-year period, he estimated that at least 5,500 U.S. patients had received a CardioMEMS device, based on data Dr. Vaduganathan obtained from the manufacturer, Abbott. This works out to an adverse event rate of about 2.8%, virtually identical to the rate reported from CHAMPION, noted Dr. Vaduganathan, a cardiologist also at Brigham and Women’s.
Analysis of both the 22 deaths as well as the episodes of pulmonary artery injury or hemoptysis showed that the preponderance occurred relatively early after introduction for U.S. use, suggesting that “a learning curve may exist for the most serious complications,” he said. “Improved safety and device durability may result from careful patient selection, increased operator training, and refined technologies.”
Dr. Vaduganathan cautioned that the MAUDE database is limited by its bias toward serious adverse events, selective reporting, and lack of adjudication for the reported events. Concurrently with his report at the meeting, a written version appeared online (JAMA Cardiol. 2017 Sep 18. doi:10.1001/jamacardio.2017.3791).
“The adverse event rate was reassuringly low, well below the accepted threshold for device safety. It bodes favorably for the device,” he said in an interview.
“But with a passive surveillance system like MAUDE, adverse events are likely underreported; we see in MAUDE the most severe adverse events. There is certainly a larger spectrum of more minor events that we are not seeing, but I think these numbers accurately reflect serious events.” A full registry of every U.S. patient who receives the device, similar to what’s in place for U.S. patients who undergo transcatheter aortic valve replacement, would provide a more complete picture of the risks, Dr. Vaduganathan suggested.
He also voiced some surprise about the frequency of pulmonary artery injury, which was not as apparent in the 550 total patients enrolled in CHAMPION. Clinicians who place the PAP monitor are required to first take a training program, but the manufacturer has no mandated minimum number of placements an operator must assist on before launching a new CardioMEMS practice, Dr. Vaduganathan said. Many of the pulmonary artery injuries reported to MAUDE resulted from wire perforations that resulted from loss of wire control, he noted.
Clarifying the optimal CardioMEMS recipients
PAP monitoring for patients with advanced heart failure “is a major advance for certain patients who have historically been very challenging to manage,” especially patients with heart failure with preserved ejection fraction, which has few other treatment options. But “it’s often difficult to know when to pull the trigger” and proceed with placing a PAP monitor in an eligible patient, he said. “Greater experience will help us better understand that,” Dr. Vaduganathan predicted.
Dr. Heywood said that, in addition to the standard criteria of NYHA class III symptoms and a recent history of a heart failure hospitalization, the other clinical feature he looks for in a patient who is a possible CardioMEMS recipient is a persistently elevated systolic PAP as measured using echocardiography.
“These are patients with evidence of an ongoing hemodynamic problem despite treatment, and I need more data to do a better job of getting their PAP down.” Although the PAP that patients self-measure once they have the device in place is their diastolic PAP, measuring systolic PAP by echo is usually a good surrogate for finding patients who also have a persistently elevated diastolic PAP, he explained.
Another important selection criterion is to look for the patients who are dying from heart failure rather than with heart failure, Dr. Heywood added.
“If heart failure is the major thing wrong, then we can improve their quality of life” by guiding fluid management with regular PAP measurement, especially patients with preserved left ventricular ejection fraction who have few other treatment options right now, he said.
The CardioMEMS HF System Post Approval Study is sponsored by Abbott, which markets CardioMEMS. Dr Heywood has been a consultant to and/or has received research funding from Abbott as well as Impedimed, Medtronic, Novartis, and Otsuka. Dr. Raval has been a consultant to Abbott. Dr. Joly and Dr. Vaduganathan had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Management of outpatients with advanced heart failure using an implanted pulmonary artery pressure monitor continues to show real-world efficacy and safety at least as impressive as in the pivotal trial for the device.
Data from the first waves of patients to receive the CardioMEMS implanted pulmonary artery pressure (PAP) monitor since it got Food and Drug Administration marketing approval in May 2014 also showed steady uptake of this fluid volume management strategy for patients with advanced heart failure, despite Medicare reimbursement issues in some U.S. regions, J. Thomas Heywood, MD, said at the at the annual scientific meeting of the Heart Failure Society of America. He estimated that more than 6,000 U.S. heart failure patients have now had a CardioMEMS PAP monitor implanted.
“The clinicians using CardioMEMS now have a lot more experience” than they had during the trial, he said in an interview. “They have more experience using the device, they know what treatments to use to lower PAP more effectively, and they are now convinced that patients will benefit from reducing diastolic PAP.”
Dr. Heywood estimated that tens of thousands more U.S. heart failure patients with New York Heart Association class III disease and a recent history of at least one heart failure hospitalization are eligible to receive an implanted PAP monitor, dwarfing the more than 6,000 patients who received a device so far.
The postapproval study
The newest efficacy data come from the first 300 patients enrolled in the CardioMEMS HF System Post Approval Study, a registry of patients receiving an implanted PAP monitor funded by the device’s manufacturer and scheduled to include a total of 1,200 patients. Dr. Heywood said full enrollment was on track for completion by the end of October 2017.
The first 300 patients enrolled in the postapproval study were older than the CHAMPION cohort; they averaged about 69 years of age, compared with about 62 years in CHAMPION, were more often women (38% vs. 28% in CHAMPION), and were more likely to have heart failure with preserved ejection fraction (41% vs. about 22%).
A similar pattern existed for the 6-month cumulative tally of PAP area under the curve, which showed an average rise of 42 mm Hg/day in the CHAMPION control patients, an average drop of 160 mm Hg/day in the CHAMPION patients managed using their CardioMEMS data, and a drop of 281 mm Hg/day in the 300 postapproval study patients.
“We’re now using the implanted sensor in a broader population of patients, and one wonders whether the effect will be diluted. What we see is at least as good as in the CHAMPION trial. This is just an early snapshot, but it is exciting that we see no erosion of the benefit. It’s a great indication that the correct patients are receiving it,” Dr. Raval said while presenting a poster at the meeting.
Further scrutiny of the same 300 patients showed another feature of the impact of PAP monitoring on patient outcomes: The first 90 days with the PAP monitor in place led to a greater number of tweaks in patient treatment and a steady fall in PAP. During days 91-180, PAP tended to level off, the number of medication adjustments dropped, and heart failure hospitalizations fell even more than in the first 90 days, Joanna M. Joly, MD, reported in a separate poster at the meeting.
The data showed “effective reduction” of PAP during the second half of the study despite fewer medication adjustments. How was that possible? Patients who transmit data on their PAPs undergo “modeling of their behavior” based on the feedback they receive from the device, Dr. Joly suggested. Regular measurement of their PAP and seeing how the number relates to their clinical status helps patients “understand the impact of their nonadherence to diet and their medications.” Another factor could be the growing familiarity clinicians develop over time with PAP fluctuations that individual patients display repeatedly that are usually self-correcting. Also, patients may undergo “hemodynamic remodeling” that results in improved self-correction of minor shifts in fluid volume and vascular tone, she said.
This pattern of a reduced need for interventions after the first 90 days with a PAP implant suggests that many patients managed this way may be able to transition to care largely delivered by local providers, or even play a greater role in their own self-care once their PAP and clinical state stabilizes, Dr. Joly said.
The findings imply that by the end of the first 90 days, “patients accept the device and manage themselves better. It becomes basically a behavioral device” that helps patients better optimize their diet and behavior, Dr. Raval observed.
Safety holds steady
Continued real-world use of PAP monitoring has also resulted in new safety insights. During the first 3 years when the CardioMEMS device was on the U.S. market, May 2014–May 2017, the FDA’s adverse event reporting system for devices, the Manufacturer and User Facility Device Experience (MAUDE) received reports on 177 unique adverse events in 155 patients implanted with a PAP monitor, Muthiah Vaduganathan, MD, reported at the meeting. During the same 3-year period, he estimated that at least 5,500 U.S. patients had received a CardioMEMS device, based on data Dr. Vaduganathan obtained from the manufacturer, Abbott. This works out to an adverse event rate of about 2.8%, virtually identical to the rate reported from CHAMPION, noted Dr. Vaduganathan, a cardiologist also at Brigham and Women’s.
Analysis of both the 22 deaths as well as the episodes of pulmonary artery injury or hemoptysis showed that the preponderance occurred relatively early after introduction for U.S. use, suggesting that “a learning curve may exist for the most serious complications,” he said. “Improved safety and device durability may result from careful patient selection, increased operator training, and refined technologies.”
Dr. Vaduganathan cautioned that the MAUDE database is limited by its bias toward serious adverse events, selective reporting, and lack of adjudication for the reported events. Concurrently with his report at the meeting, a written version appeared online (JAMA Cardiol. 2017 Sep 18. doi:10.1001/jamacardio.2017.3791).
“The adverse event rate was reassuringly low, well below the accepted threshold for device safety. It bodes favorably for the device,” he said in an interview.
“But with a passive surveillance system like MAUDE, adverse events are likely underreported; we see in MAUDE the most severe adverse events. There is certainly a larger spectrum of more minor events that we are not seeing, but I think these numbers accurately reflect serious events.” A full registry of every U.S. patient who receives the device, similar to what’s in place for U.S. patients who undergo transcatheter aortic valve replacement, would provide a more complete picture of the risks, Dr. Vaduganathan suggested.
He also voiced some surprise about the frequency of pulmonary artery injury, which was not as apparent in the 550 total patients enrolled in CHAMPION. Clinicians who place the PAP monitor are required to first take a training program, but the manufacturer has no mandated minimum number of placements an operator must assist on before launching a new CardioMEMS practice, Dr. Vaduganathan said. Many of the pulmonary artery injuries reported to MAUDE resulted from wire perforations that resulted from loss of wire control, he noted.
Clarifying the optimal CardioMEMS recipients
PAP monitoring for patients with advanced heart failure “is a major advance for certain patients who have historically been very challenging to manage,” especially patients with heart failure with preserved ejection fraction, which has few other treatment options. But “it’s often difficult to know when to pull the trigger” and proceed with placing a PAP monitor in an eligible patient, he said. “Greater experience will help us better understand that,” Dr. Vaduganathan predicted.
Dr. Heywood said that, in addition to the standard criteria of NYHA class III symptoms and a recent history of a heart failure hospitalization, the other clinical feature he looks for in a patient who is a possible CardioMEMS recipient is a persistently elevated systolic PAP as measured using echocardiography.
“These are patients with evidence of an ongoing hemodynamic problem despite treatment, and I need more data to do a better job of getting their PAP down.” Although the PAP that patients self-measure once they have the device in place is their diastolic PAP, measuring systolic PAP by echo is usually a good surrogate for finding patients who also have a persistently elevated diastolic PAP, he explained.
Another important selection criterion is to look for the patients who are dying from heart failure rather than with heart failure, Dr. Heywood added.
“If heart failure is the major thing wrong, then we can improve their quality of life” by guiding fluid management with regular PAP measurement, especially patients with preserved left ventricular ejection fraction who have few other treatment options right now, he said.
The CardioMEMS HF System Post Approval Study is sponsored by Abbott, which markets CardioMEMS. Dr Heywood has been a consultant to and/or has received research funding from Abbott as well as Impedimed, Medtronic, Novartis, and Otsuka. Dr. Raval has been a consultant to Abbott. Dr. Joly and Dr. Vaduganathan had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Management of outpatients with advanced heart failure using an implanted pulmonary artery pressure monitor continues to show real-world efficacy and safety at least as impressive as in the pivotal trial for the device.
Data from the first waves of patients to receive the CardioMEMS implanted pulmonary artery pressure (PAP) monitor since it got Food and Drug Administration marketing approval in May 2014 also showed steady uptake of this fluid volume management strategy for patients with advanced heart failure, despite Medicare reimbursement issues in some U.S. regions, J. Thomas Heywood, MD, said at the at the annual scientific meeting of the Heart Failure Society of America. He estimated that more than 6,000 U.S. heart failure patients have now had a CardioMEMS PAP monitor implanted.
“The clinicians using CardioMEMS now have a lot more experience” than they had during the trial, he said in an interview. “They have more experience using the device, they know what treatments to use to lower PAP more effectively, and they are now convinced that patients will benefit from reducing diastolic PAP.”
Dr. Heywood estimated that tens of thousands more U.S. heart failure patients with New York Heart Association class III disease and a recent history of at least one heart failure hospitalization are eligible to receive an implanted PAP monitor, dwarfing the more than 6,000 patients who received a device so far.
The postapproval study
The newest efficacy data come from the first 300 patients enrolled in the CardioMEMS HF System Post Approval Study, a registry of patients receiving an implanted PAP monitor funded by the device’s manufacturer and scheduled to include a total of 1,200 patients. Dr. Heywood said full enrollment was on track for completion by the end of October 2017.
The first 300 patients enrolled in the postapproval study were older than the CHAMPION cohort; they averaged about 69 years of age, compared with about 62 years in CHAMPION, were more often women (38% vs. 28% in CHAMPION), and were more likely to have heart failure with preserved ejection fraction (41% vs. about 22%).
A similar pattern existed for the 6-month cumulative tally of PAP area under the curve, which showed an average rise of 42 mm Hg/day in the CHAMPION control patients, an average drop of 160 mm Hg/day in the CHAMPION patients managed using their CardioMEMS data, and a drop of 281 mm Hg/day in the 300 postapproval study patients.
“We’re now using the implanted sensor in a broader population of patients, and one wonders whether the effect will be diluted. What we see is at least as good as in the CHAMPION trial. This is just an early snapshot, but it is exciting that we see no erosion of the benefit. It’s a great indication that the correct patients are receiving it,” Dr. Raval said while presenting a poster at the meeting.
Further scrutiny of the same 300 patients showed another feature of the impact of PAP monitoring on patient outcomes: The first 90 days with the PAP monitor in place led to a greater number of tweaks in patient treatment and a steady fall in PAP. During days 91-180, PAP tended to level off, the number of medication adjustments dropped, and heart failure hospitalizations fell even more than in the first 90 days, Joanna M. Joly, MD, reported in a separate poster at the meeting.
The data showed “effective reduction” of PAP during the second half of the study despite fewer medication adjustments. How was that possible? Patients who transmit data on their PAPs undergo “modeling of their behavior” based on the feedback they receive from the device, Dr. Joly suggested. Regular measurement of their PAP and seeing how the number relates to their clinical status helps patients “understand the impact of their nonadherence to diet and their medications.” Another factor could be the growing familiarity clinicians develop over time with PAP fluctuations that individual patients display repeatedly that are usually self-correcting. Also, patients may undergo “hemodynamic remodeling” that results in improved self-correction of minor shifts in fluid volume and vascular tone, she said.
This pattern of a reduced need for interventions after the first 90 days with a PAP implant suggests that many patients managed this way may be able to transition to care largely delivered by local providers, or even play a greater role in their own self-care once their PAP and clinical state stabilizes, Dr. Joly said.
The findings imply that by the end of the first 90 days, “patients accept the device and manage themselves better. It becomes basically a behavioral device” that helps patients better optimize their diet and behavior, Dr. Raval observed.
Safety holds steady
Continued real-world use of PAP monitoring has also resulted in new safety insights. During the first 3 years when the CardioMEMS device was on the U.S. market, May 2014–May 2017, the FDA’s adverse event reporting system for devices, the Manufacturer and User Facility Device Experience (MAUDE) received reports on 177 unique adverse events in 155 patients implanted with a PAP monitor, Muthiah Vaduganathan, MD, reported at the meeting. During the same 3-year period, he estimated that at least 5,500 U.S. patients had received a CardioMEMS device, based on data Dr. Vaduganathan obtained from the manufacturer, Abbott. This works out to an adverse event rate of about 2.8%, virtually identical to the rate reported from CHAMPION, noted Dr. Vaduganathan, a cardiologist also at Brigham and Women’s.
Analysis of both the 22 deaths as well as the episodes of pulmonary artery injury or hemoptysis showed that the preponderance occurred relatively early after introduction for U.S. use, suggesting that “a learning curve may exist for the most serious complications,” he said. “Improved safety and device durability may result from careful patient selection, increased operator training, and refined technologies.”
Dr. Vaduganathan cautioned that the MAUDE database is limited by its bias toward serious adverse events, selective reporting, and lack of adjudication for the reported events. Concurrently with his report at the meeting, a written version appeared online (JAMA Cardiol. 2017 Sep 18. doi:10.1001/jamacardio.2017.3791).
“The adverse event rate was reassuringly low, well below the accepted threshold for device safety. It bodes favorably for the device,” he said in an interview.
“But with a passive surveillance system like MAUDE, adverse events are likely underreported; we see in MAUDE the most severe adverse events. There is certainly a larger spectrum of more minor events that we are not seeing, but I think these numbers accurately reflect serious events.” A full registry of every U.S. patient who receives the device, similar to what’s in place for U.S. patients who undergo transcatheter aortic valve replacement, would provide a more complete picture of the risks, Dr. Vaduganathan suggested.
He also voiced some surprise about the frequency of pulmonary artery injury, which was not as apparent in the 550 total patients enrolled in CHAMPION. Clinicians who place the PAP monitor are required to first take a training program, but the manufacturer has no mandated minimum number of placements an operator must assist on before launching a new CardioMEMS practice, Dr. Vaduganathan said. Many of the pulmonary artery injuries reported to MAUDE resulted from wire perforations that resulted from loss of wire control, he noted.
Clarifying the optimal CardioMEMS recipients
PAP monitoring for patients with advanced heart failure “is a major advance for certain patients who have historically been very challenging to manage,” especially patients with heart failure with preserved ejection fraction, which has few other treatment options. But “it’s often difficult to know when to pull the trigger” and proceed with placing a PAP monitor in an eligible patient, he said. “Greater experience will help us better understand that,” Dr. Vaduganathan predicted.
Dr. Heywood said that, in addition to the standard criteria of NYHA class III symptoms and a recent history of a heart failure hospitalization, the other clinical feature he looks for in a patient who is a possible CardioMEMS recipient is a persistently elevated systolic PAP as measured using echocardiography.
“These are patients with evidence of an ongoing hemodynamic problem despite treatment, and I need more data to do a better job of getting their PAP down.” Although the PAP that patients self-measure once they have the device in place is their diastolic PAP, measuring systolic PAP by echo is usually a good surrogate for finding patients who also have a persistently elevated diastolic PAP, he explained.
Another important selection criterion is to look for the patients who are dying from heart failure rather than with heart failure, Dr. Heywood added.
“If heart failure is the major thing wrong, then we can improve their quality of life” by guiding fluid management with regular PAP measurement, especially patients with preserved left ventricular ejection fraction who have few other treatment options right now, he said.
The CardioMEMS HF System Post Approval Study is sponsored by Abbott, which markets CardioMEMS. Dr Heywood has been a consultant to and/or has received research funding from Abbott as well as Impedimed, Medtronic, Novartis, and Otsuka. Dr. Raval has been a consultant to Abbott. Dr. Joly and Dr. Vaduganathan had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
MI, stroke risk from HFrEF surpasses HFpEF
DALLAS – Patients newly diagnosed with heart failure with reduced ejection fraction had about an 8% incidence of MIs during the subsequent 9 months, and a 5% incidence of ischemic strokes in a retrospective review of more than 1,600 community-dwelling U.S. patients.
The MI and ischemic stroke incidence rates in heart failure patients with reduced ejection fraction (HFrEF) were both significantly higher than in more than 4,000 patients with heart failure with preserved ejection fraction (HFpEF), Gregg C. Fonarow, MD, said while presenting a poster at the annual scientific meeting of the Heart Failure Society of America.
The findings suggest that greater attention is needed to reduce the risks for MI and stroke in HFrEF patients, suggested Dr. Fonarow, professor and cochief of cardiology at the University of California, Los Angeles, and his associates in their poster.
The study used claims data collected during July 2009-September 2016 from more than 10 million people enrolled in the United Health Group, who received care at more than 650 hospitals and about 6,600 clinics. The study included all patients diagnosed with heart failure during a hospital or emergency room visit and who had no history of a heart failure diagnosis or episode during the preceding 18 months, a left ventricular ejection fraction measurement made close to the time of the index encounter, and no stroke or MI apparent at the time of the index event. The study included 1,622 patients with HFrEF, defined as a left ventricular ejection fraction of less than 40%, 4,288 with HFpEF, defined as an ejection fraction of 50% or more, and 1,095 with heart failure with a borderline ejection fraction of 40%-49%.
The HFrEF patients had an average ejection fraction of 28%, they averaged 72 years old, 36% were women, and 8% had a prior stroke. The HFpEF patients averaged 74 years old, their average ejection fraction was 61%, 55% were women, and 11% had a prior stroke. Follow-up data on all patients were available for an average of nearly 9 months following their index heart failure event, with some patients followed as long as 1 year.
During follow-up, the incidence of ischemic stroke was 5.4% in the HFrEF patients and 3.9% in those with HFpEF, a difference that worked out to a statistically significant 40% higher ischemic stroke rate in HFrEF patients after adjustment for baseline differences between the two patient groups, Dr. Fonarow reported. The patients with a borderline ejection fraction had a 3.7% stroke incidence that fell short of a significant difference, compared with the HFrEF patient.The rate of new MIs during follow-up was 7.5% in the HFrEF patients and 3.2% in the HFpEF patients, a statistically significant 2.5-fold relatively higher MI rate with HFrEF, a statistically significant difference after adjustments. The MI incidence in patients with a borderline ejection fraction was 5.9%
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Patients newly diagnosed with heart failure with reduced ejection fraction had about an 8% incidence of MIs during the subsequent 9 months, and a 5% incidence of ischemic strokes in a retrospective review of more than 1,600 community-dwelling U.S. patients.
The MI and ischemic stroke incidence rates in heart failure patients with reduced ejection fraction (HFrEF) were both significantly higher than in more than 4,000 patients with heart failure with preserved ejection fraction (HFpEF), Gregg C. Fonarow, MD, said while presenting a poster at the annual scientific meeting of the Heart Failure Society of America.
The findings suggest that greater attention is needed to reduce the risks for MI and stroke in HFrEF patients, suggested Dr. Fonarow, professor and cochief of cardiology at the University of California, Los Angeles, and his associates in their poster.
The study used claims data collected during July 2009-September 2016 from more than 10 million people enrolled in the United Health Group, who received care at more than 650 hospitals and about 6,600 clinics. The study included all patients diagnosed with heart failure during a hospital or emergency room visit and who had no history of a heart failure diagnosis or episode during the preceding 18 months, a left ventricular ejection fraction measurement made close to the time of the index encounter, and no stroke or MI apparent at the time of the index event. The study included 1,622 patients with HFrEF, defined as a left ventricular ejection fraction of less than 40%, 4,288 with HFpEF, defined as an ejection fraction of 50% or more, and 1,095 with heart failure with a borderline ejection fraction of 40%-49%.
The HFrEF patients had an average ejection fraction of 28%, they averaged 72 years old, 36% were women, and 8% had a prior stroke. The HFpEF patients averaged 74 years old, their average ejection fraction was 61%, 55% were women, and 11% had a prior stroke. Follow-up data on all patients were available for an average of nearly 9 months following their index heart failure event, with some patients followed as long as 1 year.
During follow-up, the incidence of ischemic stroke was 5.4% in the HFrEF patients and 3.9% in those with HFpEF, a difference that worked out to a statistically significant 40% higher ischemic stroke rate in HFrEF patients after adjustment for baseline differences between the two patient groups, Dr. Fonarow reported. The patients with a borderline ejection fraction had a 3.7% stroke incidence that fell short of a significant difference, compared with the HFrEF patient.The rate of new MIs during follow-up was 7.5% in the HFrEF patients and 3.2% in the HFpEF patients, a statistically significant 2.5-fold relatively higher MI rate with HFrEF, a statistically significant difference after adjustments. The MI incidence in patients with a borderline ejection fraction was 5.9%
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Patients newly diagnosed with heart failure with reduced ejection fraction had about an 8% incidence of MIs during the subsequent 9 months, and a 5% incidence of ischemic strokes in a retrospective review of more than 1,600 community-dwelling U.S. patients.
The MI and ischemic stroke incidence rates in heart failure patients with reduced ejection fraction (HFrEF) were both significantly higher than in more than 4,000 patients with heart failure with preserved ejection fraction (HFpEF), Gregg C. Fonarow, MD, said while presenting a poster at the annual scientific meeting of the Heart Failure Society of America.
The findings suggest that greater attention is needed to reduce the risks for MI and stroke in HFrEF patients, suggested Dr. Fonarow, professor and cochief of cardiology at the University of California, Los Angeles, and his associates in their poster.
The study used claims data collected during July 2009-September 2016 from more than 10 million people enrolled in the United Health Group, who received care at more than 650 hospitals and about 6,600 clinics. The study included all patients diagnosed with heart failure during a hospital or emergency room visit and who had no history of a heart failure diagnosis or episode during the preceding 18 months, a left ventricular ejection fraction measurement made close to the time of the index encounter, and no stroke or MI apparent at the time of the index event. The study included 1,622 patients with HFrEF, defined as a left ventricular ejection fraction of less than 40%, 4,288 with HFpEF, defined as an ejection fraction of 50% or more, and 1,095 with heart failure with a borderline ejection fraction of 40%-49%.
The HFrEF patients had an average ejection fraction of 28%, they averaged 72 years old, 36% were women, and 8% had a prior stroke. The HFpEF patients averaged 74 years old, their average ejection fraction was 61%, 55% were women, and 11% had a prior stroke. Follow-up data on all patients were available for an average of nearly 9 months following their index heart failure event, with some patients followed as long as 1 year.
During follow-up, the incidence of ischemic stroke was 5.4% in the HFrEF patients and 3.9% in those with HFpEF, a difference that worked out to a statistically significant 40% higher ischemic stroke rate in HFrEF patients after adjustment for baseline differences between the two patient groups, Dr. Fonarow reported. The patients with a borderline ejection fraction had a 3.7% stroke incidence that fell short of a significant difference, compared with the HFrEF patient.The rate of new MIs during follow-up was 7.5% in the HFrEF patients and 3.2% in the HFpEF patients, a statistically significant 2.5-fold relatively higher MI rate with HFrEF, a statistically significant difference after adjustments. The MI incidence in patients with a borderline ejection fraction was 5.9%
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point:
Major finding: HFrEF patients had a 40% higher incidence of stroke and a 2.5-fold higher incidence of MI, compared with HFpEF patients.
Data source: Retrospective review of 7,005 U.S. patients newly diagnosed with heart failure.
Disclosures: The study was funded by Janssen. Dr. Fonarow had no relevant disclosures.
VIDEO: AF ablation boosts survival in heart failure patients
BARCELONA – In patients with heart failure with reduced ejection fraction who also have atrial fibrillation, catheter ablation of the arrhythmia produced significantly improved long-term survival and a significant reduction in heart failure hospitalizations, in results from a multicenter randomized trial with more than 350 patients.
During 5-year follow-up, heart failure patients who underwent an ablative procedure for their atrial fibrillation (AF) had a statistically significant 37% lower rate of the combined primary endpoint of all-cause death or hospitalization for worsening heart failure, compared with control patients managed by standard medical therapy, Nassir F. Marrouche, MD, said at the annual congress of the European Society of Cardiology. The results also showed significant reductions from ablation, compared with controls, for the individual secondary endpoints of all-cause mortality, heart failure hospitalizations, cardiovascular mortality, and cardiovascular hospitalizations, said Dr. Marrouche, a professor of medicine and electrophysiologist at the University of Utah in Salt Lake City.
“Catheter ablation of atrial fibrillation is already done in heart failure patients, but now we have added information that this treatment may not just improve AF symptoms but also lead to a significant improvement in prognosis,” said Johannes Brachmann, MD, a coinvestigator on the study and professor and chief of cardiology at Coburg (Germany) Hospital.
The CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial was investigator initiated and run at 31 centers in nine countries. The study randomized patients with paroxysmal or persistent AF and heart failure with a left ventricular ejection fraction of 35% or less. All patients also had to have failed treatment with, been intolerant of, or refused treatment with at least one antiarrhythmic drug, and they had to have been implanted with either an implantable cardioverter defibrillator or a cardiac resynchronization therapy and defibrillation device. The researchers randomized 179 patients to catheter ablation by pulmonary vein isolation, and 184 patients to either a standard rate or rhythm-control regimen plus anticoagulation to prevent ischemic stroke.
The ablation procedure also cut the average AF burden by more than half, compared with medical therapy throughout the 5-year follow-up, Dr. Marrouche reported.
The results “support the need to monitor patients with heart failure for atrial fibrillation,” Dr. Brachmann said in a video interview. This means broader use of monitoring technologies to diagnose AF in heart failure patients, such as implanted loop recorders or implanted rhythm devices.
The prevalence of atrial fibrillation in patients with heart failure with reduced ejection fraction can run 30% or higher. In patients with NYHA class IV heart failure, the AF prevalence is about 50%, Dr. Brachmann said.
CASTLE AF was funded by Biotronik. Dr. Marrouche has been a consultant to and received research funding from Biotronik and from several other companies. Dr. Brachmann has been a speaker for and has received research funding from Biotronik and from Abbott and Medtronic.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The results of several studies have shown that patients with both atrial fibrillation and heart failure have about a 40% increased mortality, compared with heart failure patients without atrial fibrillation.
Five prior randomized controlled trials assessed the impact of AF ablation, compared with rate or rhythm control, in heart failure patients. But unlike CASTLE AF, all the prior studies used freedom from AF as the primary endpoint.
Enrolled patients were symptomatic from AF. Would asymptomatic patients get the same benefits? All enrolled patients had failed prior antiarrhythmic treatment or were intolerant or unwilling to take it. Does this mean the trial enrolled patients who generally were unresponsive to antiarrhythmic drugs, thereby skewing the results toward worse outcomes in control patients? Also, the 5-week run-in period used before randomization may have shifted enrollment toward patients well suited to ablation. The enrolled patients were also relatively young (averaging 64 years of age), and about 60% were New York Heart Association functional class II. A minority had longstanding AF. Were these younger and healthier patients better able to tolerate ablation? And can centers with less experience performing ablations have similar results?
The CASTLE AF results suggest that the time has come to offer AF ablation to patients with heart failure with reduced ejection fraction and AF, but we must be careful to select patients who are similar to the ones enrolled in this trial.
Carina Blomström-Lundqvist, MD, an electrophysiologist at Uppsala (Sweden) University Hospital, made these comments as designated discussant for the report. She has received research funding from Medtronic and Cardiome, and she has received honoraria from Biotronik, Bayer, Bristol-Myers Squibb, Medtronic, Merck, Pfizer, and Sanofi.
The results of several studies have shown that patients with both atrial fibrillation and heart failure have about a 40% increased mortality, compared with heart failure patients without atrial fibrillation.
Five prior randomized controlled trials assessed the impact of AF ablation, compared with rate or rhythm control, in heart failure patients. But unlike CASTLE AF, all the prior studies used freedom from AF as the primary endpoint.
Enrolled patients were symptomatic from AF. Would asymptomatic patients get the same benefits? All enrolled patients had failed prior antiarrhythmic treatment or were intolerant or unwilling to take it. Does this mean the trial enrolled patients who generally were unresponsive to antiarrhythmic drugs, thereby skewing the results toward worse outcomes in control patients? Also, the 5-week run-in period used before randomization may have shifted enrollment toward patients well suited to ablation. The enrolled patients were also relatively young (averaging 64 years of age), and about 60% were New York Heart Association functional class II. A minority had longstanding AF. Were these younger and healthier patients better able to tolerate ablation? And can centers with less experience performing ablations have similar results?
The CASTLE AF results suggest that the time has come to offer AF ablation to patients with heart failure with reduced ejection fraction and AF, but we must be careful to select patients who are similar to the ones enrolled in this trial.
Carina Blomström-Lundqvist, MD, an electrophysiologist at Uppsala (Sweden) University Hospital, made these comments as designated discussant for the report. She has received research funding from Medtronic and Cardiome, and she has received honoraria from Biotronik, Bayer, Bristol-Myers Squibb, Medtronic, Merck, Pfizer, and Sanofi.
The results of several studies have shown that patients with both atrial fibrillation and heart failure have about a 40% increased mortality, compared with heart failure patients without atrial fibrillation.
Five prior randomized controlled trials assessed the impact of AF ablation, compared with rate or rhythm control, in heart failure patients. But unlike CASTLE AF, all the prior studies used freedom from AF as the primary endpoint.
Enrolled patients were symptomatic from AF. Would asymptomatic patients get the same benefits? All enrolled patients had failed prior antiarrhythmic treatment or were intolerant or unwilling to take it. Does this mean the trial enrolled patients who generally were unresponsive to antiarrhythmic drugs, thereby skewing the results toward worse outcomes in control patients? Also, the 5-week run-in period used before randomization may have shifted enrollment toward patients well suited to ablation. The enrolled patients were also relatively young (averaging 64 years of age), and about 60% were New York Heart Association functional class II. A minority had longstanding AF. Were these younger and healthier patients better able to tolerate ablation? And can centers with less experience performing ablations have similar results?
The CASTLE AF results suggest that the time has come to offer AF ablation to patients with heart failure with reduced ejection fraction and AF, but we must be careful to select patients who are similar to the ones enrolled in this trial.
Carina Blomström-Lundqvist, MD, an electrophysiologist at Uppsala (Sweden) University Hospital, made these comments as designated discussant for the report. She has received research funding from Medtronic and Cardiome, and she has received honoraria from Biotronik, Bayer, Bristol-Myers Squibb, Medtronic, Merck, Pfizer, and Sanofi.
BARCELONA – In patients with heart failure with reduced ejection fraction who also have atrial fibrillation, catheter ablation of the arrhythmia produced significantly improved long-term survival and a significant reduction in heart failure hospitalizations, in results from a multicenter randomized trial with more than 350 patients.
During 5-year follow-up, heart failure patients who underwent an ablative procedure for their atrial fibrillation (AF) had a statistically significant 37% lower rate of the combined primary endpoint of all-cause death or hospitalization for worsening heart failure, compared with control patients managed by standard medical therapy, Nassir F. Marrouche, MD, said at the annual congress of the European Society of Cardiology. The results also showed significant reductions from ablation, compared with controls, for the individual secondary endpoints of all-cause mortality, heart failure hospitalizations, cardiovascular mortality, and cardiovascular hospitalizations, said Dr. Marrouche, a professor of medicine and electrophysiologist at the University of Utah in Salt Lake City.
“Catheter ablation of atrial fibrillation is already done in heart failure patients, but now we have added information that this treatment may not just improve AF symptoms but also lead to a significant improvement in prognosis,” said Johannes Brachmann, MD, a coinvestigator on the study and professor and chief of cardiology at Coburg (Germany) Hospital.
The CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial was investigator initiated and run at 31 centers in nine countries. The study randomized patients with paroxysmal or persistent AF and heart failure with a left ventricular ejection fraction of 35% or less. All patients also had to have failed treatment with, been intolerant of, or refused treatment with at least one antiarrhythmic drug, and they had to have been implanted with either an implantable cardioverter defibrillator or a cardiac resynchronization therapy and defibrillation device. The researchers randomized 179 patients to catheter ablation by pulmonary vein isolation, and 184 patients to either a standard rate or rhythm-control regimen plus anticoagulation to prevent ischemic stroke.
The ablation procedure also cut the average AF burden by more than half, compared with medical therapy throughout the 5-year follow-up, Dr. Marrouche reported.
The results “support the need to monitor patients with heart failure for atrial fibrillation,” Dr. Brachmann said in a video interview. This means broader use of monitoring technologies to diagnose AF in heart failure patients, such as implanted loop recorders or implanted rhythm devices.
The prevalence of atrial fibrillation in patients with heart failure with reduced ejection fraction can run 30% or higher. In patients with NYHA class IV heart failure, the AF prevalence is about 50%, Dr. Brachmann said.
CASTLE AF was funded by Biotronik. Dr. Marrouche has been a consultant to and received research funding from Biotronik and from several other companies. Dr. Brachmann has been a speaker for and has received research funding from Biotronik and from Abbott and Medtronic.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
BARCELONA – In patients with heart failure with reduced ejection fraction who also have atrial fibrillation, catheter ablation of the arrhythmia produced significantly improved long-term survival and a significant reduction in heart failure hospitalizations, in results from a multicenter randomized trial with more than 350 patients.
During 5-year follow-up, heart failure patients who underwent an ablative procedure for their atrial fibrillation (AF) had a statistically significant 37% lower rate of the combined primary endpoint of all-cause death or hospitalization for worsening heart failure, compared with control patients managed by standard medical therapy, Nassir F. Marrouche, MD, said at the annual congress of the European Society of Cardiology. The results also showed significant reductions from ablation, compared with controls, for the individual secondary endpoints of all-cause mortality, heart failure hospitalizations, cardiovascular mortality, and cardiovascular hospitalizations, said Dr. Marrouche, a professor of medicine and electrophysiologist at the University of Utah in Salt Lake City.
“Catheter ablation of atrial fibrillation is already done in heart failure patients, but now we have added information that this treatment may not just improve AF symptoms but also lead to a significant improvement in prognosis,” said Johannes Brachmann, MD, a coinvestigator on the study and professor and chief of cardiology at Coburg (Germany) Hospital.
The CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial was investigator initiated and run at 31 centers in nine countries. The study randomized patients with paroxysmal or persistent AF and heart failure with a left ventricular ejection fraction of 35% or less. All patients also had to have failed treatment with, been intolerant of, or refused treatment with at least one antiarrhythmic drug, and they had to have been implanted with either an implantable cardioverter defibrillator or a cardiac resynchronization therapy and defibrillation device. The researchers randomized 179 patients to catheter ablation by pulmonary vein isolation, and 184 patients to either a standard rate or rhythm-control regimen plus anticoagulation to prevent ischemic stroke.
The ablation procedure also cut the average AF burden by more than half, compared with medical therapy throughout the 5-year follow-up, Dr. Marrouche reported.
The results “support the need to monitor patients with heart failure for atrial fibrillation,” Dr. Brachmann said in a video interview. This means broader use of monitoring technologies to diagnose AF in heart failure patients, such as implanted loop recorders or implanted rhythm devices.
The prevalence of atrial fibrillation in patients with heart failure with reduced ejection fraction can run 30% or higher. In patients with NYHA class IV heart failure, the AF prevalence is about 50%, Dr. Brachmann said.
CASTLE AF was funded by Biotronik. Dr. Marrouche has been a consultant to and received research funding from Biotronik and from several other companies. Dr. Brachmann has been a speaker for and has received research funding from Biotronik and from Abbott and Medtronic.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: AF ablation was linked to a 37% 5-year reduction in mortality and heart failure hospitalization, compared with standard treatment.
Data source: CASTLE AF, a multicenter randomized trial with 363 patients.
Disclosures: CASTLE AF was funded by Biotronik. Dr. Marrouche has been a consultant to and received research funding from Biotronik and from several other companies. Dr. Brachmann has been a speaker for and has received research funding from Biotronik and from Abbott and Medtronic.
Intensified approach reduces long-term heart failure risk in T2DM
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
AT EASD 2017
Key clinical point: Intensified, multifactorial treatment reduces the risk of heart failure in people with type 2 diabetes mellitus versus a conventional treatment approach.
Major finding: The risk of heart failure was reduced by 70% (P = .002).
Data source: Post hoc analysis from 21 years follow-up on the Steno-2 randomized trial conducted in 160 patients with type 2 diabetes and microalbuminuria who were randomized to an intensive or conventional treatment arm.
Disclosures: The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
VIDEO: Intermittent furosemide during acute HFpEF favors kidneys
DALLAS – Patients with heart failure with preserved ejection fraction who were hospitalized for acute decompensation had a significantly smaller rise in serum creatinine when treated with intermittent, bolus doses of furosemide, compared with patients who received a continuous furosemide infusion in a single-center, randomized trial with 90 patients.
Intermittent furosemide also resulted in many fewer episodes of worsening renal function. In the trial, 12% of patients who received bolus furosemide doses developed worsening renal function during hospitalization compared with 36% of patients treated with a continuous furosemide infusion, Kavita Sharma, MD, said at the annual scientific meeting of the Heart Failure Society of America.
While acknowledging that this finding is preliminary because it was made in a relatively small, single-center study, “I’d be cautious about continuous infusion” in acute decompensated patients with heart failure with preserved ejection fraction (HFpEF); “bolus is preferred,” Dr. Sharma said in a video interview.
Results from the prior Diuretic Optimization Strategies Evaluation (DOSE) trial, published in 2011, had shown no significant difference in renal function in hospitalized heart failure patients randomized to receive either bolus or continuous furosemide, but that study largely enrolled patients with heart failure with reduced ejection fraction (HFrEF) (N Engl J Med. 2011 Mar 3;364[9]:797-805).
“When patients with HFpEF are hospitalized with acute heart failure there is a high rate of kidney injury, that often results in slowing diuresis leading to longer hospital stays. With adjustment for changes in blood pressure and volume of diuresis we saw a fourfold increase in worsening renal failure [with continuous infusion], so you should think twice before using continuous dosing,” said Dr. Sharma, a heart failure cardiologist at Johns Hopkins Medicine in Baltimore.
She presented results from Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction (ROPA-DOP), which randomized 90 hospitalized heart failure patients with a left ventricular ejection fraction of at least 50% and an estimated glomerular filtration rate of more than 15 mL/min/1.73 m2. The enrolled patients averaged 66 years old, 61% were women, their average body mass index was 41 kg/m2, and their average estimated glomerular filtration rate was 58 mL/min/1.73 m2.
The study’s primary endpoint was percent change in creatinine during hospitalization, which rose by an average 5% in the patients who received intermittent bolus furosemide and by an average 16% in patient who received a continuous infusion, a statistically significant difference. In a regression analysis that controlled for between-group differences in patient’s age, sex, race, body mass index, smoking status, changes in systolic blood pressure, heart rate, fluid balance after 72 hours, and other variables, patients treated with continuous furosemide infusion averaged an 11% greater increase in serum creatinine, Dr. Sharma reported. After similar adjustments, the secondary endpoint rate of worsening renal function was more than four times more likely to occur in the patients on continuous infusion compared with those who received intermittent bolus treatment, she said.
A second aspect of the ROPA-DOP trial randomized the same patients to received either low dose (3 mcg/kg per min) dopamine or placebo during hospitalization. The results showed that low-dose dopamine had no significant impact on either change in creatinine levels or on the incidence of worsening renal function compared with placebo, though dopamine treatment did link with a nonsignificant trend toward somewhat greater diuresis. These results were consistent with prior findings in the Renal Optimization Strategies Evaluation (ROSE) trial (JAMA. 2013 Nov 18;310[23]:2533-43), which used a mixed population of patients with HFpEF or HFrEF but predominantly patients with HFrEF, Dr. Sharma noted.
“It was a neutral finding [for dopamine in ROPA-DOP], and while there was no harm from dopamine there was clearly no benefit,” she said. It is possible that HFpEF patients with right ventricular dysfunction secondary to pulmonary hypertension might benefit from low-dose dopamine, but this needs further study, Dr. Sharma said.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
In the Diuretic Optimization Strategies Evaluation (DOSE) trial, we enrolled heart failure patients with a mix of reduced ejection fraction and preserved ejection fraction. The DOSE results showed no relationship between ejection fraction and the response to furosemide treatment by intermittent bolus or by continuous infusion in patients hospitalized with acute decompensated heart failure. The results also showed that continuous infusion was no better than intermittent bolus treatment, and following our report in 2011 (N Engl J Med. 2011 Mar 3;364[9]:797-805), many centers that had previously relied on continuous furosemide switched to use of bolus doses primarily because continuous infusion is much less convenient.
But it is important to keep in mind that trial results focus on averages and populations of patients. Anecdotally, we see some acute heart failure patients who seem to respond better to continuous infusion, and so some clinicians switch patients who do not respond well to bolus treatment to continuous infusion. In DOSE, we only tested the efficacy of the initial strategy; we have no evidence on whether or not changing the dosing strategy helps patients who do not respond adequately to an initial strategy of intermittent bolus doses.
G. Michael Felker, MD , professor of medicine at Duke University, Durham, N.C., made these comments in an interview. He has been a consultant to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, MyoKardia, Novartis, Stealth, and Trevena.
In the Diuretic Optimization Strategies Evaluation (DOSE) trial, we enrolled heart failure patients with a mix of reduced ejection fraction and preserved ejection fraction. The DOSE results showed no relationship between ejection fraction and the response to furosemide treatment by intermittent bolus or by continuous infusion in patients hospitalized with acute decompensated heart failure. The results also showed that continuous infusion was no better than intermittent bolus treatment, and following our report in 2011 (N Engl J Med. 2011 Mar 3;364[9]:797-805), many centers that had previously relied on continuous furosemide switched to use of bolus doses primarily because continuous infusion is much less convenient.
But it is important to keep in mind that trial results focus on averages and populations of patients. Anecdotally, we see some acute heart failure patients who seem to respond better to continuous infusion, and so some clinicians switch patients who do not respond well to bolus treatment to continuous infusion. In DOSE, we only tested the efficacy of the initial strategy; we have no evidence on whether or not changing the dosing strategy helps patients who do not respond adequately to an initial strategy of intermittent bolus doses.
G. Michael Felker, MD , professor of medicine at Duke University, Durham, N.C., made these comments in an interview. He has been a consultant to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, MyoKardia, Novartis, Stealth, and Trevena.
In the Diuretic Optimization Strategies Evaluation (DOSE) trial, we enrolled heart failure patients with a mix of reduced ejection fraction and preserved ejection fraction. The DOSE results showed no relationship between ejection fraction and the response to furosemide treatment by intermittent bolus or by continuous infusion in patients hospitalized with acute decompensated heart failure. The results also showed that continuous infusion was no better than intermittent bolus treatment, and following our report in 2011 (N Engl J Med. 2011 Mar 3;364[9]:797-805), many centers that had previously relied on continuous furosemide switched to use of bolus doses primarily because continuous infusion is much less convenient.
But it is important to keep in mind that trial results focus on averages and populations of patients. Anecdotally, we see some acute heart failure patients who seem to respond better to continuous infusion, and so some clinicians switch patients who do not respond well to bolus treatment to continuous infusion. In DOSE, we only tested the efficacy of the initial strategy; we have no evidence on whether or not changing the dosing strategy helps patients who do not respond adequately to an initial strategy of intermittent bolus doses.
G. Michael Felker, MD , professor of medicine at Duke University, Durham, N.C., made these comments in an interview. He has been a consultant to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, MyoKardia, Novartis, Stealth, and Trevena.
DALLAS – Patients with heart failure with preserved ejection fraction who were hospitalized for acute decompensation had a significantly smaller rise in serum creatinine when treated with intermittent, bolus doses of furosemide, compared with patients who received a continuous furosemide infusion in a single-center, randomized trial with 90 patients.
Intermittent furosemide also resulted in many fewer episodes of worsening renal function. In the trial, 12% of patients who received bolus furosemide doses developed worsening renal function during hospitalization compared with 36% of patients treated with a continuous furosemide infusion, Kavita Sharma, MD, said at the annual scientific meeting of the Heart Failure Society of America.
While acknowledging that this finding is preliminary because it was made in a relatively small, single-center study, “I’d be cautious about continuous infusion” in acute decompensated patients with heart failure with preserved ejection fraction (HFpEF); “bolus is preferred,” Dr. Sharma said in a video interview.
Results from the prior Diuretic Optimization Strategies Evaluation (DOSE) trial, published in 2011, had shown no significant difference in renal function in hospitalized heart failure patients randomized to receive either bolus or continuous furosemide, but that study largely enrolled patients with heart failure with reduced ejection fraction (HFrEF) (N Engl J Med. 2011 Mar 3;364[9]:797-805).
“When patients with HFpEF are hospitalized with acute heart failure there is a high rate of kidney injury, that often results in slowing diuresis leading to longer hospital stays. With adjustment for changes in blood pressure and volume of diuresis we saw a fourfold increase in worsening renal failure [with continuous infusion], so you should think twice before using continuous dosing,” said Dr. Sharma, a heart failure cardiologist at Johns Hopkins Medicine in Baltimore.
She presented results from Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction (ROPA-DOP), which randomized 90 hospitalized heart failure patients with a left ventricular ejection fraction of at least 50% and an estimated glomerular filtration rate of more than 15 mL/min/1.73 m2. The enrolled patients averaged 66 years old, 61% were women, their average body mass index was 41 kg/m2, and their average estimated glomerular filtration rate was 58 mL/min/1.73 m2.
The study’s primary endpoint was percent change in creatinine during hospitalization, which rose by an average 5% in the patients who received intermittent bolus furosemide and by an average 16% in patient who received a continuous infusion, a statistically significant difference. In a regression analysis that controlled for between-group differences in patient’s age, sex, race, body mass index, smoking status, changes in systolic blood pressure, heart rate, fluid balance after 72 hours, and other variables, patients treated with continuous furosemide infusion averaged an 11% greater increase in serum creatinine, Dr. Sharma reported. After similar adjustments, the secondary endpoint rate of worsening renal function was more than four times more likely to occur in the patients on continuous infusion compared with those who received intermittent bolus treatment, she said.
A second aspect of the ROPA-DOP trial randomized the same patients to received either low dose (3 mcg/kg per min) dopamine or placebo during hospitalization. The results showed that low-dose dopamine had no significant impact on either change in creatinine levels or on the incidence of worsening renal function compared with placebo, though dopamine treatment did link with a nonsignificant trend toward somewhat greater diuresis. These results were consistent with prior findings in the Renal Optimization Strategies Evaluation (ROSE) trial (JAMA. 2013 Nov 18;310[23]:2533-43), which used a mixed population of patients with HFpEF or HFrEF but predominantly patients with HFrEF, Dr. Sharma noted.
“It was a neutral finding [for dopamine in ROPA-DOP], and while there was no harm from dopamine there was clearly no benefit,” she said. It is possible that HFpEF patients with right ventricular dysfunction secondary to pulmonary hypertension might benefit from low-dose dopamine, but this needs further study, Dr. Sharma said.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Patients with heart failure with preserved ejection fraction who were hospitalized for acute decompensation had a significantly smaller rise in serum creatinine when treated with intermittent, bolus doses of furosemide, compared with patients who received a continuous furosemide infusion in a single-center, randomized trial with 90 patients.
Intermittent furosemide also resulted in many fewer episodes of worsening renal function. In the trial, 12% of patients who received bolus furosemide doses developed worsening renal function during hospitalization compared with 36% of patients treated with a continuous furosemide infusion, Kavita Sharma, MD, said at the annual scientific meeting of the Heart Failure Society of America.
While acknowledging that this finding is preliminary because it was made in a relatively small, single-center study, “I’d be cautious about continuous infusion” in acute decompensated patients with heart failure with preserved ejection fraction (HFpEF); “bolus is preferred,” Dr. Sharma said in a video interview.
Results from the prior Diuretic Optimization Strategies Evaluation (DOSE) trial, published in 2011, had shown no significant difference in renal function in hospitalized heart failure patients randomized to receive either bolus or continuous furosemide, but that study largely enrolled patients with heart failure with reduced ejection fraction (HFrEF) (N Engl J Med. 2011 Mar 3;364[9]:797-805).
“When patients with HFpEF are hospitalized with acute heart failure there is a high rate of kidney injury, that often results in slowing diuresis leading to longer hospital stays. With adjustment for changes in blood pressure and volume of diuresis we saw a fourfold increase in worsening renal failure [with continuous infusion], so you should think twice before using continuous dosing,” said Dr. Sharma, a heart failure cardiologist at Johns Hopkins Medicine in Baltimore.
She presented results from Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction (ROPA-DOP), which randomized 90 hospitalized heart failure patients with a left ventricular ejection fraction of at least 50% and an estimated glomerular filtration rate of more than 15 mL/min/1.73 m2. The enrolled patients averaged 66 years old, 61% were women, their average body mass index was 41 kg/m2, and their average estimated glomerular filtration rate was 58 mL/min/1.73 m2.
The study’s primary endpoint was percent change in creatinine during hospitalization, which rose by an average 5% in the patients who received intermittent bolus furosemide and by an average 16% in patient who received a continuous infusion, a statistically significant difference. In a regression analysis that controlled for between-group differences in patient’s age, sex, race, body mass index, smoking status, changes in systolic blood pressure, heart rate, fluid balance after 72 hours, and other variables, patients treated with continuous furosemide infusion averaged an 11% greater increase in serum creatinine, Dr. Sharma reported. After similar adjustments, the secondary endpoint rate of worsening renal function was more than four times more likely to occur in the patients on continuous infusion compared with those who received intermittent bolus treatment, she said.
A second aspect of the ROPA-DOP trial randomized the same patients to received either low dose (3 mcg/kg per min) dopamine or placebo during hospitalization. The results showed that low-dose dopamine had no significant impact on either change in creatinine levels or on the incidence of worsening renal function compared with placebo, though dopamine treatment did link with a nonsignificant trend toward somewhat greater diuresis. These results were consistent with prior findings in the Renal Optimization Strategies Evaluation (ROSE) trial (JAMA. 2013 Nov 18;310[23]:2533-43), which used a mixed population of patients with HFpEF or HFrEF but predominantly patients with HFrEF, Dr. Sharma noted.
“It was a neutral finding [for dopamine in ROPA-DOP], and while there was no harm from dopamine there was clearly no benefit,” she said. It is possible that HFpEF patients with right ventricular dysfunction secondary to pulmonary hypertension might benefit from low-dose dopamine, but this needs further study, Dr. Sharma said.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point:
Major finding: Serum creatinine rose by an average 5% with intermittent bolus furosemide and by 16% with continuous infusion.
Data source: ROPA-DOP, a single-center randomized trial with 90 patients.
Disclosures: Dr. Sharma had no disclosures.
Phrenic nerve stimulator shows heart failure benefits
DALLAS– Heart failure patients with central sleep apnea who received treatment with a transvenous phrenic nerve–stimulating device showed dramatic improvement in their global self-assessment, compared with control patients, in a subgroup analysis of 80 patients enrolled in the device’s pivotal trial.
Among 35 patients with heart failure enrolled in the remedē System pivotal trial and treated for 6 months with phrenic nerve stimulation, 57% reported that they had “markedly” or “moderately” improved, compared with a 9% rate for this self-rating among 44 control heart failure patients in the trial, a statistically significant difference, Lee R. Goldberg, MD, said at the annual scientific meeting of the Heart Failure Society of America.
Further analysis focused on echocardiographic examinations after 12 months in 23 of the heart failure patients who entered the study with a left ventricular ejection fraction of 45% or less and received 12 months of phrenic nerve stimulation. The average LVEF rose in these patients from 30% at baseline to 35%, a statistically significant difference, and left ventricular end systolic volume fell by an average of almost 11 mL from baseline, a difference just short of statistical significance, findings Dr. Goldberg called “a little exciting.”
“It is very encouraging to see some evidence for ventricular remodeling,” commented Lynne W. Stevenson, MD, professor of medicine and a heart failure specialist at Vanderbilt University in Nashville, Tenn.
The FDA approved the use of this device for the treatment of moderate to severe central sleep apnea on Oct. 6. “I think we would use it” in heart failure patients with intolerable symptoms from central sleep apnea, Dr. Goldberg said in an interview during the meeting.
“There is a tight connection between sleep-disordered breathing, sleep apnea, heart failure, and cardiovascular disease, and we have been pretty aggressive in trying to treat the sleep apnea. Even if phrenic nerve stimulation just improves patients’ quality of life and is neutral for other outcomes,” it would be reasonable to offer it to patients, he said. “But many of us think there is a bigger connection that results in a therapeutic benefit [to heart failure patients] by treating their central sleep apnea.”
The pivotal trial enrolled a total of 151 patients with central sleep apnea at 31 centers in Germany, Poland, and the United States who were selected based on having an apnea-hypopnea index of at least 20 events per hour. All participants received a transvenous phrenic nerve–stimulator implant, and then randomization assigned 73 patients to have the device turned on for the first 6 months while 78 device recipients had their devices left off to serve as controls. The study’s primary efficacy endpoint was the percentage of patients having at least a 50% cut in their apnea-hypopnea index, which happened in 51% of evaluable patients in the active treatment arm and in 11% of the evaluable controls. The primary results were published last year (Lancet. 2016 Sep 3;388[10048]974-82).
“We hope this treatment will have the collateral effect of improving cardiovascular disease outcomes, but we don’t know that yet. The initial target will be patients with apnea-hypopnea episodes that affect their quality of life,” Dr. Goldberg said.
The apparent safety of this approach for treating central sleep apnea may relate to its mechanism of action, he suggested. The mortality-boosting effect of adaptive servo-ventilation may correlate with the positive pressure it creates in a patient’s chest that perhaps causes myocardial stress or hemodynamic problems. In contrast, phrenic nerve stimulation produces diaphragm motion that mimics normal breathing and creates negative chest pressure. “A lot of hypothesis generation needs to happen to better understand the underlying physiology,” Dr. Goldberg conceded.
At the end of the 6-month period that compared active treatment with control, the heart failure subgroup also showed statistically significant benefits from treatment for several sleep metrics, including apnea-hypopnea index, the central apnea index, and oxygen desaturation, and also for daytime sleepiness measured on the Epworth Sleepiness Scale. After 12 months on active treatment, patients also showed a significant improvement over baseline in their score on the Minnesota Living With Heart Failure Questionnaire, Dr. Goldberg reported.
The trial was sponsored by Respicardia, the company developing the remedē System. Dr. Goldberg has been a consultant to and has received research funding from Respicardia. Dr. Stevenson had no relevant disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS– Heart failure patients with central sleep apnea who received treatment with a transvenous phrenic nerve–stimulating device showed dramatic improvement in their global self-assessment, compared with control patients, in a subgroup analysis of 80 patients enrolled in the device’s pivotal trial.
Among 35 patients with heart failure enrolled in the remedē System pivotal trial and treated for 6 months with phrenic nerve stimulation, 57% reported that they had “markedly” or “moderately” improved, compared with a 9% rate for this self-rating among 44 control heart failure patients in the trial, a statistically significant difference, Lee R. Goldberg, MD, said at the annual scientific meeting of the Heart Failure Society of America.
Further analysis focused on echocardiographic examinations after 12 months in 23 of the heart failure patients who entered the study with a left ventricular ejection fraction of 45% or less and received 12 months of phrenic nerve stimulation. The average LVEF rose in these patients from 30% at baseline to 35%, a statistically significant difference, and left ventricular end systolic volume fell by an average of almost 11 mL from baseline, a difference just short of statistical significance, findings Dr. Goldberg called “a little exciting.”
“It is very encouraging to see some evidence for ventricular remodeling,” commented Lynne W. Stevenson, MD, professor of medicine and a heart failure specialist at Vanderbilt University in Nashville, Tenn.
The FDA approved the use of this device for the treatment of moderate to severe central sleep apnea on Oct. 6. “I think we would use it” in heart failure patients with intolerable symptoms from central sleep apnea, Dr. Goldberg said in an interview during the meeting.
“There is a tight connection between sleep-disordered breathing, sleep apnea, heart failure, and cardiovascular disease, and we have been pretty aggressive in trying to treat the sleep apnea. Even if phrenic nerve stimulation just improves patients’ quality of life and is neutral for other outcomes,” it would be reasonable to offer it to patients, he said. “But many of us think there is a bigger connection that results in a therapeutic benefit [to heart failure patients] by treating their central sleep apnea.”
The pivotal trial enrolled a total of 151 patients with central sleep apnea at 31 centers in Germany, Poland, and the United States who were selected based on having an apnea-hypopnea index of at least 20 events per hour. All participants received a transvenous phrenic nerve–stimulator implant, and then randomization assigned 73 patients to have the device turned on for the first 6 months while 78 device recipients had their devices left off to serve as controls. The study’s primary efficacy endpoint was the percentage of patients having at least a 50% cut in their apnea-hypopnea index, which happened in 51% of evaluable patients in the active treatment arm and in 11% of the evaluable controls. The primary results were published last year (Lancet. 2016 Sep 3;388[10048]974-82).
“We hope this treatment will have the collateral effect of improving cardiovascular disease outcomes, but we don’t know that yet. The initial target will be patients with apnea-hypopnea episodes that affect their quality of life,” Dr. Goldberg said.
The apparent safety of this approach for treating central sleep apnea may relate to its mechanism of action, he suggested. The mortality-boosting effect of adaptive servo-ventilation may correlate with the positive pressure it creates in a patient’s chest that perhaps causes myocardial stress or hemodynamic problems. In contrast, phrenic nerve stimulation produces diaphragm motion that mimics normal breathing and creates negative chest pressure. “A lot of hypothesis generation needs to happen to better understand the underlying physiology,” Dr. Goldberg conceded.
At the end of the 6-month period that compared active treatment with control, the heart failure subgroup also showed statistically significant benefits from treatment for several sleep metrics, including apnea-hypopnea index, the central apnea index, and oxygen desaturation, and also for daytime sleepiness measured on the Epworth Sleepiness Scale. After 12 months on active treatment, patients also showed a significant improvement over baseline in their score on the Minnesota Living With Heart Failure Questionnaire, Dr. Goldberg reported.
The trial was sponsored by Respicardia, the company developing the remedē System. Dr. Goldberg has been a consultant to and has received research funding from Respicardia. Dr. Stevenson had no relevant disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS– Heart failure patients with central sleep apnea who received treatment with a transvenous phrenic nerve–stimulating device showed dramatic improvement in their global self-assessment, compared with control patients, in a subgroup analysis of 80 patients enrolled in the device’s pivotal trial.
Among 35 patients with heart failure enrolled in the remedē System pivotal trial and treated for 6 months with phrenic nerve stimulation, 57% reported that they had “markedly” or “moderately” improved, compared with a 9% rate for this self-rating among 44 control heart failure patients in the trial, a statistically significant difference, Lee R. Goldberg, MD, said at the annual scientific meeting of the Heart Failure Society of America.
Further analysis focused on echocardiographic examinations after 12 months in 23 of the heart failure patients who entered the study with a left ventricular ejection fraction of 45% or less and received 12 months of phrenic nerve stimulation. The average LVEF rose in these patients from 30% at baseline to 35%, a statistically significant difference, and left ventricular end systolic volume fell by an average of almost 11 mL from baseline, a difference just short of statistical significance, findings Dr. Goldberg called “a little exciting.”
“It is very encouraging to see some evidence for ventricular remodeling,” commented Lynne W. Stevenson, MD, professor of medicine and a heart failure specialist at Vanderbilt University in Nashville, Tenn.
The FDA approved the use of this device for the treatment of moderate to severe central sleep apnea on Oct. 6. “I think we would use it” in heart failure patients with intolerable symptoms from central sleep apnea, Dr. Goldberg said in an interview during the meeting.
“There is a tight connection between sleep-disordered breathing, sleep apnea, heart failure, and cardiovascular disease, and we have been pretty aggressive in trying to treat the sleep apnea. Even if phrenic nerve stimulation just improves patients’ quality of life and is neutral for other outcomes,” it would be reasonable to offer it to patients, he said. “But many of us think there is a bigger connection that results in a therapeutic benefit [to heart failure patients] by treating their central sleep apnea.”
The pivotal trial enrolled a total of 151 patients with central sleep apnea at 31 centers in Germany, Poland, and the United States who were selected based on having an apnea-hypopnea index of at least 20 events per hour. All participants received a transvenous phrenic nerve–stimulator implant, and then randomization assigned 73 patients to have the device turned on for the first 6 months while 78 device recipients had their devices left off to serve as controls. The study’s primary efficacy endpoint was the percentage of patients having at least a 50% cut in their apnea-hypopnea index, which happened in 51% of evaluable patients in the active treatment arm and in 11% of the evaluable controls. The primary results were published last year (Lancet. 2016 Sep 3;388[10048]974-82).
“We hope this treatment will have the collateral effect of improving cardiovascular disease outcomes, but we don’t know that yet. The initial target will be patients with apnea-hypopnea episodes that affect their quality of life,” Dr. Goldberg said.
The apparent safety of this approach for treating central sleep apnea may relate to its mechanism of action, he suggested. The mortality-boosting effect of adaptive servo-ventilation may correlate with the positive pressure it creates in a patient’s chest that perhaps causes myocardial stress or hemodynamic problems. In contrast, phrenic nerve stimulation produces diaphragm motion that mimics normal breathing and creates negative chest pressure. “A lot of hypothesis generation needs to happen to better understand the underlying physiology,” Dr. Goldberg conceded.
At the end of the 6-month period that compared active treatment with control, the heart failure subgroup also showed statistically significant benefits from treatment for several sleep metrics, including apnea-hypopnea index, the central apnea index, and oxygen desaturation, and also for daytime sleepiness measured on the Epworth Sleepiness Scale. After 12 months on active treatment, patients also showed a significant improvement over baseline in their score on the Minnesota Living With Heart Failure Questionnaire, Dr. Goldberg reported.
The trial was sponsored by Respicardia, the company developing the remedē System. Dr. Goldberg has been a consultant to and has received research funding from Respicardia. Dr. Stevenson had no relevant disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point:
Major finding: Patient-reported global assessment improved markedly or moderately in 57% of treated patients and in 9% of controls.
Data source: Subgroup analysis of the remedē System pivotal trial.
Disclosures: The trial was sponsored by Respicardia, the company developing the remedē System. Dr. Goldberg has been a consultant to and has received research funding from Respicardia. Dr. Stevenson had no relevant disclosures.
Cardio-oncology booms but awareness lags
Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.
During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.
“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.
More than just heart failure
A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.
While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.
But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.
“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”
In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).
In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.
But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.
“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.
“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.
Cardio-oncology centers or community practice?
The rise of cardio-oncology, especially over the last decade or so, has given rise to a new academic niche, the cardio-oncology clinic. Starting from almost no programs a few years ago, by 2016 one tally put the total number of U.S. self-designated cardio-oncology centers at about 40 (Heart Fail Clin. 2017 April;13[2]:347-55), and that number undoubtedly grew even more during the year since. While these programs promote and advance the nascent subspecialty of cardio-oncology, and provide a foundation for development of formalized training programs, many experts see a clear hierarchy of risk that distinguishes the patients who should ideally be managed at these focused, multidisciplinary programs from the lower-risk patients who probably do fine under the care of just their oncologist or their oncologist in collaboration with a community cardiologist or primary care physician.
“The cardio-oncology community recognizes that it is nice to have programs at academic centers but it’s more important to deliver this care in the community,” said Dr. Lenihan. “Many cancer patients have no prior history of cardiovascular disease. These low-risk patients don’t necessarily need a cardio-oncologist. They may need to have their blood pressure managed more effectively or receive other preventive care, but that can certainly be done locally. There are low-risk patients who don’t need to go to a major center.” Dr. Lenihan and other cardio-oncologists see the majority of cancer patients as low risk when it comes to cardiovascular complications.
But it’s different when patients receive an anthracycline or an anthracycline plus trastuzumab. “This high-risk population is best seen at a cardio-oncology center.” Dr. Lenihan also included in this high-risk subgroup patients treated with mediastinal radiation, an option often used during the 1980s-2000s.
“Any time a patient receives treatment with the potential to cause a cardiovascular effect, which is pretty much any drug that now comes out, you need an accurate baseline assessment. But that doesn’t mean you need do anything different; you still treat the patient’s cancer. A thorough baseline assessment is a necessity, but it does not need to be done at a cardio-oncology center,” Dr. Lenihan said in an interview.
“For the vast majority of patients, care can be at community hospitals, similar to the delivery of the vast majority of oncology care. Some patients need referral to tertiary cardiology centers for advanced heart failure or to undergo advanced procedures, but that is a very small percentage of patients,” said Ana Barac, MD, director of the cardio-oncology program at the MedStar Heart Institute in Washington, and chair of the ACC’s Cardio-Oncology Section.
“Patients receiving more novel or unusual therapies, and those participating in trials” are appropriate for centers, while community care by a cardiologist and oncologist should suffice for more routine patients, said Dr. Fradley.
“Cardio-oncology centers are good for patients with type I damage from anthracycline treatment, especially patients who already had underlying heart disease,” said Michael S. Ewer, MD, a cardiologist and professor of medicine at MD Anderson Cancer Center in Houston. Specialist centers are also for patients with cardiovascular risk factors: older age, diabetes, preexisting coronary artery disease, and patients who receive cardiotoxic type I therapy (J Clin Oncol. 2005 May;23[13]:2900-2). Also, patients with a significant, immediate cardiac reaction to treatment, and those with an unexpected cardiac reaction, Dr. Ewer said.
A somewhat more expansive view of the typical cardio-oncology patient came from Dr. Neilan, based on the patients he sees at his program in Boston. Dr. Neilan estimated that roughly 60%-70% of his patients first present while they undergo active cancer treatment, with another 20% coming to the program as cancer survivors, and a small percentage of patients showing up for cardiology assessments and treatments without a cancer history. Among those with a cancer history, he guessed that perhaps 10%-20% were treated with an anthracycline, at least 10% received trastuzumab, and about 10% received radiation treatment. “I also see a lot of patients with complications from treatment” with tyrosine kinase inhibitors, VEGF inhibitors, and immunotherapies. “I don’t see a lot of patients for cardiovascular disease assessment before they start cancer therapy,” Dr. Neilan added.
Cardio-oncology heads toward a new cardiology subspecialty
These views of how cardio-oncology is practiced in the real world raise a question about the role of the growing roster of U.S. cardio-oncology programs. If most cancer patients can have their cardiology needs taken care of in the community, how do all the academic programs fit in? The answer seems to be that they model successful oncology and cardiology collaborations, provide a training ground for physicians from both specialties to learn how to collaborate, and serve as the home for research that broadens the field’s evidence base and moves knowledge forward.
“Education and partnerships with oncology teams is the key,” said Dr. Barac. “Our traditional subspecialty training focused on ‘treating cancer’ and ‘treating cardiovascular disease.’ Learning about and seeing effective partnerships during training” is the best model to foster cardiology and oncology partnerships among early-career physicians, she suggested.
“What is the spectrum of knowledge required to be proficient in cardio-oncology, and how do we enhance training at the resident or fellowship level? How do we get [all cardiology] trainees exposed to this knowledge?” wondered Dr. Lenihan, who viewed cardio-oncology programs as a way to meet these needs. “Cardio-oncology is not an established subspecialty. A goal is to establish training requirements and expand training opportunities. And the whole field needs to contribute to clinical research. We need cardio-oncologists to share their experience and improve our level of research.”
ASCO’s cardiac dysfunction practice guideline, first released last December and formally published in March, is likely helping to further entrench cardio-oncology as a new subspecialty. The guideline was “a remarkable step forward,” said Dr. Barac. In addition to establishing a U.S. standard of care for preventing and monitoring cardiac dysfunction in cancer patients, “I use it as a guide for creation of referral pathways with my oncology colleagues, as well as in education of cardiovascular and oncology trainees,” she said in an interview.
Though produced primarily through ASCO’s leadership, the target audience for the guideline seems to be as much cardiologists as it is oncologists. Dissemination of the guideline to cardiologists snagged when it failed to appear in the cardiology literature. That wasn’t the original plan, said guideline participants.
“Before we started, it was agreed that both ASCO and the ACC would publish it. We had a [letter] signed by the president of the ACC saying the ACC would publish it,” recalled Dr. Lenihan, a guideline coauthor. “After all the details were settled, the ACC bailed. They said that they had changed their organizational structure and that they wouldn’t publish the guideline even though they had agreed to.” Not having the guideline appear simultaneously in the cardiology literature “hinders getting the message to the cardiology community,” he said, a sentiment echoed by other cardio-oncologists.
“I served as the ACC representative on the guideline, and the lack of ACC endorsement was the unfortunate consequence of approval and publication timing that coincided with restructuring of the ACC committees,” said Dr. Barac. “It absolutely does not reflect a lack of interest from the ACC.” As an example of the College’s commitment example, she cited an ACC 1.5-day educational course on cardiovascular care of oncology patients held for the first time in February 2017 and scheduled for a second edition next February.
Publication of the guideline in a cardiology journal “would indeed help dissemination among U.S. cardiologists,” agreed Pamela S. Douglas, MD, professor of medicine at Duke University in Durham, N.C., and another of the several cardiologists who served on the ASCO guideline’s panel.
Further advancing awareness of patients with cardio-oncology issues, what Dr. Moslehi has called “an emerging epidemic,” seems the most fundamental of the goals currently advanced by many active in this field.
One step to grow the subspecialty that he and his associates at Vanderbilt have taken is to start this year a formally recognized fellowship program in cardio-oncology; an initial class of three cardiologists started in the program this summer. The Vanderbilt group also plans to launch a website before the end of 2017 that will include an oncology-drug database that compiles all available information on each agent’s cardiovascular effects. The planned website will aggregate links to all existing cardio-oncology programs.
“We will absolutely see the field grow,” said Dr. Swain. “It has only sprung up in the past 10 or so years. It is now getting recognition, people are being trained in cardio-oncology, and it will grow as a subspecialty. It’s very exciting, and it’s better for patients.”
“A cardiologist with no cancer patients or survivors in their practice is unheard of; many cardiologists just don’t realize that,” Dr. Lenihan said. At least 10%-15% of the U.S. population in their 60s or older has a cancer history, he noted. The common mindset among cardiologists has been that cancer patients and survivors are not among their patients.
“It’s unlikely that a busy cardiology practice has no cancer survivors or active cancer patients,” Dr. Douglas suggested. When this happens, a likely explanations is that the cardiologist simply failed to elicit a completely comprehensive history from the practice’s patient roster. And even a cardiology practice today that includes no cancer patients or survivors will likely see some turning up soon, she predicted, because so many are receiving cardiovascular-toxic therapies and then surviving longer than ever before.
“What oncologists and cardiologists want to do is to optimize oncologic outcomes but with an acceptable adverse event profile. The cardio-oncologist helps push that envelope. The goal is not to eliminate cardiac events at the expense of oncologic outcomes, but to shift the balance to fewer and less severe cardiac events without unduly compromising oncologic outcomes,” explained Dr. Ewer. Cardio-oncology grapples with one of the core challenges of medicine, how to balance the potential risks from treatment against its potential benefits, he observed.
Dr. Neilan has been a consultant to Ariad and Takeda. Dr. Lenihan has been a consultant to Janssen and Roche and has received research funding from Takeda. Dr. Moslehi has been a consultant to Acceleron, Ariad, Bristol-Myers Squibb, Incyte, Pfizer, Takeda/Millennium, Verastem and Vertex. Dr. Ewer, Dr. Fradley, and Dr. Barac had no relevant disclosures. Dr. Swain has been a consultant to Genentech and Roche. Dr. Douglas has been a consultant to CardioDx, Interleukin Genetics, and Omicia, and has an ownership interest in CardioDx.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.
During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.
“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.
More than just heart failure
A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.
While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.
But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.
“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”
In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).
In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.
But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.
“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.
“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.
Cardio-oncology centers or community practice?
The rise of cardio-oncology, especially over the last decade or so, has given rise to a new academic niche, the cardio-oncology clinic. Starting from almost no programs a few years ago, by 2016 one tally put the total number of U.S. self-designated cardio-oncology centers at about 40 (Heart Fail Clin. 2017 April;13[2]:347-55), and that number undoubtedly grew even more during the year since. While these programs promote and advance the nascent subspecialty of cardio-oncology, and provide a foundation for development of formalized training programs, many experts see a clear hierarchy of risk that distinguishes the patients who should ideally be managed at these focused, multidisciplinary programs from the lower-risk patients who probably do fine under the care of just their oncologist or their oncologist in collaboration with a community cardiologist or primary care physician.
“The cardio-oncology community recognizes that it is nice to have programs at academic centers but it’s more important to deliver this care in the community,” said Dr. Lenihan. “Many cancer patients have no prior history of cardiovascular disease. These low-risk patients don’t necessarily need a cardio-oncologist. They may need to have their blood pressure managed more effectively or receive other preventive care, but that can certainly be done locally. There are low-risk patients who don’t need to go to a major center.” Dr. Lenihan and other cardio-oncologists see the majority of cancer patients as low risk when it comes to cardiovascular complications.
But it’s different when patients receive an anthracycline or an anthracycline plus trastuzumab. “This high-risk population is best seen at a cardio-oncology center.” Dr. Lenihan also included in this high-risk subgroup patients treated with mediastinal radiation, an option often used during the 1980s-2000s.
“Any time a patient receives treatment with the potential to cause a cardiovascular effect, which is pretty much any drug that now comes out, you need an accurate baseline assessment. But that doesn’t mean you need do anything different; you still treat the patient’s cancer. A thorough baseline assessment is a necessity, but it does not need to be done at a cardio-oncology center,” Dr. Lenihan said in an interview.
“For the vast majority of patients, care can be at community hospitals, similar to the delivery of the vast majority of oncology care. Some patients need referral to tertiary cardiology centers for advanced heart failure or to undergo advanced procedures, but that is a very small percentage of patients,” said Ana Barac, MD, director of the cardio-oncology program at the MedStar Heart Institute in Washington, and chair of the ACC’s Cardio-Oncology Section.
“Patients receiving more novel or unusual therapies, and those participating in trials” are appropriate for centers, while community care by a cardiologist and oncologist should suffice for more routine patients, said Dr. Fradley.
“Cardio-oncology centers are good for patients with type I damage from anthracycline treatment, especially patients who already had underlying heart disease,” said Michael S. Ewer, MD, a cardiologist and professor of medicine at MD Anderson Cancer Center in Houston. Specialist centers are also for patients with cardiovascular risk factors: older age, diabetes, preexisting coronary artery disease, and patients who receive cardiotoxic type I therapy (J Clin Oncol. 2005 May;23[13]:2900-2). Also, patients with a significant, immediate cardiac reaction to treatment, and those with an unexpected cardiac reaction, Dr. Ewer said.
A somewhat more expansive view of the typical cardio-oncology patient came from Dr. Neilan, based on the patients he sees at his program in Boston. Dr. Neilan estimated that roughly 60%-70% of his patients first present while they undergo active cancer treatment, with another 20% coming to the program as cancer survivors, and a small percentage of patients showing up for cardiology assessments and treatments without a cancer history. Among those with a cancer history, he guessed that perhaps 10%-20% were treated with an anthracycline, at least 10% received trastuzumab, and about 10% received radiation treatment. “I also see a lot of patients with complications from treatment” with tyrosine kinase inhibitors, VEGF inhibitors, and immunotherapies. “I don’t see a lot of patients for cardiovascular disease assessment before they start cancer therapy,” Dr. Neilan added.
Cardio-oncology heads toward a new cardiology subspecialty
These views of how cardio-oncology is practiced in the real world raise a question about the role of the growing roster of U.S. cardio-oncology programs. If most cancer patients can have their cardiology needs taken care of in the community, how do all the academic programs fit in? The answer seems to be that they model successful oncology and cardiology collaborations, provide a training ground for physicians from both specialties to learn how to collaborate, and serve as the home for research that broadens the field’s evidence base and moves knowledge forward.
“Education and partnerships with oncology teams is the key,” said Dr. Barac. “Our traditional subspecialty training focused on ‘treating cancer’ and ‘treating cardiovascular disease.’ Learning about and seeing effective partnerships during training” is the best model to foster cardiology and oncology partnerships among early-career physicians, she suggested.
“What is the spectrum of knowledge required to be proficient in cardio-oncology, and how do we enhance training at the resident or fellowship level? How do we get [all cardiology] trainees exposed to this knowledge?” wondered Dr. Lenihan, who viewed cardio-oncology programs as a way to meet these needs. “Cardio-oncology is not an established subspecialty. A goal is to establish training requirements and expand training opportunities. And the whole field needs to contribute to clinical research. We need cardio-oncologists to share their experience and improve our level of research.”
ASCO’s cardiac dysfunction practice guideline, first released last December and formally published in March, is likely helping to further entrench cardio-oncology as a new subspecialty. The guideline was “a remarkable step forward,” said Dr. Barac. In addition to establishing a U.S. standard of care for preventing and monitoring cardiac dysfunction in cancer patients, “I use it as a guide for creation of referral pathways with my oncology colleagues, as well as in education of cardiovascular and oncology trainees,” she said in an interview.
Though produced primarily through ASCO’s leadership, the target audience for the guideline seems to be as much cardiologists as it is oncologists. Dissemination of the guideline to cardiologists snagged when it failed to appear in the cardiology literature. That wasn’t the original plan, said guideline participants.
“Before we started, it was agreed that both ASCO and the ACC would publish it. We had a [letter] signed by the president of the ACC saying the ACC would publish it,” recalled Dr. Lenihan, a guideline coauthor. “After all the details were settled, the ACC bailed. They said that they had changed their organizational structure and that they wouldn’t publish the guideline even though they had agreed to.” Not having the guideline appear simultaneously in the cardiology literature “hinders getting the message to the cardiology community,” he said, a sentiment echoed by other cardio-oncologists.
“I served as the ACC representative on the guideline, and the lack of ACC endorsement was the unfortunate consequence of approval and publication timing that coincided with restructuring of the ACC committees,” said Dr. Barac. “It absolutely does not reflect a lack of interest from the ACC.” As an example of the College’s commitment example, she cited an ACC 1.5-day educational course on cardiovascular care of oncology patients held for the first time in February 2017 and scheduled for a second edition next February.
Publication of the guideline in a cardiology journal “would indeed help dissemination among U.S. cardiologists,” agreed Pamela S. Douglas, MD, professor of medicine at Duke University in Durham, N.C., and another of the several cardiologists who served on the ASCO guideline’s panel.
Further advancing awareness of patients with cardio-oncology issues, what Dr. Moslehi has called “an emerging epidemic,” seems the most fundamental of the goals currently advanced by many active in this field.
One step to grow the subspecialty that he and his associates at Vanderbilt have taken is to start this year a formally recognized fellowship program in cardio-oncology; an initial class of three cardiologists started in the program this summer. The Vanderbilt group also plans to launch a website before the end of 2017 that will include an oncology-drug database that compiles all available information on each agent’s cardiovascular effects. The planned website will aggregate links to all existing cardio-oncology programs.
“We will absolutely see the field grow,” said Dr. Swain. “It has only sprung up in the past 10 or so years. It is now getting recognition, people are being trained in cardio-oncology, and it will grow as a subspecialty. It’s very exciting, and it’s better for patients.”
“A cardiologist with no cancer patients or survivors in their practice is unheard of; many cardiologists just don’t realize that,” Dr. Lenihan said. At least 10%-15% of the U.S. population in their 60s or older has a cancer history, he noted. The common mindset among cardiologists has been that cancer patients and survivors are not among their patients.
“It’s unlikely that a busy cardiology practice has no cancer survivors or active cancer patients,” Dr. Douglas suggested. When this happens, a likely explanations is that the cardiologist simply failed to elicit a completely comprehensive history from the practice’s patient roster. And even a cardiology practice today that includes no cancer patients or survivors will likely see some turning up soon, she predicted, because so many are receiving cardiovascular-toxic therapies and then surviving longer than ever before.
“What oncologists and cardiologists want to do is to optimize oncologic outcomes but with an acceptable adverse event profile. The cardio-oncologist helps push that envelope. The goal is not to eliminate cardiac events at the expense of oncologic outcomes, but to shift the balance to fewer and less severe cardiac events without unduly compromising oncologic outcomes,” explained Dr. Ewer. Cardio-oncology grapples with one of the core challenges of medicine, how to balance the potential risks from treatment against its potential benefits, he observed.
Dr. Neilan has been a consultant to Ariad and Takeda. Dr. Lenihan has been a consultant to Janssen and Roche and has received research funding from Takeda. Dr. Moslehi has been a consultant to Acceleron, Ariad, Bristol-Myers Squibb, Incyte, Pfizer, Takeda/Millennium, Verastem and Vertex. Dr. Ewer, Dr. Fradley, and Dr. Barac had no relevant disclosures. Dr. Swain has been a consultant to Genentech and Roche. Dr. Douglas has been a consultant to CardioDx, Interleukin Genetics, and Omicia, and has an ownership interest in CardioDx.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.
During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.
“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.
More than just heart failure
A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.
While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.
But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.
“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”
In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).
In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.
But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.
“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.
“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.
Cardio-oncology centers or community practice?
The rise of cardio-oncology, especially over the last decade or so, has given rise to a new academic niche, the cardio-oncology clinic. Starting from almost no programs a few years ago, by 2016 one tally put the total number of U.S. self-designated cardio-oncology centers at about 40 (Heart Fail Clin. 2017 April;13[2]:347-55), and that number undoubtedly grew even more during the year since. While these programs promote and advance the nascent subspecialty of cardio-oncology, and provide a foundation for development of formalized training programs, many experts see a clear hierarchy of risk that distinguishes the patients who should ideally be managed at these focused, multidisciplinary programs from the lower-risk patients who probably do fine under the care of just their oncologist or their oncologist in collaboration with a community cardiologist or primary care physician.
“The cardio-oncology community recognizes that it is nice to have programs at academic centers but it’s more important to deliver this care in the community,” said Dr. Lenihan. “Many cancer patients have no prior history of cardiovascular disease. These low-risk patients don’t necessarily need a cardio-oncologist. They may need to have their blood pressure managed more effectively or receive other preventive care, but that can certainly be done locally. There are low-risk patients who don’t need to go to a major center.” Dr. Lenihan and other cardio-oncologists see the majority of cancer patients as low risk when it comes to cardiovascular complications.
But it’s different when patients receive an anthracycline or an anthracycline plus trastuzumab. “This high-risk population is best seen at a cardio-oncology center.” Dr. Lenihan also included in this high-risk subgroup patients treated with mediastinal radiation, an option often used during the 1980s-2000s.
“Any time a patient receives treatment with the potential to cause a cardiovascular effect, which is pretty much any drug that now comes out, you need an accurate baseline assessment. But that doesn’t mean you need do anything different; you still treat the patient’s cancer. A thorough baseline assessment is a necessity, but it does not need to be done at a cardio-oncology center,” Dr. Lenihan said in an interview.
“For the vast majority of patients, care can be at community hospitals, similar to the delivery of the vast majority of oncology care. Some patients need referral to tertiary cardiology centers for advanced heart failure or to undergo advanced procedures, but that is a very small percentage of patients,” said Ana Barac, MD, director of the cardio-oncology program at the MedStar Heart Institute in Washington, and chair of the ACC’s Cardio-Oncology Section.
“Patients receiving more novel or unusual therapies, and those participating in trials” are appropriate for centers, while community care by a cardiologist and oncologist should suffice for more routine patients, said Dr. Fradley.
“Cardio-oncology centers are good for patients with type I damage from anthracycline treatment, especially patients who already had underlying heart disease,” said Michael S. Ewer, MD, a cardiologist and professor of medicine at MD Anderson Cancer Center in Houston. Specialist centers are also for patients with cardiovascular risk factors: older age, diabetes, preexisting coronary artery disease, and patients who receive cardiotoxic type I therapy (J Clin Oncol. 2005 May;23[13]:2900-2). Also, patients with a significant, immediate cardiac reaction to treatment, and those with an unexpected cardiac reaction, Dr. Ewer said.
A somewhat more expansive view of the typical cardio-oncology patient came from Dr. Neilan, based on the patients he sees at his program in Boston. Dr. Neilan estimated that roughly 60%-70% of his patients first present while they undergo active cancer treatment, with another 20% coming to the program as cancer survivors, and a small percentage of patients showing up for cardiology assessments and treatments without a cancer history. Among those with a cancer history, he guessed that perhaps 10%-20% were treated with an anthracycline, at least 10% received trastuzumab, and about 10% received radiation treatment. “I also see a lot of patients with complications from treatment” with tyrosine kinase inhibitors, VEGF inhibitors, and immunotherapies. “I don’t see a lot of patients for cardiovascular disease assessment before they start cancer therapy,” Dr. Neilan added.
Cardio-oncology heads toward a new cardiology subspecialty
These views of how cardio-oncology is practiced in the real world raise a question about the role of the growing roster of U.S. cardio-oncology programs. If most cancer patients can have their cardiology needs taken care of in the community, how do all the academic programs fit in? The answer seems to be that they model successful oncology and cardiology collaborations, provide a training ground for physicians from both specialties to learn how to collaborate, and serve as the home for research that broadens the field’s evidence base and moves knowledge forward.
“Education and partnerships with oncology teams is the key,” said Dr. Barac. “Our traditional subspecialty training focused on ‘treating cancer’ and ‘treating cardiovascular disease.’ Learning about and seeing effective partnerships during training” is the best model to foster cardiology and oncology partnerships among early-career physicians, she suggested.
“What is the spectrum of knowledge required to be proficient in cardio-oncology, and how do we enhance training at the resident or fellowship level? How do we get [all cardiology] trainees exposed to this knowledge?” wondered Dr. Lenihan, who viewed cardio-oncology programs as a way to meet these needs. “Cardio-oncology is not an established subspecialty. A goal is to establish training requirements and expand training opportunities. And the whole field needs to contribute to clinical research. We need cardio-oncologists to share their experience and improve our level of research.”
ASCO’s cardiac dysfunction practice guideline, first released last December and formally published in March, is likely helping to further entrench cardio-oncology as a new subspecialty. The guideline was “a remarkable step forward,” said Dr. Barac. In addition to establishing a U.S. standard of care for preventing and monitoring cardiac dysfunction in cancer patients, “I use it as a guide for creation of referral pathways with my oncology colleagues, as well as in education of cardiovascular and oncology trainees,” she said in an interview.
Though produced primarily through ASCO’s leadership, the target audience for the guideline seems to be as much cardiologists as it is oncologists. Dissemination of the guideline to cardiologists snagged when it failed to appear in the cardiology literature. That wasn’t the original plan, said guideline participants.
“Before we started, it was agreed that both ASCO and the ACC would publish it. We had a [letter] signed by the president of the ACC saying the ACC would publish it,” recalled Dr. Lenihan, a guideline coauthor. “After all the details were settled, the ACC bailed. They said that they had changed their organizational structure and that they wouldn’t publish the guideline even though they had agreed to.” Not having the guideline appear simultaneously in the cardiology literature “hinders getting the message to the cardiology community,” he said, a sentiment echoed by other cardio-oncologists.
“I served as the ACC representative on the guideline, and the lack of ACC endorsement was the unfortunate consequence of approval and publication timing that coincided with restructuring of the ACC committees,” said Dr. Barac. “It absolutely does not reflect a lack of interest from the ACC.” As an example of the College’s commitment example, she cited an ACC 1.5-day educational course on cardiovascular care of oncology patients held for the first time in February 2017 and scheduled for a second edition next February.
Publication of the guideline in a cardiology journal “would indeed help dissemination among U.S. cardiologists,” agreed Pamela S. Douglas, MD, professor of medicine at Duke University in Durham, N.C., and another of the several cardiologists who served on the ASCO guideline’s panel.
Further advancing awareness of patients with cardio-oncology issues, what Dr. Moslehi has called “an emerging epidemic,” seems the most fundamental of the goals currently advanced by many active in this field.
One step to grow the subspecialty that he and his associates at Vanderbilt have taken is to start this year a formally recognized fellowship program in cardio-oncology; an initial class of three cardiologists started in the program this summer. The Vanderbilt group also plans to launch a website before the end of 2017 that will include an oncology-drug database that compiles all available information on each agent’s cardiovascular effects. The planned website will aggregate links to all existing cardio-oncology programs.
“We will absolutely see the field grow,” said Dr. Swain. “It has only sprung up in the past 10 or so years. It is now getting recognition, people are being trained in cardio-oncology, and it will grow as a subspecialty. It’s very exciting, and it’s better for patients.”
“A cardiologist with no cancer patients or survivors in their practice is unheard of; many cardiologists just don’t realize that,” Dr. Lenihan said. At least 10%-15% of the U.S. population in their 60s or older has a cancer history, he noted. The common mindset among cardiologists has been that cancer patients and survivors are not among their patients.
“It’s unlikely that a busy cardiology practice has no cancer survivors or active cancer patients,” Dr. Douglas suggested. When this happens, a likely explanations is that the cardiologist simply failed to elicit a completely comprehensive history from the practice’s patient roster. And even a cardiology practice today that includes no cancer patients or survivors will likely see some turning up soon, she predicted, because so many are receiving cardiovascular-toxic therapies and then surviving longer than ever before.
“What oncologists and cardiologists want to do is to optimize oncologic outcomes but with an acceptable adverse event profile. The cardio-oncologist helps push that envelope. The goal is not to eliminate cardiac events at the expense of oncologic outcomes, but to shift the balance to fewer and less severe cardiac events without unduly compromising oncologic outcomes,” explained Dr. Ewer. Cardio-oncology grapples with one of the core challenges of medicine, how to balance the potential risks from treatment against its potential benefits, he observed.
Dr. Neilan has been a consultant to Ariad and Takeda. Dr. Lenihan has been a consultant to Janssen and Roche and has received research funding from Takeda. Dr. Moslehi has been a consultant to Acceleron, Ariad, Bristol-Myers Squibb, Incyte, Pfizer, Takeda/Millennium, Verastem and Vertex. Dr. Ewer, Dr. Fradley, and Dr. Barac had no relevant disclosures. Dr. Swain has been a consultant to Genentech and Roche. Dr. Douglas has been a consultant to CardioDx, Interleukin Genetics, and Omicia, and has an ownership interest in CardioDx.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Carpal tunnel syndrome may flag cardiac amyloidosis in elderly
DALLAS – Older patients with carpal tunnel syndrome that requires release surgery appear to have a relatively high prevalence of amyloidosis that, in some, involves their heart, suggesting that routine screening for amyloidosis is warranted in elderly patients undergoing the surgery.
Routine Congo red staining of a tenosynovial biopsy taken at the time of carpal tunnel release surgery in a single-center experience with 96 patients showed that 10 (10%) were positive for amyloidosis, Mazen Hanna, MD, said at the annual scientific meeting of the Heart Failure Society of America.
Clinicians “should be aware of the association between carpal tunnel syndrome [CTS] and amyloidosis.” When a 60-year old shows up with bilateral CTS without a clear cause, it’s reasonable to suspect amyloidosis, he suggested.
The prospective study run by Dr. Hanna and his associates included men at least 50 years old and women at least 60 years old who underwent CTS release surgery at the Cleveland Clinic during May 2016–June 2017. Enrollment excluded patients with known amyloidosis or rheumatoid arthritis. The patients averaged 68 years of age, 51% were men, and 85% had bilateral CTS that required surgery. The surgeons removed a tenosynovial biopsy at the time of surgery from each of the 96 patients, a “low-risk procedure,” Dr. Hanna said.
The 10 patients with positive staining for amyloid underwent a work-up that included a comprehensive physical examination, a series of blood tests for cardiac biomarkers, an ECG, echocardiography including assessment of cardiac strain, and a technetium-99m pyrophosphate scan. This identified two patients with cardiac involvement. The examinations identified one case by the echocardiographic strain findings and the second case by the technetium pyrophosphate scan. Seven of the 10 patients with amyloid had a history of prior carpal tunnel release surgery.
The researchers also used mass spectroscopy to identify the amyloid type. Seven patients had the transthyretin subtype, including one patient with cardiac involvement; two patients had light chain amyloidosis, including the second patient with cardiac involvement. The tenth patient had inconclusive results but the researchers presumed the amyloid was of the transthyretin type, Dr. Hanna said.
The eight patients identified with amyloid but no cardiac involvement at baseline will continue to receive annual work ups to see whether their hearts become affected over time. The protocol delays a repeat technetium pyrophosphate scan until the 4th year following study entry.
The potential usefulness of early identification and treatment of cardiac amyloidosis received support in results from another study reported at the meeting. Researchers from Columbia University Medical Center, New York, and New York Presbyterian Hospital reported their retrospective, nonrandomized experience with 126 patients who had been diagnosed with transthyretin cardiac amyloidosis. Thirty of these patients had received treatment with a transthyretin-stabilizing drug, either the investigational agent tafamidis or diflunisal, while the other 96 patients received no stabilizing treatment. During a median follow-up of 2 years, patients treated with a stabilizing agent had a statistically significant 68% reduced rate of either death or orthotopic heart transplant, compared with the untreated patients in a multivariate analysis that controlled for various baseline differences between the treated and untreated patients.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Older patients with carpal tunnel syndrome that requires release surgery appear to have a relatively high prevalence of amyloidosis that, in some, involves their heart, suggesting that routine screening for amyloidosis is warranted in elderly patients undergoing the surgery.
Routine Congo red staining of a tenosynovial biopsy taken at the time of carpal tunnel release surgery in a single-center experience with 96 patients showed that 10 (10%) were positive for amyloidosis, Mazen Hanna, MD, said at the annual scientific meeting of the Heart Failure Society of America.
Clinicians “should be aware of the association between carpal tunnel syndrome [CTS] and amyloidosis.” When a 60-year old shows up with bilateral CTS without a clear cause, it’s reasonable to suspect amyloidosis, he suggested.
The prospective study run by Dr. Hanna and his associates included men at least 50 years old and women at least 60 years old who underwent CTS release surgery at the Cleveland Clinic during May 2016–June 2017. Enrollment excluded patients with known amyloidosis or rheumatoid arthritis. The patients averaged 68 years of age, 51% were men, and 85% had bilateral CTS that required surgery. The surgeons removed a tenosynovial biopsy at the time of surgery from each of the 96 patients, a “low-risk procedure,” Dr. Hanna said.
The 10 patients with positive staining for amyloid underwent a work-up that included a comprehensive physical examination, a series of blood tests for cardiac biomarkers, an ECG, echocardiography including assessment of cardiac strain, and a technetium-99m pyrophosphate scan. This identified two patients with cardiac involvement. The examinations identified one case by the echocardiographic strain findings and the second case by the technetium pyrophosphate scan. Seven of the 10 patients with amyloid had a history of prior carpal tunnel release surgery.
The researchers also used mass spectroscopy to identify the amyloid type. Seven patients had the transthyretin subtype, including one patient with cardiac involvement; two patients had light chain amyloidosis, including the second patient with cardiac involvement. The tenth patient had inconclusive results but the researchers presumed the amyloid was of the transthyretin type, Dr. Hanna said.
The eight patients identified with amyloid but no cardiac involvement at baseline will continue to receive annual work ups to see whether their hearts become affected over time. The protocol delays a repeat technetium pyrophosphate scan until the 4th year following study entry.
The potential usefulness of early identification and treatment of cardiac amyloidosis received support in results from another study reported at the meeting. Researchers from Columbia University Medical Center, New York, and New York Presbyterian Hospital reported their retrospective, nonrandomized experience with 126 patients who had been diagnosed with transthyretin cardiac amyloidosis. Thirty of these patients had received treatment with a transthyretin-stabilizing drug, either the investigational agent tafamidis or diflunisal, while the other 96 patients received no stabilizing treatment. During a median follow-up of 2 years, patients treated with a stabilizing agent had a statistically significant 68% reduced rate of either death or orthotopic heart transplant, compared with the untreated patients in a multivariate analysis that controlled for various baseline differences between the treated and untreated patients.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – Older patients with carpal tunnel syndrome that requires release surgery appear to have a relatively high prevalence of amyloidosis that, in some, involves their heart, suggesting that routine screening for amyloidosis is warranted in elderly patients undergoing the surgery.
Routine Congo red staining of a tenosynovial biopsy taken at the time of carpal tunnel release surgery in a single-center experience with 96 patients showed that 10 (10%) were positive for amyloidosis, Mazen Hanna, MD, said at the annual scientific meeting of the Heart Failure Society of America.
Clinicians “should be aware of the association between carpal tunnel syndrome [CTS] and amyloidosis.” When a 60-year old shows up with bilateral CTS without a clear cause, it’s reasonable to suspect amyloidosis, he suggested.
The prospective study run by Dr. Hanna and his associates included men at least 50 years old and women at least 60 years old who underwent CTS release surgery at the Cleveland Clinic during May 2016–June 2017. Enrollment excluded patients with known amyloidosis or rheumatoid arthritis. The patients averaged 68 years of age, 51% were men, and 85% had bilateral CTS that required surgery. The surgeons removed a tenosynovial biopsy at the time of surgery from each of the 96 patients, a “low-risk procedure,” Dr. Hanna said.
The 10 patients with positive staining for amyloid underwent a work-up that included a comprehensive physical examination, a series of blood tests for cardiac biomarkers, an ECG, echocardiography including assessment of cardiac strain, and a technetium-99m pyrophosphate scan. This identified two patients with cardiac involvement. The examinations identified one case by the echocardiographic strain findings and the second case by the technetium pyrophosphate scan. Seven of the 10 patients with amyloid had a history of prior carpal tunnel release surgery.
The researchers also used mass spectroscopy to identify the amyloid type. Seven patients had the transthyretin subtype, including one patient with cardiac involvement; two patients had light chain amyloidosis, including the second patient with cardiac involvement. The tenth patient had inconclusive results but the researchers presumed the amyloid was of the transthyretin type, Dr. Hanna said.
The eight patients identified with amyloid but no cardiac involvement at baseline will continue to receive annual work ups to see whether their hearts become affected over time. The protocol delays a repeat technetium pyrophosphate scan until the 4th year following study entry.
The potential usefulness of early identification and treatment of cardiac amyloidosis received support in results from another study reported at the meeting. Researchers from Columbia University Medical Center, New York, and New York Presbyterian Hospital reported their retrospective, nonrandomized experience with 126 patients who had been diagnosed with transthyretin cardiac amyloidosis. Thirty of these patients had received treatment with a transthyretin-stabilizing drug, either the investigational agent tafamidis or diflunisal, while the other 96 patients received no stabilizing treatment. During a median follow-up of 2 years, patients treated with a stabilizing agent had a statistically significant 68% reduced rate of either death or orthotopic heart transplant, compared with the untreated patients in a multivariate analysis that controlled for various baseline differences between the treated and untreated patients.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point:
Major finding: Ten of 96 patients undergoing carpal tunnel release surgery had amyloidosis, and two had cardiac involvement.
Data source: Prospective, single-center series of 96 patients undergoing carpal tunnel release surgery.
Disclosures: Dr. Hanna had no disclosures.
LVAD use soars in elderly Americans
DALLAS – The percentage of left ventricular assist devices placed in U.S. heart failure patients at least 75 years of age jumped sharply during 2003-2014, and concurrently the short-term survival of these patients improved dramatically, according to data collected by the National Inpatient Sample.
During the 12-year period examined, the percentage of left-ventricular assist devices (LVADs) placed in U.S. heart failure patients aged 75 years and older rose from 3% of all LVADs in 2003 to 11% in 2014, Aniket S. Rali, MD, said at the annual scientific meeting of the Heart Failure Society of America.
The U.S. national numbers also showed that throughout the period studied, elderly U.S. patients who received an LVAD were increasingly sicker, with steadily increasing numbers of patients with a Charlson Comorbidity Index score of four or greater. Despite this, in-hospital mortality rates of elderly patients receiving an LVAD plummeted, dropping from 61% of elderly LVAD recipients in 2003 to 18% in 2014. During the same time, the percentage of elderly patients with a Charlson Comorbidity Index score greater than four doubled from 33% in 2003 to 66% in 2014, said Dr. Rali, a cardiologist at the University of Kansas Medical Center in Kansas City.
“If the Charlson Comorbidity Index score is increasing but in-hospital mortality is decreasing, then increased LVAD use is not a bad trend,” Dr. Rali said in an interview. He hopes that future analysis of longitudinal data from patients could identify clinical factors that link with better patient survival and help target LVAD placement to the patients who stand to gain the most benefit.
“We may be able to give these elderly patients not just longer life but improved quality of life” by a more informed targeting of LVADs, he suggested. “I think these numbers will help convince people that all is not lost,” he noted, for elderly heart failure patients who receive an LVAD as destination therapy. Patients at least 75 years old are not eligible for heart transplantation, so when these patients receive an LVAD it is, by definition, destination therapy.
The data also showed a marked sex disparity in LVAD use, with LVAD placement in men at least 75 years old rising from 1.4/1,000 patients in 2003 to 2.78/1,000 patients in 2014. In contrast, among women these rates rose from 0.8/1,000 patients in 2003 to 1.36/1,000 patients in 2014.
The average age for elderly U.S. LVAD recipients for the entire 12-year period studied was 77.6 years among a total of 2,090 recipients. For all 21,323 U.S. LVAD recipients during 2003-2014 the average age was 51.5 years old.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – The percentage of left ventricular assist devices placed in U.S. heart failure patients at least 75 years of age jumped sharply during 2003-2014, and concurrently the short-term survival of these patients improved dramatically, according to data collected by the National Inpatient Sample.
During the 12-year period examined, the percentage of left-ventricular assist devices (LVADs) placed in U.S. heart failure patients aged 75 years and older rose from 3% of all LVADs in 2003 to 11% in 2014, Aniket S. Rali, MD, said at the annual scientific meeting of the Heart Failure Society of America.
The U.S. national numbers also showed that throughout the period studied, elderly U.S. patients who received an LVAD were increasingly sicker, with steadily increasing numbers of patients with a Charlson Comorbidity Index score of four or greater. Despite this, in-hospital mortality rates of elderly patients receiving an LVAD plummeted, dropping from 61% of elderly LVAD recipients in 2003 to 18% in 2014. During the same time, the percentage of elderly patients with a Charlson Comorbidity Index score greater than four doubled from 33% in 2003 to 66% in 2014, said Dr. Rali, a cardiologist at the University of Kansas Medical Center in Kansas City.
“If the Charlson Comorbidity Index score is increasing but in-hospital mortality is decreasing, then increased LVAD use is not a bad trend,” Dr. Rali said in an interview. He hopes that future analysis of longitudinal data from patients could identify clinical factors that link with better patient survival and help target LVAD placement to the patients who stand to gain the most benefit.
“We may be able to give these elderly patients not just longer life but improved quality of life” by a more informed targeting of LVADs, he suggested. “I think these numbers will help convince people that all is not lost,” he noted, for elderly heart failure patients who receive an LVAD as destination therapy. Patients at least 75 years old are not eligible for heart transplantation, so when these patients receive an LVAD it is, by definition, destination therapy.
The data also showed a marked sex disparity in LVAD use, with LVAD placement in men at least 75 years old rising from 1.4/1,000 patients in 2003 to 2.78/1,000 patients in 2014. In contrast, among women these rates rose from 0.8/1,000 patients in 2003 to 1.36/1,000 patients in 2014.
The average age for elderly U.S. LVAD recipients for the entire 12-year period studied was 77.6 years among a total of 2,090 recipients. For all 21,323 U.S. LVAD recipients during 2003-2014 the average age was 51.5 years old.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
DALLAS – The percentage of left ventricular assist devices placed in U.S. heart failure patients at least 75 years of age jumped sharply during 2003-2014, and concurrently the short-term survival of these patients improved dramatically, according to data collected by the National Inpatient Sample.
During the 12-year period examined, the percentage of left-ventricular assist devices (LVADs) placed in U.S. heart failure patients aged 75 years and older rose from 3% of all LVADs in 2003 to 11% in 2014, Aniket S. Rali, MD, said at the annual scientific meeting of the Heart Failure Society of America.
The U.S. national numbers also showed that throughout the period studied, elderly U.S. patients who received an LVAD were increasingly sicker, with steadily increasing numbers of patients with a Charlson Comorbidity Index score of four or greater. Despite this, in-hospital mortality rates of elderly patients receiving an LVAD plummeted, dropping from 61% of elderly LVAD recipients in 2003 to 18% in 2014. During the same time, the percentage of elderly patients with a Charlson Comorbidity Index score greater than four doubled from 33% in 2003 to 66% in 2014, said Dr. Rali, a cardiologist at the University of Kansas Medical Center in Kansas City.
“If the Charlson Comorbidity Index score is increasing but in-hospital mortality is decreasing, then increased LVAD use is not a bad trend,” Dr. Rali said in an interview. He hopes that future analysis of longitudinal data from patients could identify clinical factors that link with better patient survival and help target LVAD placement to the patients who stand to gain the most benefit.
“We may be able to give these elderly patients not just longer life but improved quality of life” by a more informed targeting of LVADs, he suggested. “I think these numbers will help convince people that all is not lost,” he noted, for elderly heart failure patients who receive an LVAD as destination therapy. Patients at least 75 years old are not eligible for heart transplantation, so when these patients receive an LVAD it is, by definition, destination therapy.
The data also showed a marked sex disparity in LVAD use, with LVAD placement in men at least 75 years old rising from 1.4/1,000 patients in 2003 to 2.78/1,000 patients in 2014. In contrast, among women these rates rose from 0.8/1,000 patients in 2003 to 1.36/1,000 patients in 2014.
The average age for elderly U.S. LVAD recipients for the entire 12-year period studied was 77.6 years among a total of 2,090 recipients. For all 21,323 U.S. LVAD recipients during 2003-2014 the average age was 51.5 years old.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point:
Major finding: Elderly U.S. patients receiving an LVAD rose from 3% of all LVADs placed in 2003 to 11% in 2014.
Data source: The U.S. National Inpatient Survey during 2003-2014.
Disclosures: Dr. Rali had no disclosures.
Empagliflozin’s effects independent of CVD risk factors
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
AT EASD 2017
Key clinical point:
Major finding: The 38% reduction in CV deaths and 32% reduction in all-cause mortality were largely unchanged after adjustment for blood pressure, LDL cholesterol, and HbA1c at baseline and during the study.
Data source: Secondary analyses of EMPA-REG OUTCOME, a phase 3, randomized controlled trial of 7,020 people with type 2 diabetes at high risk for cardiovascular events who were receiving standard care.
Disclosures: The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.