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Vigilance safely keeps AFib patients off anticoagulants post ablation
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
REPORTING FROM THE AF SYMPOSIUM 2020
AFib link with titin mutations warrants selected genetic testing
NATIONAL HARBOR, MD. – Testing to identify mutations in the gene that codes for the muscle protein titin is now a reasonable step in routine clinical practice for selected people with either early-onset atrial fibrillation (AFib) or a family history of atrial fibrillation, or other cardiac disorders that have been strongly linked with titin-gene mutations, Patrick T. Ellinor, MD, said at the annual International AF Symposium.
About one out of every 250 people carries a loss of function (LOF) mutation in one of their TTN genes that codes for the titin protein, making these mutations about as common as mutations for familial hypercholesterolemia, noted Dr. Ellinor, professor of medicine at Harvard Medical School in Boston and director of the Cardiovascular Disease Initiative at the Broad Institute in Cambridge, Mass. TTN LOF mutations are “bad and very frequent,” he said in an interview. “This is evolving quickly as we start to appreciate how frequent these mutations are.”
Several commercial genetic testing companies now offer testing of blood specimens for TTN LOF mutations, often as part of an “arrhythmia test” panel, with a turnaround time of about 4 weeks at a cost to the patient of about $100, noted Dr. Ellinor, who said that he has begun to discuss such testing with a small number of patients in his practice. “It’s reasonable for selected people; the jury is still out on which ones,” a subject that guideline writers will soon need to address, he said.
Patients already diagnosed with early-onset atrial fibrillation (AFib) could benefit from knowing if they had a TTN LOF mutation because that diagnosis would warrant a magnetic resonance scan to look for “subtle myopathies” not detectable with echocardiography, Dr. Ellinor explained. Identification of a TTN LOF would also be a reason to then test the patient’s children. “Perhaps we should offer testing to everyone 40 years old or younger with AFib,” Dr. Ellinor suggested. Many of these patients are now getting genetic testing for TTN on their own “whether or not their physician wants it done,” he noted.
The most recent, and perhaps most persuasive evidence for the link between TTN LOF mutations and AFib came from a recent report from Dr. Ellinor and associates that examined genome-wide associations in 1,546 people with AFib and 41,593 controls using information contained in the UK Biobank, which holds complete gene sequencing data for about half a million U.K. residents (Circ Res. 2020 Jan 17;126[2]: 200-9). The results showed that just under 0.5% of the entire population carried a TTN LOF mutation, and among patients with AFib the prevalence of a TTN LOF mutation was about 2%, but among people who carry this type of mutation 14% were diagnosed with AFib. This penetrance of 14% for AFib among people with a TTN LOF mutation makes AFib the most frequent clinical consequence identified so far for people with this type of mutation. Other cardiac disorders linked with TTN LOF mutations include heart failure and nonischemic cardiomyopathy. The Biobank study findings showed a penetrance for heart failure of about 7% among those with a TTN LOF mutation, and a penetrance of these mutations for nonischemic cardiomyopathy of about 3%.
Dr. Ellinor cited three other recently published studies with consistent results documenting a strong link between TTN LOF mutations and AFib: a study he worked on with lead author Seung H. Choi, Ph.D., and associates that ran an analysis on 2,781 AFib patients and 4,959 controls in a U.S. database of people who underwent whole-genome sequencing (JAMA. 2018 Dec 11; 320[22]:2354-64); a study of 24 Danish families with clusters of three or more affected members with AFib as well as 399 Danish residents with lone, early-onset AFib (Nat Commun. 2018 Oct 17;9[1]:4316); and a study of 25 patients with “very early onset” (less than 45 years old) AFib, which identified four of the 25 patients with a TTN LOF mutation (Circ Genom Precis Med. 2019 Nov 12[11]; 526-8).
Titin is the largest protein in humans and is critical for normal myocardial function. Titin acts as a molecular scaffold for sarcomere assembly and signaling, providing passive stiffness to the sarcomere. Mutations in TTN have been associated with tibial muscular dystrophy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. The relationship now established between TTN mutations and AFib, cardiomyopathy, and heart failure may in the future help explain the tight clinical association of AFib and heart failure, Dr. Ellinor noted. The TTN gene is also notable as the largest gene in the human genome.
Dr. Ellinor has received research funding from Bayer, and he has served as an adviser or consultant to Bayer, Quest Diagnostics, and Novartis.
SOURCE: Choi SH et al. Circ Res. 2020 Jan 17;126[2]: 200-9.
NATIONAL HARBOR, MD. – Testing to identify mutations in the gene that codes for the muscle protein titin is now a reasonable step in routine clinical practice for selected people with either early-onset atrial fibrillation (AFib) or a family history of atrial fibrillation, or other cardiac disorders that have been strongly linked with titin-gene mutations, Patrick T. Ellinor, MD, said at the annual International AF Symposium.
About one out of every 250 people carries a loss of function (LOF) mutation in one of their TTN genes that codes for the titin protein, making these mutations about as common as mutations for familial hypercholesterolemia, noted Dr. Ellinor, professor of medicine at Harvard Medical School in Boston and director of the Cardiovascular Disease Initiative at the Broad Institute in Cambridge, Mass. TTN LOF mutations are “bad and very frequent,” he said in an interview. “This is evolving quickly as we start to appreciate how frequent these mutations are.”
Several commercial genetic testing companies now offer testing of blood specimens for TTN LOF mutations, often as part of an “arrhythmia test” panel, with a turnaround time of about 4 weeks at a cost to the patient of about $100, noted Dr. Ellinor, who said that he has begun to discuss such testing with a small number of patients in his practice. “It’s reasonable for selected people; the jury is still out on which ones,” a subject that guideline writers will soon need to address, he said.
Patients already diagnosed with early-onset atrial fibrillation (AFib) could benefit from knowing if they had a TTN LOF mutation because that diagnosis would warrant a magnetic resonance scan to look for “subtle myopathies” not detectable with echocardiography, Dr. Ellinor explained. Identification of a TTN LOF would also be a reason to then test the patient’s children. “Perhaps we should offer testing to everyone 40 years old or younger with AFib,” Dr. Ellinor suggested. Many of these patients are now getting genetic testing for TTN on their own “whether or not their physician wants it done,” he noted.
The most recent, and perhaps most persuasive evidence for the link between TTN LOF mutations and AFib came from a recent report from Dr. Ellinor and associates that examined genome-wide associations in 1,546 people with AFib and 41,593 controls using information contained in the UK Biobank, which holds complete gene sequencing data for about half a million U.K. residents (Circ Res. 2020 Jan 17;126[2]: 200-9). The results showed that just under 0.5% of the entire population carried a TTN LOF mutation, and among patients with AFib the prevalence of a TTN LOF mutation was about 2%, but among people who carry this type of mutation 14% were diagnosed with AFib. This penetrance of 14% for AFib among people with a TTN LOF mutation makes AFib the most frequent clinical consequence identified so far for people with this type of mutation. Other cardiac disorders linked with TTN LOF mutations include heart failure and nonischemic cardiomyopathy. The Biobank study findings showed a penetrance for heart failure of about 7% among those with a TTN LOF mutation, and a penetrance of these mutations for nonischemic cardiomyopathy of about 3%.
Dr. Ellinor cited three other recently published studies with consistent results documenting a strong link between TTN LOF mutations and AFib: a study he worked on with lead author Seung H. Choi, Ph.D., and associates that ran an analysis on 2,781 AFib patients and 4,959 controls in a U.S. database of people who underwent whole-genome sequencing (JAMA. 2018 Dec 11; 320[22]:2354-64); a study of 24 Danish families with clusters of three or more affected members with AFib as well as 399 Danish residents with lone, early-onset AFib (Nat Commun. 2018 Oct 17;9[1]:4316); and a study of 25 patients with “very early onset” (less than 45 years old) AFib, which identified four of the 25 patients with a TTN LOF mutation (Circ Genom Precis Med. 2019 Nov 12[11]; 526-8).
Titin is the largest protein in humans and is critical for normal myocardial function. Titin acts as a molecular scaffold for sarcomere assembly and signaling, providing passive stiffness to the sarcomere. Mutations in TTN have been associated with tibial muscular dystrophy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. The relationship now established between TTN mutations and AFib, cardiomyopathy, and heart failure may in the future help explain the tight clinical association of AFib and heart failure, Dr. Ellinor noted. The TTN gene is also notable as the largest gene in the human genome.
Dr. Ellinor has received research funding from Bayer, and he has served as an adviser or consultant to Bayer, Quest Diagnostics, and Novartis.
SOURCE: Choi SH et al. Circ Res. 2020 Jan 17;126[2]: 200-9.
NATIONAL HARBOR, MD. – Testing to identify mutations in the gene that codes for the muscle protein titin is now a reasonable step in routine clinical practice for selected people with either early-onset atrial fibrillation (AFib) or a family history of atrial fibrillation, or other cardiac disorders that have been strongly linked with titin-gene mutations, Patrick T. Ellinor, MD, said at the annual International AF Symposium.
About one out of every 250 people carries a loss of function (LOF) mutation in one of their TTN genes that codes for the titin protein, making these mutations about as common as mutations for familial hypercholesterolemia, noted Dr. Ellinor, professor of medicine at Harvard Medical School in Boston and director of the Cardiovascular Disease Initiative at the Broad Institute in Cambridge, Mass. TTN LOF mutations are “bad and very frequent,” he said in an interview. “This is evolving quickly as we start to appreciate how frequent these mutations are.”
Several commercial genetic testing companies now offer testing of blood specimens for TTN LOF mutations, often as part of an “arrhythmia test” panel, with a turnaround time of about 4 weeks at a cost to the patient of about $100, noted Dr. Ellinor, who said that he has begun to discuss such testing with a small number of patients in his practice. “It’s reasonable for selected people; the jury is still out on which ones,” a subject that guideline writers will soon need to address, he said.
Patients already diagnosed with early-onset atrial fibrillation (AFib) could benefit from knowing if they had a TTN LOF mutation because that diagnosis would warrant a magnetic resonance scan to look for “subtle myopathies” not detectable with echocardiography, Dr. Ellinor explained. Identification of a TTN LOF would also be a reason to then test the patient’s children. “Perhaps we should offer testing to everyone 40 years old or younger with AFib,” Dr. Ellinor suggested. Many of these patients are now getting genetic testing for TTN on their own “whether or not their physician wants it done,” he noted.
The most recent, and perhaps most persuasive evidence for the link between TTN LOF mutations and AFib came from a recent report from Dr. Ellinor and associates that examined genome-wide associations in 1,546 people with AFib and 41,593 controls using information contained in the UK Biobank, which holds complete gene sequencing data for about half a million U.K. residents (Circ Res. 2020 Jan 17;126[2]: 200-9). The results showed that just under 0.5% of the entire population carried a TTN LOF mutation, and among patients with AFib the prevalence of a TTN LOF mutation was about 2%, but among people who carry this type of mutation 14% were diagnosed with AFib. This penetrance of 14% for AFib among people with a TTN LOF mutation makes AFib the most frequent clinical consequence identified so far for people with this type of mutation. Other cardiac disorders linked with TTN LOF mutations include heart failure and nonischemic cardiomyopathy. The Biobank study findings showed a penetrance for heart failure of about 7% among those with a TTN LOF mutation, and a penetrance of these mutations for nonischemic cardiomyopathy of about 3%.
Dr. Ellinor cited three other recently published studies with consistent results documenting a strong link between TTN LOF mutations and AFib: a study he worked on with lead author Seung H. Choi, Ph.D., and associates that ran an analysis on 2,781 AFib patients and 4,959 controls in a U.S. database of people who underwent whole-genome sequencing (JAMA. 2018 Dec 11; 320[22]:2354-64); a study of 24 Danish families with clusters of three or more affected members with AFib as well as 399 Danish residents with lone, early-onset AFib (Nat Commun. 2018 Oct 17;9[1]:4316); and a study of 25 patients with “very early onset” (less than 45 years old) AFib, which identified four of the 25 patients with a TTN LOF mutation (Circ Genom Precis Med. 2019 Nov 12[11]; 526-8).
Titin is the largest protein in humans and is critical for normal myocardial function. Titin acts as a molecular scaffold for sarcomere assembly and signaling, providing passive stiffness to the sarcomere. Mutations in TTN have been associated with tibial muscular dystrophy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. The relationship now established between TTN mutations and AFib, cardiomyopathy, and heart failure may in the future help explain the tight clinical association of AFib and heart failure, Dr. Ellinor noted. The TTN gene is also notable as the largest gene in the human genome.
Dr. Ellinor has received research funding from Bayer, and he has served as an adviser or consultant to Bayer, Quest Diagnostics, and Novartis.
SOURCE: Choi SH et al. Circ Res. 2020 Jan 17;126[2]: 200-9.
REPORTING FROM THE AF SYMPOSIUM 2020
Cardiovascular risks associated with cannabis use
Researchers are recommending routine screening of marijuana use in cardiovascular care settings.
A review of current evidence suggests an association between marijuana use and adverse cardiovascular effects, as well as interactions between marijuana and cardiovascular medications.
Although more research is needed, the review authors suggested patients may benefit from marijuana screening and testing as well as discussions about the potential risks of marijuana use in the setting of cardiovascular disease.
Ersilia M. DeFilippis, MD, of Columbia University Irving Medical Center in New York and colleagues conducted this review, which was published in the Journal of the American College of Cardiology.
The authors noted that research on marijuana use and cardiovascular disease is limited. The different forms of cannabis and various routes of administration have made it difficult to draw concrete conclusions about marijuana products. Additionally, there have been no randomized, controlled trials of marijuana products in the United States because such trials are illegal; however, there are observational studies linking marijuana use and adverse cardiovascular effects.
Snapshot of available evidence
One study showed that smoking marijuana produces many of the same cardiotoxic chemicals produced by smoking tobacco (BMJ. 2003 May 3;326[7396]:942-3). Another study suggested marijuana smokers may have greater exposure to harmful chemicals (J Psychoactive Drugs. 1988 Jan-Mar;20[1]:43-6).
More specifically, a meta-analysis suggested that smoking marijuana was one of the top three triggers of myocardial infarction (Lancet. 2011 Feb 26;377[9767]:732-40). And in a systematic analysis, 28 of 33 studies linked marijuana use to an increased risk of acute coronary syndromes (Clin Toxicol [Phila]. 2019 Oct;57[10]:831-41).
Furthermore, a study of 2.5 million marijuana users showed that 3% experienced arrhythmias (Int J Cardiol. 2018 Aug 1;264:91-2). A population survey showed that people who smoked marijuana in the past year experienced a 3.3-fold higher rate of cerebrovascular events (Aust N Z J Public Health. 2016 Jun;40[3]:226-30).
Studies have also indicated that cannabinoids can affect cardiovascular medications, including antiarrhythmics, calcium-channel blockers, isosorbide dinitrate/mononitrate, statins, beta-blockers, warfarin, theophylline, and nonsteroidal anti-inflammatory drugs (Medicines [Basel]. 2018 Dec 23;6[1] pii: E3; Curr Top Behav Neurosci. 2017;32:249-62; Pharmacogenet Genomics. 2009 Jul;19[7]:559-62; Ann Pharmacother. 2009 Jul;43[7]:1347-53; Pharmacol Ther. 2019 Sep;201:25-38).
Reviewer recommendations
Cardiovascular specialists should be informed about regulations governing marijuana products, as well as “potential health consequences of marijuana and its derivatives,” according to Dr. DeFilippis and colleagues.
The authors recommend routinely screening patients for marijuana use, perhaps using the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (PLoS One. 2017 May 26;12[5]:e0178194) or the Cannabis Abuse Screening Test (Int J Methods Psychiatr Res. 2018 Jun;27[2]:e1597).
The authors say urine toxicology “may be reasonable” for patients with myocardial infarction or new-onset heart failure. Such testing is required for patients undergoing a heart transplant because marijuana use may affect their candidacy.
Dr. DeFilippis and colleagues say cardiovascular specialists should inform patients about the risks associated with marijuana use. The authors recommend shared decision making for patients who use marijuana for symptom management or palliative purposes.
Three review authors disclosed relationships with many different pharmaceutical companies. One author disclosed relationships with Medscape Cardiology and WebMD, which are owned by the same parent company as MDedge.
SOURCE: J Am Coll Cardiol. 2020 Jan 20. doi: 10.1016/j.jacc.2019.11.025.
Researchers are recommending routine screening of marijuana use in cardiovascular care settings.
A review of current evidence suggests an association between marijuana use and adverse cardiovascular effects, as well as interactions between marijuana and cardiovascular medications.
Although more research is needed, the review authors suggested patients may benefit from marijuana screening and testing as well as discussions about the potential risks of marijuana use in the setting of cardiovascular disease.
Ersilia M. DeFilippis, MD, of Columbia University Irving Medical Center in New York and colleagues conducted this review, which was published in the Journal of the American College of Cardiology.
The authors noted that research on marijuana use and cardiovascular disease is limited. The different forms of cannabis and various routes of administration have made it difficult to draw concrete conclusions about marijuana products. Additionally, there have been no randomized, controlled trials of marijuana products in the United States because such trials are illegal; however, there are observational studies linking marijuana use and adverse cardiovascular effects.
Snapshot of available evidence
One study showed that smoking marijuana produces many of the same cardiotoxic chemicals produced by smoking tobacco (BMJ. 2003 May 3;326[7396]:942-3). Another study suggested marijuana smokers may have greater exposure to harmful chemicals (J Psychoactive Drugs. 1988 Jan-Mar;20[1]:43-6).
More specifically, a meta-analysis suggested that smoking marijuana was one of the top three triggers of myocardial infarction (Lancet. 2011 Feb 26;377[9767]:732-40). And in a systematic analysis, 28 of 33 studies linked marijuana use to an increased risk of acute coronary syndromes (Clin Toxicol [Phila]. 2019 Oct;57[10]:831-41).
Furthermore, a study of 2.5 million marijuana users showed that 3% experienced arrhythmias (Int J Cardiol. 2018 Aug 1;264:91-2). A population survey showed that people who smoked marijuana in the past year experienced a 3.3-fold higher rate of cerebrovascular events (Aust N Z J Public Health. 2016 Jun;40[3]:226-30).
Studies have also indicated that cannabinoids can affect cardiovascular medications, including antiarrhythmics, calcium-channel blockers, isosorbide dinitrate/mononitrate, statins, beta-blockers, warfarin, theophylline, and nonsteroidal anti-inflammatory drugs (Medicines [Basel]. 2018 Dec 23;6[1] pii: E3; Curr Top Behav Neurosci. 2017;32:249-62; Pharmacogenet Genomics. 2009 Jul;19[7]:559-62; Ann Pharmacother. 2009 Jul;43[7]:1347-53; Pharmacol Ther. 2019 Sep;201:25-38).
Reviewer recommendations
Cardiovascular specialists should be informed about regulations governing marijuana products, as well as “potential health consequences of marijuana and its derivatives,” according to Dr. DeFilippis and colleagues.
The authors recommend routinely screening patients for marijuana use, perhaps using the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (PLoS One. 2017 May 26;12[5]:e0178194) or the Cannabis Abuse Screening Test (Int J Methods Psychiatr Res. 2018 Jun;27[2]:e1597).
The authors say urine toxicology “may be reasonable” for patients with myocardial infarction or new-onset heart failure. Such testing is required for patients undergoing a heart transplant because marijuana use may affect their candidacy.
Dr. DeFilippis and colleagues say cardiovascular specialists should inform patients about the risks associated with marijuana use. The authors recommend shared decision making for patients who use marijuana for symptom management or palliative purposes.
Three review authors disclosed relationships with many different pharmaceutical companies. One author disclosed relationships with Medscape Cardiology and WebMD, which are owned by the same parent company as MDedge.
SOURCE: J Am Coll Cardiol. 2020 Jan 20. doi: 10.1016/j.jacc.2019.11.025.
Researchers are recommending routine screening of marijuana use in cardiovascular care settings.
A review of current evidence suggests an association between marijuana use and adverse cardiovascular effects, as well as interactions between marijuana and cardiovascular medications.
Although more research is needed, the review authors suggested patients may benefit from marijuana screening and testing as well as discussions about the potential risks of marijuana use in the setting of cardiovascular disease.
Ersilia M. DeFilippis, MD, of Columbia University Irving Medical Center in New York and colleagues conducted this review, which was published in the Journal of the American College of Cardiology.
The authors noted that research on marijuana use and cardiovascular disease is limited. The different forms of cannabis and various routes of administration have made it difficult to draw concrete conclusions about marijuana products. Additionally, there have been no randomized, controlled trials of marijuana products in the United States because such trials are illegal; however, there are observational studies linking marijuana use and adverse cardiovascular effects.
Snapshot of available evidence
One study showed that smoking marijuana produces many of the same cardiotoxic chemicals produced by smoking tobacco (BMJ. 2003 May 3;326[7396]:942-3). Another study suggested marijuana smokers may have greater exposure to harmful chemicals (J Psychoactive Drugs. 1988 Jan-Mar;20[1]:43-6).
More specifically, a meta-analysis suggested that smoking marijuana was one of the top three triggers of myocardial infarction (Lancet. 2011 Feb 26;377[9767]:732-40). And in a systematic analysis, 28 of 33 studies linked marijuana use to an increased risk of acute coronary syndromes (Clin Toxicol [Phila]. 2019 Oct;57[10]:831-41).
Furthermore, a study of 2.5 million marijuana users showed that 3% experienced arrhythmias (Int J Cardiol. 2018 Aug 1;264:91-2). A population survey showed that people who smoked marijuana in the past year experienced a 3.3-fold higher rate of cerebrovascular events (Aust N Z J Public Health. 2016 Jun;40[3]:226-30).
Studies have also indicated that cannabinoids can affect cardiovascular medications, including antiarrhythmics, calcium-channel blockers, isosorbide dinitrate/mononitrate, statins, beta-blockers, warfarin, theophylline, and nonsteroidal anti-inflammatory drugs (Medicines [Basel]. 2018 Dec 23;6[1] pii: E3; Curr Top Behav Neurosci. 2017;32:249-62; Pharmacogenet Genomics. 2009 Jul;19[7]:559-62; Ann Pharmacother. 2009 Jul;43[7]:1347-53; Pharmacol Ther. 2019 Sep;201:25-38).
Reviewer recommendations
Cardiovascular specialists should be informed about regulations governing marijuana products, as well as “potential health consequences of marijuana and its derivatives,” according to Dr. DeFilippis and colleagues.
The authors recommend routinely screening patients for marijuana use, perhaps using the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (PLoS One. 2017 May 26;12[5]:e0178194) or the Cannabis Abuse Screening Test (Int J Methods Psychiatr Res. 2018 Jun;27[2]:e1597).
The authors say urine toxicology “may be reasonable” for patients with myocardial infarction or new-onset heart failure. Such testing is required for patients undergoing a heart transplant because marijuana use may affect their candidacy.
Dr. DeFilippis and colleagues say cardiovascular specialists should inform patients about the risks associated with marijuana use. The authors recommend shared decision making for patients who use marijuana for symptom management or palliative purposes.
Three review authors disclosed relationships with many different pharmaceutical companies. One author disclosed relationships with Medscape Cardiology and WebMD, which are owned by the same parent company as MDedge.
SOURCE: J Am Coll Cardiol. 2020 Jan 20. doi: 10.1016/j.jacc.2019.11.025.
FROM JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
HRS urges consumers to direct questions about wearables’ data to clinicians
With much of the public now wearing devices on their wrists or elsewhere capable of recording a range of vital signs, including heart rate abnormalities, the Heart Rhythm Society launched a guide for American consumers about wearables and the data they collect during a session on Jan. 9 at CES 2020 in Las Vegas.
While providing a succinct but comprehensive overview of the types of wearables and the health metrics they can record, the main and recurring message of the 10-page e-pamphlet is that, when a layperson has a question or concern about their data, the best course is to consult a clinician.
The “Guidance for Wearable Health Solutions,” produced by the Heart Rhythm Society (HRS) along with the Consumer Technology Association (CTA, which presents the annual CES exhibition), cautions that “most wearables are primarily suited for fitness and wellness,” and stresses that wearables “are not a substitute for medical devices prescribed by a clinician.” And in all cases, the document advises, when questions arise about the data – including an apparently high heart rate; a reading the device identifies as abnormal; and when symptoms appear such as a rapid heart rate, dizziness, or fluttering or flopping of the heart – the response that the guidance advocates is consistent: Talk with your clinician.
“Heart Rhythm Society members are seeing more and more patients with their own data collected by wearables,” said Nassir F. Marrouche, MD, professor of medicine and director of electrophysiology at Tulane University, New Orleans, and a member of the panel that wrote the guidance document for the HRS and CTA. “Every provider is dealing with consumer wearable data. The need is important for consumers to be supported. Consumers and patients are buying over-the-counter devices and using them for diagnosis and management, with little to no guidance, and we want to help them feel supported in managing their data and understand what to do with it,” Dr. Marrouche said in an interview.
“This is a new reality in medicine; the direction of information is changing. Consumers are collecting data themselves and coming to physicians already informed. There is a new shift in how information is collected, shared, and used.” Dr. Marrouche was 1 of 5 cardiac electrophysiologists who served on the 11-member writing group.
The new document for consumers “addresses an unmet need,” and the HRS collaboration with the CTA was “a unique opportunity to develop useful guidance that supports education and empowers consumers,” said Christina Wurster, chief strategy officer for the HRS in Washington and a member of the writing panel. “The questions outlined in the document are questions our members receive daily. The document is a resource they can direct people to.”
The HRS and CTA will “partner with consumer advocacy groups and professional societies to further disseminate the document,” added Ms. Wurster. “We’ll also have a strong push on social media to reach consumer audiences and drive awareness of this new resource,” she said in an interview. In addition, HRS “has strategic partnerships with other societies and will aim to work with them for dissemination, including societies related to internal medicine, emergency medicine, cardiology, and nursing, as well as also working with patient and consumer advocacy groups to reach the public.” The CTA will also actively publicize and disseminate the guidance document through their members.
Clinical guidelines play catch-up
Ironically, the HRS has issued this guidance to the public and has told people to take their wearable-collected heart data to clinicians before the HRS or any other medical group has advised clinicians on how they should handle, interpret, and use heart rhythm data collected this way.
Presumably, many if not most of the people with questions about their heart data from wearables are asymptomatic, because symptoms are what usually drive patients with a cardiac arrhythmia to consult a physician – they don’t wait to see what their device tells them. But the best way to manage asymptomatic arrhythmias like atrial fibrillation (AFib) remains a big clinical uncertainty today, with no evidence base as a guide, although several studies exploring this question are in progress.
“There are no clear and definitive data showing that treating subclinical atrial fibrillation improves outcomes. That’s what we need, and until we get these data you won’t see strong recommendations in guidelines” to screen patients for asymptomatic AFib or other arrhythmias, said Sana M. Al-Khatib, MD, a cardiac electrophysiologist and professor of medicine at Duke University, Durham, N.C., during the 2019 American Heart Association scientific sessions in Philadelphia in a talk about wearables and guidelines.
“If you intervene with silent AFib, do you improve outcomes? That evidence is lacking,” she said. Another shortcoming of current evidence is a clear understanding of what AFib burden warrants intervention, added Dr. Al-Khatib. “We see high-rate AFib episodes recorded in patients with implanted cardiac devices [and no symptoms], and we don’t know what to do with that either.”
The closest any existing guideline from a medical society comes to currently endorsing screening for AFib by a wearable is the 2016 European Society of Cardiology’s AFib management guidelines, which give “opportunistic screening” among people aged older than 65 years a IB recommendation, but specifically for screening by taking a patient’s pulse or with a ECG recording, with no mention of the screening role for wearables (Eur Heart J. 2016 Oct 7;37[38]:2893-967), Dr. Al-Khatib noted.
The most extensive data on screening for asymptomatic AFib in an unselected population came in the recently reported results from the Apple Heart Study, which enrolled more than 419,000 people monitored by a smart watch for a median of 117 days. During this screening, 2,161 people (0.52%) received a notification of having an irregular pulse (including 3.1% of those who were aged at least 65 years), which triggered more intensive assessment with an ECG patch for a median of 13 days in 450 of the 2,161 screening positives (21%) who agreed to participate in this follow-up. Among those 450 people, the patch test identified 34% as having actual AFib (N Engl J Med. 2019 Nov 14;381[20]:1909-17). But while this study provided evidence that screening for an irregular heartbeat with a wearable can identify AFib with some level of success, the results did not address whether this approach improved short- or long-term patient outcomes.
In addition, what the Apple Heart Study results showed was that this sort of screening results in a relatively large volume of follow-up testing. Of the 2,161 participants who received an irregular pulse notification, 1,376 (64%) returned a 90-day survey. Of these, 787 (57%) reported contact with a health care provider outside the study, 28% were prescribed a new medication, 33% were recommended to see a specialist (such as a cardiologist), and 36% were recommended to have additional testing.
“The results raise the question that a lot of resources were used,” to assess patients with a positive screening result, noted Paul A. Heidenreich, MD, a cardiologist and professor of medicine at Stanford (Calif.) University who studies quality of care for patients with heart disease. He estimated that, in the Apple Heart Study, each of the more than 2,000 patients who screening positive for an irregular heartbeat and underwent subsequent assessment ran up about $700 worth of follow-up testing. But he added that, in the case of AFib, the primary intervention that many previously undiagnosed AFib patients receive is some sort of anticoagulation for stroke prevention. Moreover, because this intervention is so effective there is a lot of money to play with to make AFib screening cost effective, as judged by typical, contemporary metrics of cost efficacy that value a quality-adjusted life-year (QALY) gain as reasonable for society to pay if the cost of an incremental QALY is $50,000-$150,000.
If the benchmark is a cost that’s within $50,000/QALY, then an average follow-up cost of $116/person to assess screened positives can fall within this cost ceiling. If the benchmark is $150,000/QALY, then follow-up costs can run as high as $491/person screened, said Dr. Heidenreich during the same AHA session where Dr. Al-Khatib spoke last November.
Despite this good news for screening for AFib with a wearable from a cost-effectiveness perspective, “there is so much uncertainty regarding the benefit and the consequences of incidental findings that we need an outcomes study before widespread implementation” of this type of screening, Dr. Heidenreich concluded. “We need an outcomes study to feel comfortable” with screening. “There is a huge potential for extra care that we don’t understand.”
Dr. Marrouche agreed that collecting adequate evidence to drive changes in clinical guidelines on how to use data from wearables has lagged behind the rapid spread of wearables and the information they can produce among the American public. “Outcomes and evidence will support guidelines development, but in the meantime, we’re offering education to clinicians, patients, and consumers. Consumers own their data, and they can share them with whomever they choose.”
The document notes that people who use wearables are, in general, “enthusiastic about tracking their data, not only for their own use, but also to share” with others, often on social media websites.
“We cannot control that, but our goal in the document is focused on the clinical relevance [of the data] and to help people better understand their data and use it in a meaningful and safe way,” Dr. Marrouche said.
Dr. Marrouche has been a consultant to, advisor to, or received research support from Abbott, Biosense Webster, Biotronik, GE Healthcare, Medtronic, Preventice, Sanofi-Aventis, Siemens, and Vytronus. Ms. Wurster is an employee of the Heart Rhythm Society. Dr. Al-Khatib has been a consultant to Milestone Pharmaceuticals and Medtronic, and she has also received other financial benefits from Medtronic. Dr. Heidenreich had no disclosures,
With much of the public now wearing devices on their wrists or elsewhere capable of recording a range of vital signs, including heart rate abnormalities, the Heart Rhythm Society launched a guide for American consumers about wearables and the data they collect during a session on Jan. 9 at CES 2020 in Las Vegas.
While providing a succinct but comprehensive overview of the types of wearables and the health metrics they can record, the main and recurring message of the 10-page e-pamphlet is that, when a layperson has a question or concern about their data, the best course is to consult a clinician.
The “Guidance for Wearable Health Solutions,” produced by the Heart Rhythm Society (HRS) along with the Consumer Technology Association (CTA, which presents the annual CES exhibition), cautions that “most wearables are primarily suited for fitness and wellness,” and stresses that wearables “are not a substitute for medical devices prescribed by a clinician.” And in all cases, the document advises, when questions arise about the data – including an apparently high heart rate; a reading the device identifies as abnormal; and when symptoms appear such as a rapid heart rate, dizziness, or fluttering or flopping of the heart – the response that the guidance advocates is consistent: Talk with your clinician.
“Heart Rhythm Society members are seeing more and more patients with their own data collected by wearables,” said Nassir F. Marrouche, MD, professor of medicine and director of electrophysiology at Tulane University, New Orleans, and a member of the panel that wrote the guidance document for the HRS and CTA. “Every provider is dealing with consumer wearable data. The need is important for consumers to be supported. Consumers and patients are buying over-the-counter devices and using them for diagnosis and management, with little to no guidance, and we want to help them feel supported in managing their data and understand what to do with it,” Dr. Marrouche said in an interview.
“This is a new reality in medicine; the direction of information is changing. Consumers are collecting data themselves and coming to physicians already informed. There is a new shift in how information is collected, shared, and used.” Dr. Marrouche was 1 of 5 cardiac electrophysiologists who served on the 11-member writing group.
The new document for consumers “addresses an unmet need,” and the HRS collaboration with the CTA was “a unique opportunity to develop useful guidance that supports education and empowers consumers,” said Christina Wurster, chief strategy officer for the HRS in Washington and a member of the writing panel. “The questions outlined in the document are questions our members receive daily. The document is a resource they can direct people to.”
The HRS and CTA will “partner with consumer advocacy groups and professional societies to further disseminate the document,” added Ms. Wurster. “We’ll also have a strong push on social media to reach consumer audiences and drive awareness of this new resource,” she said in an interview. In addition, HRS “has strategic partnerships with other societies and will aim to work with them for dissemination, including societies related to internal medicine, emergency medicine, cardiology, and nursing, as well as also working with patient and consumer advocacy groups to reach the public.” The CTA will also actively publicize and disseminate the guidance document through their members.
Clinical guidelines play catch-up
Ironically, the HRS has issued this guidance to the public and has told people to take their wearable-collected heart data to clinicians before the HRS or any other medical group has advised clinicians on how they should handle, interpret, and use heart rhythm data collected this way.
Presumably, many if not most of the people with questions about their heart data from wearables are asymptomatic, because symptoms are what usually drive patients with a cardiac arrhythmia to consult a physician – they don’t wait to see what their device tells them. But the best way to manage asymptomatic arrhythmias like atrial fibrillation (AFib) remains a big clinical uncertainty today, with no evidence base as a guide, although several studies exploring this question are in progress.
“There are no clear and definitive data showing that treating subclinical atrial fibrillation improves outcomes. That’s what we need, and until we get these data you won’t see strong recommendations in guidelines” to screen patients for asymptomatic AFib or other arrhythmias, said Sana M. Al-Khatib, MD, a cardiac electrophysiologist and professor of medicine at Duke University, Durham, N.C., during the 2019 American Heart Association scientific sessions in Philadelphia in a talk about wearables and guidelines.
“If you intervene with silent AFib, do you improve outcomes? That evidence is lacking,” she said. Another shortcoming of current evidence is a clear understanding of what AFib burden warrants intervention, added Dr. Al-Khatib. “We see high-rate AFib episodes recorded in patients with implanted cardiac devices [and no symptoms], and we don’t know what to do with that either.”
The closest any existing guideline from a medical society comes to currently endorsing screening for AFib by a wearable is the 2016 European Society of Cardiology’s AFib management guidelines, which give “opportunistic screening” among people aged older than 65 years a IB recommendation, but specifically for screening by taking a patient’s pulse or with a ECG recording, with no mention of the screening role for wearables (Eur Heart J. 2016 Oct 7;37[38]:2893-967), Dr. Al-Khatib noted.
The most extensive data on screening for asymptomatic AFib in an unselected population came in the recently reported results from the Apple Heart Study, which enrolled more than 419,000 people monitored by a smart watch for a median of 117 days. During this screening, 2,161 people (0.52%) received a notification of having an irregular pulse (including 3.1% of those who were aged at least 65 years), which triggered more intensive assessment with an ECG patch for a median of 13 days in 450 of the 2,161 screening positives (21%) who agreed to participate in this follow-up. Among those 450 people, the patch test identified 34% as having actual AFib (N Engl J Med. 2019 Nov 14;381[20]:1909-17). But while this study provided evidence that screening for an irregular heartbeat with a wearable can identify AFib with some level of success, the results did not address whether this approach improved short- or long-term patient outcomes.
In addition, what the Apple Heart Study results showed was that this sort of screening results in a relatively large volume of follow-up testing. Of the 2,161 participants who received an irregular pulse notification, 1,376 (64%) returned a 90-day survey. Of these, 787 (57%) reported contact with a health care provider outside the study, 28% were prescribed a new medication, 33% were recommended to see a specialist (such as a cardiologist), and 36% were recommended to have additional testing.
“The results raise the question that a lot of resources were used,” to assess patients with a positive screening result, noted Paul A. Heidenreich, MD, a cardiologist and professor of medicine at Stanford (Calif.) University who studies quality of care for patients with heart disease. He estimated that, in the Apple Heart Study, each of the more than 2,000 patients who screening positive for an irregular heartbeat and underwent subsequent assessment ran up about $700 worth of follow-up testing. But he added that, in the case of AFib, the primary intervention that many previously undiagnosed AFib patients receive is some sort of anticoagulation for stroke prevention. Moreover, because this intervention is so effective there is a lot of money to play with to make AFib screening cost effective, as judged by typical, contemporary metrics of cost efficacy that value a quality-adjusted life-year (QALY) gain as reasonable for society to pay if the cost of an incremental QALY is $50,000-$150,000.
If the benchmark is a cost that’s within $50,000/QALY, then an average follow-up cost of $116/person to assess screened positives can fall within this cost ceiling. If the benchmark is $150,000/QALY, then follow-up costs can run as high as $491/person screened, said Dr. Heidenreich during the same AHA session where Dr. Al-Khatib spoke last November.
Despite this good news for screening for AFib with a wearable from a cost-effectiveness perspective, “there is so much uncertainty regarding the benefit and the consequences of incidental findings that we need an outcomes study before widespread implementation” of this type of screening, Dr. Heidenreich concluded. “We need an outcomes study to feel comfortable” with screening. “There is a huge potential for extra care that we don’t understand.”
Dr. Marrouche agreed that collecting adequate evidence to drive changes in clinical guidelines on how to use data from wearables has lagged behind the rapid spread of wearables and the information they can produce among the American public. “Outcomes and evidence will support guidelines development, but in the meantime, we’re offering education to clinicians, patients, and consumers. Consumers own their data, and they can share them with whomever they choose.”
The document notes that people who use wearables are, in general, “enthusiastic about tracking their data, not only for their own use, but also to share” with others, often on social media websites.
“We cannot control that, but our goal in the document is focused on the clinical relevance [of the data] and to help people better understand their data and use it in a meaningful and safe way,” Dr. Marrouche said.
Dr. Marrouche has been a consultant to, advisor to, or received research support from Abbott, Biosense Webster, Biotronik, GE Healthcare, Medtronic, Preventice, Sanofi-Aventis, Siemens, and Vytronus. Ms. Wurster is an employee of the Heart Rhythm Society. Dr. Al-Khatib has been a consultant to Milestone Pharmaceuticals and Medtronic, and she has also received other financial benefits from Medtronic. Dr. Heidenreich had no disclosures,
With much of the public now wearing devices on their wrists or elsewhere capable of recording a range of vital signs, including heart rate abnormalities, the Heart Rhythm Society launched a guide for American consumers about wearables and the data they collect during a session on Jan. 9 at CES 2020 in Las Vegas.
While providing a succinct but comprehensive overview of the types of wearables and the health metrics they can record, the main and recurring message of the 10-page e-pamphlet is that, when a layperson has a question or concern about their data, the best course is to consult a clinician.
The “Guidance for Wearable Health Solutions,” produced by the Heart Rhythm Society (HRS) along with the Consumer Technology Association (CTA, which presents the annual CES exhibition), cautions that “most wearables are primarily suited for fitness and wellness,” and stresses that wearables “are not a substitute for medical devices prescribed by a clinician.” And in all cases, the document advises, when questions arise about the data – including an apparently high heart rate; a reading the device identifies as abnormal; and when symptoms appear such as a rapid heart rate, dizziness, or fluttering or flopping of the heart – the response that the guidance advocates is consistent: Talk with your clinician.
“Heart Rhythm Society members are seeing more and more patients with their own data collected by wearables,” said Nassir F. Marrouche, MD, professor of medicine and director of electrophysiology at Tulane University, New Orleans, and a member of the panel that wrote the guidance document for the HRS and CTA. “Every provider is dealing with consumer wearable data. The need is important for consumers to be supported. Consumers and patients are buying over-the-counter devices and using them for diagnosis and management, with little to no guidance, and we want to help them feel supported in managing their data and understand what to do with it,” Dr. Marrouche said in an interview.
“This is a new reality in medicine; the direction of information is changing. Consumers are collecting data themselves and coming to physicians already informed. There is a new shift in how information is collected, shared, and used.” Dr. Marrouche was 1 of 5 cardiac electrophysiologists who served on the 11-member writing group.
The new document for consumers “addresses an unmet need,” and the HRS collaboration with the CTA was “a unique opportunity to develop useful guidance that supports education and empowers consumers,” said Christina Wurster, chief strategy officer for the HRS in Washington and a member of the writing panel. “The questions outlined in the document are questions our members receive daily. The document is a resource they can direct people to.”
The HRS and CTA will “partner with consumer advocacy groups and professional societies to further disseminate the document,” added Ms. Wurster. “We’ll also have a strong push on social media to reach consumer audiences and drive awareness of this new resource,” she said in an interview. In addition, HRS “has strategic partnerships with other societies and will aim to work with them for dissemination, including societies related to internal medicine, emergency medicine, cardiology, and nursing, as well as also working with patient and consumer advocacy groups to reach the public.” The CTA will also actively publicize and disseminate the guidance document through their members.
Clinical guidelines play catch-up
Ironically, the HRS has issued this guidance to the public and has told people to take their wearable-collected heart data to clinicians before the HRS or any other medical group has advised clinicians on how they should handle, interpret, and use heart rhythm data collected this way.
Presumably, many if not most of the people with questions about their heart data from wearables are asymptomatic, because symptoms are what usually drive patients with a cardiac arrhythmia to consult a physician – they don’t wait to see what their device tells them. But the best way to manage asymptomatic arrhythmias like atrial fibrillation (AFib) remains a big clinical uncertainty today, with no evidence base as a guide, although several studies exploring this question are in progress.
“There are no clear and definitive data showing that treating subclinical atrial fibrillation improves outcomes. That’s what we need, and until we get these data you won’t see strong recommendations in guidelines” to screen patients for asymptomatic AFib or other arrhythmias, said Sana M. Al-Khatib, MD, a cardiac electrophysiologist and professor of medicine at Duke University, Durham, N.C., during the 2019 American Heart Association scientific sessions in Philadelphia in a talk about wearables and guidelines.
“If you intervene with silent AFib, do you improve outcomes? That evidence is lacking,” she said. Another shortcoming of current evidence is a clear understanding of what AFib burden warrants intervention, added Dr. Al-Khatib. “We see high-rate AFib episodes recorded in patients with implanted cardiac devices [and no symptoms], and we don’t know what to do with that either.”
The closest any existing guideline from a medical society comes to currently endorsing screening for AFib by a wearable is the 2016 European Society of Cardiology’s AFib management guidelines, which give “opportunistic screening” among people aged older than 65 years a IB recommendation, but specifically for screening by taking a patient’s pulse or with a ECG recording, with no mention of the screening role for wearables (Eur Heart J. 2016 Oct 7;37[38]:2893-967), Dr. Al-Khatib noted.
The most extensive data on screening for asymptomatic AFib in an unselected population came in the recently reported results from the Apple Heart Study, which enrolled more than 419,000 people monitored by a smart watch for a median of 117 days. During this screening, 2,161 people (0.52%) received a notification of having an irregular pulse (including 3.1% of those who were aged at least 65 years), which triggered more intensive assessment with an ECG patch for a median of 13 days in 450 of the 2,161 screening positives (21%) who agreed to participate in this follow-up. Among those 450 people, the patch test identified 34% as having actual AFib (N Engl J Med. 2019 Nov 14;381[20]:1909-17). But while this study provided evidence that screening for an irregular heartbeat with a wearable can identify AFib with some level of success, the results did not address whether this approach improved short- or long-term patient outcomes.
In addition, what the Apple Heart Study results showed was that this sort of screening results in a relatively large volume of follow-up testing. Of the 2,161 participants who received an irregular pulse notification, 1,376 (64%) returned a 90-day survey. Of these, 787 (57%) reported contact with a health care provider outside the study, 28% were prescribed a new medication, 33% were recommended to see a specialist (such as a cardiologist), and 36% were recommended to have additional testing.
“The results raise the question that a lot of resources were used,” to assess patients with a positive screening result, noted Paul A. Heidenreich, MD, a cardiologist and professor of medicine at Stanford (Calif.) University who studies quality of care for patients with heart disease. He estimated that, in the Apple Heart Study, each of the more than 2,000 patients who screening positive for an irregular heartbeat and underwent subsequent assessment ran up about $700 worth of follow-up testing. But he added that, in the case of AFib, the primary intervention that many previously undiagnosed AFib patients receive is some sort of anticoagulation for stroke prevention. Moreover, because this intervention is so effective there is a lot of money to play with to make AFib screening cost effective, as judged by typical, contemporary metrics of cost efficacy that value a quality-adjusted life-year (QALY) gain as reasonable for society to pay if the cost of an incremental QALY is $50,000-$150,000.
If the benchmark is a cost that’s within $50,000/QALY, then an average follow-up cost of $116/person to assess screened positives can fall within this cost ceiling. If the benchmark is $150,000/QALY, then follow-up costs can run as high as $491/person screened, said Dr. Heidenreich during the same AHA session where Dr. Al-Khatib spoke last November.
Despite this good news for screening for AFib with a wearable from a cost-effectiveness perspective, “there is so much uncertainty regarding the benefit and the consequences of incidental findings that we need an outcomes study before widespread implementation” of this type of screening, Dr. Heidenreich concluded. “We need an outcomes study to feel comfortable” with screening. “There is a huge potential for extra care that we don’t understand.”
Dr. Marrouche agreed that collecting adequate evidence to drive changes in clinical guidelines on how to use data from wearables has lagged behind the rapid spread of wearables and the information they can produce among the American public. “Outcomes and evidence will support guidelines development, but in the meantime, we’re offering education to clinicians, patients, and consumers. Consumers own their data, and they can share them with whomever they choose.”
The document notes that people who use wearables are, in general, “enthusiastic about tracking their data, not only for their own use, but also to share” with others, often on social media websites.
“We cannot control that, but our goal in the document is focused on the clinical relevance [of the data] and to help people better understand their data and use it in a meaningful and safe way,” Dr. Marrouche said.
Dr. Marrouche has been a consultant to, advisor to, or received research support from Abbott, Biosense Webster, Biotronik, GE Healthcare, Medtronic, Preventice, Sanofi-Aventis, Siemens, and Vytronus. Ms. Wurster is an employee of the Heart Rhythm Society. Dr. Al-Khatib has been a consultant to Milestone Pharmaceuticals and Medtronic, and she has also received other financial benefits from Medtronic. Dr. Heidenreich had no disclosures,
FDA okays first generics for Eliquis
The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.
“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”
It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.
Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.
The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.
As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.
Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.
This story first appeared on Medscape.com.
The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.
“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”
It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.
Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.
The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.
As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.
Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.
This story first appeared on Medscape.com.
The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.
“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”
It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.
Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.
The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.
As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.
Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.
This story first appeared on Medscape.com.
Hydroxychloroquine prevents congenital heart block recurrence in anti-Ro pregnancies
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
REPORTING FROM ACR 2019
FDA panel rejects vernakalant bid for AFib cardioversion indication
for cardioversion of recent-onset atrial fibrillation (AFib).
It was the second time before an FDA advisory panel for vernakalant (Brinavess, Correvio International Sàrl), which the agency had declined to approve in 2008 due to safety concerns. That time, however, its advisors had given the agency a decidedly positive recommendation.
Since then, registry data collected for the drug’s resubmission seemed only to raise further safety issues, especially evidence that a single infusion may cause severe hypotension and suppress left ventricular function.
Some members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), including a number who voted against approval, expressed hopes for further research aimed at identifying specific AFib patient groups who might safely benefit from vernakalant.
Of note, the drug has long been available for AFib cardioversion in Europe, where there are a number of other pharmacologic options, and was recently approved in Canada.
“We do recognize there’s a significant clinical need here,” observed Paul M. Ridker, MD, MPH, of Harvard Medical School and Brigham and Women’s Hospital Boston, a CRDAC panelist.
The results of the safety study that Correvio presented to the panel were “pretty marginal,” Dr. Ridker said. Given the negative safety signals and the available cardioversion alternatives, he questioned whether vernakalant represented a “substantial advance versus just another option. Right now, I’m not convinced it’s a substantial advance.”
FDA representatives were skeptical about vernakalant when they walked into the meeting room, as noted in briefing documents they had circulated beforehand. The drug’s safety experience under consideration included one case of ventricular arrhythmia and cardiogenic shock in a treated patient without apparent structural heart disease, who subsequently died. That case was much discussed throughout the meeting.
In its resubmission of vernakalant to regulators, Correvio also pointed to a significant unmet need for AFib cardioversion options in the United States, given the few alternatives.
For example, ibutilide is FDA-approved for recent-onset AFib or atrial flutter; but as the company and panelists noted, the drug isn’t often used for that indication. Patients with recent-onset AFib are often put on rate-control meds without cardioversion. Or clinicians may resort to electrical cardioversion, which can be logistically cumbersome and require anesthesia and generally a hospital stay.
Oral or intravenous amiodarone and oral dofetilide, flecainide, and propafenone are guideline-recommended but not actually FDA-approved for recent-onset AFib, the company noted.
Correvio made its “pre-infusion checklist” a core feature of its case. It was designed to guide selection of patients for vernakalant cardioversion based on contraindications such as a systolic blood pressure under 100 mm Hg, severe heart failure, aortic stenosis, severe bradycardia or heart block, or a prolonged QT interval.
In his presentation to the panel, FDA medical officer Preston Dunnmon, MD, said the safety results from the SPECTRUM registry, another main pillar of support for the vernakalant resubmission, “are not reassuring.”
As reasons, Dr. Dunnmon cited likely patient-selection bias and its high proportion of patients who were not prospectively enrolled; 21% were retrospectively entered from records.
Moreover, “the proposed preinfusion checklist will not reliably predict which subjects will experience serious cardiovascular adverse events with vernakalant,” he said.
“Vernakalant has induced harm that cannot be reliably predicted, prevented, or in some cases, treated. In contrast to vernakalant, electrical cardioversion and ibutilide pharmacologic cardioversion can cause adverse events, but these are transient and treatable,” he said.
Many on the panel agreed. “I thought the totality of evidence supported the hypothesis that this drug has a potential for a fatal side effect in a disease that you can live with, potentially, and that there are other treatments for,” said Julia B. Lewis, MD, Vanderbilt Medical Center, Nashville, Tenn., who chaired the CRDAC panel.
“The drug clearly converts atrial fibrillation, although it’s only transient,” observed John H. Alexander, MD, MHSc, Duke University, Durham, N.C., one of the two panelists who voted to recommend approval of vernakalant.
“And, there clearly is a serious safety signal in some populations of patients,” he agreed. “However, I was more reassured by the SPECTRUM data.” There is likely to be a low-risk group of patients for whom vernakalant could represent an important option that “outweighs the relatively low risk of serious complications,” Dr. Alexander said.
“So more work needs to be done to clarify who are the low risk patients where it would be favorable.”
Panelist Matthew Needleman, MD, Walter Reed National Military Medical Center, Bethesda, Md., also voted in favor of approval.
“We’ve all known patients with normal ejection fractions who keep coming in with symptomatic atrial fib, want to get out of it quickly, and get back to their lives. So having an option like this I think would be good for a very select group of patients,” Dr. Needleman said.
But the preinfusion checklist and other potential ways to select low-risk patients for vernakalant could potentially backfire, warned John M. Mandrola, MD, Baptist Medical Associates, Louisville, Ky., from the panel.
The FDA representatives had presented evidence that the drug can seriously depress ventricular function, and that the lower cardiac output is what leads to hypotension, he elaborated in an interview after the meeting.
If the checklist is used to exclude hemodynamically unstable patients from receiving vernakalant, he said, “Then you’re really giving this drug to relatively healthy patients for convenience, to decrease hospitalization or the hospital stay.”
The signal for substantial harm, Dr. Mandrola said, has to be balanced against that modest benefit.
Moreover, those in whom the drug doesn’t work may be left in a worse situation, he proposed. Only about half of patients are successfully converted on vernakalant, the company and FDA data suggested. The other half of patients who don’t achieve sinus rhythm on the drug still must face the significant hazards of depressed ejection fraction and hypotension, a high price to pay for an unsuccessful treatment.
Dr. Mandrola is Chief Cardiology Correspondent for theheart.org | Medscape Cardiology; his disclosure statement states no relevant financial relationships.
This article first appeared on Medscape.com.
for cardioversion of recent-onset atrial fibrillation (AFib).
It was the second time before an FDA advisory panel for vernakalant (Brinavess, Correvio International Sàrl), which the agency had declined to approve in 2008 due to safety concerns. That time, however, its advisors had given the agency a decidedly positive recommendation.
Since then, registry data collected for the drug’s resubmission seemed only to raise further safety issues, especially evidence that a single infusion may cause severe hypotension and suppress left ventricular function.
Some members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), including a number who voted against approval, expressed hopes for further research aimed at identifying specific AFib patient groups who might safely benefit from vernakalant.
Of note, the drug has long been available for AFib cardioversion in Europe, where there are a number of other pharmacologic options, and was recently approved in Canada.
“We do recognize there’s a significant clinical need here,” observed Paul M. Ridker, MD, MPH, of Harvard Medical School and Brigham and Women’s Hospital Boston, a CRDAC panelist.
The results of the safety study that Correvio presented to the panel were “pretty marginal,” Dr. Ridker said. Given the negative safety signals and the available cardioversion alternatives, he questioned whether vernakalant represented a “substantial advance versus just another option. Right now, I’m not convinced it’s a substantial advance.”
FDA representatives were skeptical about vernakalant when they walked into the meeting room, as noted in briefing documents they had circulated beforehand. The drug’s safety experience under consideration included one case of ventricular arrhythmia and cardiogenic shock in a treated patient without apparent structural heart disease, who subsequently died. That case was much discussed throughout the meeting.
In its resubmission of vernakalant to regulators, Correvio also pointed to a significant unmet need for AFib cardioversion options in the United States, given the few alternatives.
For example, ibutilide is FDA-approved for recent-onset AFib or atrial flutter; but as the company and panelists noted, the drug isn’t often used for that indication. Patients with recent-onset AFib are often put on rate-control meds without cardioversion. Or clinicians may resort to electrical cardioversion, which can be logistically cumbersome and require anesthesia and generally a hospital stay.
Oral or intravenous amiodarone and oral dofetilide, flecainide, and propafenone are guideline-recommended but not actually FDA-approved for recent-onset AFib, the company noted.
Correvio made its “pre-infusion checklist” a core feature of its case. It was designed to guide selection of patients for vernakalant cardioversion based on contraindications such as a systolic blood pressure under 100 mm Hg, severe heart failure, aortic stenosis, severe bradycardia or heart block, or a prolonged QT interval.
In his presentation to the panel, FDA medical officer Preston Dunnmon, MD, said the safety results from the SPECTRUM registry, another main pillar of support for the vernakalant resubmission, “are not reassuring.”
As reasons, Dr. Dunnmon cited likely patient-selection bias and its high proportion of patients who were not prospectively enrolled; 21% were retrospectively entered from records.
Moreover, “the proposed preinfusion checklist will not reliably predict which subjects will experience serious cardiovascular adverse events with vernakalant,” he said.
“Vernakalant has induced harm that cannot be reliably predicted, prevented, or in some cases, treated. In contrast to vernakalant, electrical cardioversion and ibutilide pharmacologic cardioversion can cause adverse events, but these are transient and treatable,” he said.
Many on the panel agreed. “I thought the totality of evidence supported the hypothesis that this drug has a potential for a fatal side effect in a disease that you can live with, potentially, and that there are other treatments for,” said Julia B. Lewis, MD, Vanderbilt Medical Center, Nashville, Tenn., who chaired the CRDAC panel.
“The drug clearly converts atrial fibrillation, although it’s only transient,” observed John H. Alexander, MD, MHSc, Duke University, Durham, N.C., one of the two panelists who voted to recommend approval of vernakalant.
“And, there clearly is a serious safety signal in some populations of patients,” he agreed. “However, I was more reassured by the SPECTRUM data.” There is likely to be a low-risk group of patients for whom vernakalant could represent an important option that “outweighs the relatively low risk of serious complications,” Dr. Alexander said.
“So more work needs to be done to clarify who are the low risk patients where it would be favorable.”
Panelist Matthew Needleman, MD, Walter Reed National Military Medical Center, Bethesda, Md., also voted in favor of approval.
“We’ve all known patients with normal ejection fractions who keep coming in with symptomatic atrial fib, want to get out of it quickly, and get back to their lives. So having an option like this I think would be good for a very select group of patients,” Dr. Needleman said.
But the preinfusion checklist and other potential ways to select low-risk patients for vernakalant could potentially backfire, warned John M. Mandrola, MD, Baptist Medical Associates, Louisville, Ky., from the panel.
The FDA representatives had presented evidence that the drug can seriously depress ventricular function, and that the lower cardiac output is what leads to hypotension, he elaborated in an interview after the meeting.
If the checklist is used to exclude hemodynamically unstable patients from receiving vernakalant, he said, “Then you’re really giving this drug to relatively healthy patients for convenience, to decrease hospitalization or the hospital stay.”
The signal for substantial harm, Dr. Mandrola said, has to be balanced against that modest benefit.
Moreover, those in whom the drug doesn’t work may be left in a worse situation, he proposed. Only about half of patients are successfully converted on vernakalant, the company and FDA data suggested. The other half of patients who don’t achieve sinus rhythm on the drug still must face the significant hazards of depressed ejection fraction and hypotension, a high price to pay for an unsuccessful treatment.
Dr. Mandrola is Chief Cardiology Correspondent for theheart.org | Medscape Cardiology; his disclosure statement states no relevant financial relationships.
This article first appeared on Medscape.com.
for cardioversion of recent-onset atrial fibrillation (AFib).
It was the second time before an FDA advisory panel for vernakalant (Brinavess, Correvio International Sàrl), which the agency had declined to approve in 2008 due to safety concerns. That time, however, its advisors had given the agency a decidedly positive recommendation.
Since then, registry data collected for the drug’s resubmission seemed only to raise further safety issues, especially evidence that a single infusion may cause severe hypotension and suppress left ventricular function.
Some members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), including a number who voted against approval, expressed hopes for further research aimed at identifying specific AFib patient groups who might safely benefit from vernakalant.
Of note, the drug has long been available for AFib cardioversion in Europe, where there are a number of other pharmacologic options, and was recently approved in Canada.
“We do recognize there’s a significant clinical need here,” observed Paul M. Ridker, MD, MPH, of Harvard Medical School and Brigham and Women’s Hospital Boston, a CRDAC panelist.
The results of the safety study that Correvio presented to the panel were “pretty marginal,” Dr. Ridker said. Given the negative safety signals and the available cardioversion alternatives, he questioned whether vernakalant represented a “substantial advance versus just another option. Right now, I’m not convinced it’s a substantial advance.”
FDA representatives were skeptical about vernakalant when they walked into the meeting room, as noted in briefing documents they had circulated beforehand. The drug’s safety experience under consideration included one case of ventricular arrhythmia and cardiogenic shock in a treated patient without apparent structural heart disease, who subsequently died. That case was much discussed throughout the meeting.
In its resubmission of vernakalant to regulators, Correvio also pointed to a significant unmet need for AFib cardioversion options in the United States, given the few alternatives.
For example, ibutilide is FDA-approved for recent-onset AFib or atrial flutter; but as the company and panelists noted, the drug isn’t often used for that indication. Patients with recent-onset AFib are often put on rate-control meds without cardioversion. Or clinicians may resort to electrical cardioversion, which can be logistically cumbersome and require anesthesia and generally a hospital stay.
Oral or intravenous amiodarone and oral dofetilide, flecainide, and propafenone are guideline-recommended but not actually FDA-approved for recent-onset AFib, the company noted.
Correvio made its “pre-infusion checklist” a core feature of its case. It was designed to guide selection of patients for vernakalant cardioversion based on contraindications such as a systolic blood pressure under 100 mm Hg, severe heart failure, aortic stenosis, severe bradycardia or heart block, or a prolonged QT interval.
In his presentation to the panel, FDA medical officer Preston Dunnmon, MD, said the safety results from the SPECTRUM registry, another main pillar of support for the vernakalant resubmission, “are not reassuring.”
As reasons, Dr. Dunnmon cited likely patient-selection bias and its high proportion of patients who were not prospectively enrolled; 21% were retrospectively entered from records.
Moreover, “the proposed preinfusion checklist will not reliably predict which subjects will experience serious cardiovascular adverse events with vernakalant,” he said.
“Vernakalant has induced harm that cannot be reliably predicted, prevented, or in some cases, treated. In contrast to vernakalant, electrical cardioversion and ibutilide pharmacologic cardioversion can cause adverse events, but these are transient and treatable,” he said.
Many on the panel agreed. “I thought the totality of evidence supported the hypothesis that this drug has a potential for a fatal side effect in a disease that you can live with, potentially, and that there are other treatments for,” said Julia B. Lewis, MD, Vanderbilt Medical Center, Nashville, Tenn., who chaired the CRDAC panel.
“The drug clearly converts atrial fibrillation, although it’s only transient,” observed John H. Alexander, MD, MHSc, Duke University, Durham, N.C., one of the two panelists who voted to recommend approval of vernakalant.
“And, there clearly is a serious safety signal in some populations of patients,” he agreed. “However, I was more reassured by the SPECTRUM data.” There is likely to be a low-risk group of patients for whom vernakalant could represent an important option that “outweighs the relatively low risk of serious complications,” Dr. Alexander said.
“So more work needs to be done to clarify who are the low risk patients where it would be favorable.”
Panelist Matthew Needleman, MD, Walter Reed National Military Medical Center, Bethesda, Md., also voted in favor of approval.
“We’ve all known patients with normal ejection fractions who keep coming in with symptomatic atrial fib, want to get out of it quickly, and get back to their lives. So having an option like this I think would be good for a very select group of patients,” Dr. Needleman said.
But the preinfusion checklist and other potential ways to select low-risk patients for vernakalant could potentially backfire, warned John M. Mandrola, MD, Baptist Medical Associates, Louisville, Ky., from the panel.
The FDA representatives had presented evidence that the drug can seriously depress ventricular function, and that the lower cardiac output is what leads to hypotension, he elaborated in an interview after the meeting.
If the checklist is used to exclude hemodynamically unstable patients from receiving vernakalant, he said, “Then you’re really giving this drug to relatively healthy patients for convenience, to decrease hospitalization or the hospital stay.”
The signal for substantial harm, Dr. Mandrola said, has to be balanced against that modest benefit.
Moreover, those in whom the drug doesn’t work may be left in a worse situation, he proposed. Only about half of patients are successfully converted on vernakalant, the company and FDA data suggested. The other half of patients who don’t achieve sinus rhythm on the drug still must face the significant hazards of depressed ejection fraction and hypotension, a high price to pay for an unsuccessful treatment.
Dr. Mandrola is Chief Cardiology Correspondent for theheart.org | Medscape Cardiology; his disclosure statement states no relevant financial relationships.
This article first appeared on Medscape.com.
Genetic test stratified AFib patients with low CHA2DS2-VASc scores
PHILADELPHIA – A 32-gene screening test for stroke risk identified a subgroup of atrial fibrillation (AFib) patients with an elevated rate of ischemic strokes despite having a low stroke risk by conventional criteria by their CHA2DS2-VASc score in a post-hoc analysis of more than 11,000 patients enrolled in a recent drug trial.
Overall, AFib patients in the highest tertile for genetic risk based on a 32 gene-loci test had a 31% increase rate of ischemic stroke during a median 2.8 years of follow-up compared with patients in the tertile with the lowest risk based on the 32-loci screen, Nicholas A. Marston, MD, said at the American Heart Association scientific sessions. This suggested that the genetic test had roughly the same association with an increased stroke risk as several components of the CHA2DS2-VASc score, such as female sex, an age of 65-74 years old, or having heart failure as a comorbidity, each of which links with an increased risk for ischemic stroke of about 31%-38%, Dr. Marston noted.
The genetic test produced even sharper discrimination among the patients with the lowest stroke risk as measured by their CHA2DS2-VASc score (Circulation. 2012 Aug 14;126[7]: 860-5). Among the slightly more than 3,000 patients in the study with a CHA2DS2-VASc score of three or less, those in the subgroup with the highest risk by the 32-loci screen had a stroke rate during follow-up that was 76% higher than those in the low or intermediate tertile for their genetic score. Among the 796 patients with a CHA2DS2-VASc score of just 1 or 2, those who also fell into the highest level of risk on the 32-loci screen had a stroke rate 3.5-fold higher than those with a similar CHA2DS2-VASc score but in the low and intermediate tertiles by the 32-loci screen.
The additional risk prediction provided by the 32-loci test was statistically significant in the analysis of the 3,071 patients with a CHA2DS2-VASc score of 3 or less after adjustment for age, sex, ancestry, and the individual components of the CHA2DS2-VASc score, which includes factors such as hypertension, diabetes, and heart failure, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. The 3.5-fold elevation among patients with a high genetic-risk score in the cohort of 796 patients with a CHA2DS2-VASc score of 1 or 2 just missed statistical significance (P = .06), possibly because the number of patients in the analysis was relatively low. Future research should explore the predictive value of the genetic risk score in patients with a CHA2DS2-VASc score of 0 or 1, the “group where therapeutic decisions could be altered” depending on the genetic risk score, he explained.
Dr. Marston and his associates used data collected in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial, which was designed to assess the safety and efficacy of the direct-acting oral anticoagulant edoxaban in patients with AFib (New Engl J Med. 2013 Nov 28; 369[21]: 2091-2104). The 32-loci panel to measure a person’s genetic risk for stroke came from a 2018 report by a multinational team of researchers (Nature Genetics. 2018 Apr;50[4]: 524-37). The new analysis applied this 32-loci genetic test panel to 11.164 unrelated AFib patients with European ancestry from the ENGAGE AF-TIMIT 48 database. They divided this cohort into tertiles based on having a low, intermediate, or high stroke risk as assessed by the 32-loci genetic test. The analysis focused on patients enrolled in the trial who had European ancestry because the 32-loci screening test relied predominantly on data collected from people with this genetic background, Dr. Marston said.
SOURCE: Marston NA et al. AHA 2019, Abstract 336.
PHILADELPHIA – A 32-gene screening test for stroke risk identified a subgroup of atrial fibrillation (AFib) patients with an elevated rate of ischemic strokes despite having a low stroke risk by conventional criteria by their CHA2DS2-VASc score in a post-hoc analysis of more than 11,000 patients enrolled in a recent drug trial.
Overall, AFib patients in the highest tertile for genetic risk based on a 32 gene-loci test had a 31% increase rate of ischemic stroke during a median 2.8 years of follow-up compared with patients in the tertile with the lowest risk based on the 32-loci screen, Nicholas A. Marston, MD, said at the American Heart Association scientific sessions. This suggested that the genetic test had roughly the same association with an increased stroke risk as several components of the CHA2DS2-VASc score, such as female sex, an age of 65-74 years old, or having heart failure as a comorbidity, each of which links with an increased risk for ischemic stroke of about 31%-38%, Dr. Marston noted.
The genetic test produced even sharper discrimination among the patients with the lowest stroke risk as measured by their CHA2DS2-VASc score (Circulation. 2012 Aug 14;126[7]: 860-5). Among the slightly more than 3,000 patients in the study with a CHA2DS2-VASc score of three or less, those in the subgroup with the highest risk by the 32-loci screen had a stroke rate during follow-up that was 76% higher than those in the low or intermediate tertile for their genetic score. Among the 796 patients with a CHA2DS2-VASc score of just 1 or 2, those who also fell into the highest level of risk on the 32-loci screen had a stroke rate 3.5-fold higher than those with a similar CHA2DS2-VASc score but in the low and intermediate tertiles by the 32-loci screen.
The additional risk prediction provided by the 32-loci test was statistically significant in the analysis of the 3,071 patients with a CHA2DS2-VASc score of 3 or less after adjustment for age, sex, ancestry, and the individual components of the CHA2DS2-VASc score, which includes factors such as hypertension, diabetes, and heart failure, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. The 3.5-fold elevation among patients with a high genetic-risk score in the cohort of 796 patients with a CHA2DS2-VASc score of 1 or 2 just missed statistical significance (P = .06), possibly because the number of patients in the analysis was relatively low. Future research should explore the predictive value of the genetic risk score in patients with a CHA2DS2-VASc score of 0 or 1, the “group where therapeutic decisions could be altered” depending on the genetic risk score, he explained.
Dr. Marston and his associates used data collected in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial, which was designed to assess the safety and efficacy of the direct-acting oral anticoagulant edoxaban in patients with AFib (New Engl J Med. 2013 Nov 28; 369[21]: 2091-2104). The 32-loci panel to measure a person’s genetic risk for stroke came from a 2018 report by a multinational team of researchers (Nature Genetics. 2018 Apr;50[4]: 524-37). The new analysis applied this 32-loci genetic test panel to 11.164 unrelated AFib patients with European ancestry from the ENGAGE AF-TIMIT 48 database. They divided this cohort into tertiles based on having a low, intermediate, or high stroke risk as assessed by the 32-loci genetic test. The analysis focused on patients enrolled in the trial who had European ancestry because the 32-loci screening test relied predominantly on data collected from people with this genetic background, Dr. Marston said.
SOURCE: Marston NA et al. AHA 2019, Abstract 336.
PHILADELPHIA – A 32-gene screening test for stroke risk identified a subgroup of atrial fibrillation (AFib) patients with an elevated rate of ischemic strokes despite having a low stroke risk by conventional criteria by their CHA2DS2-VASc score in a post-hoc analysis of more than 11,000 patients enrolled in a recent drug trial.
Overall, AFib patients in the highest tertile for genetic risk based on a 32 gene-loci test had a 31% increase rate of ischemic stroke during a median 2.8 years of follow-up compared with patients in the tertile with the lowest risk based on the 32-loci screen, Nicholas A. Marston, MD, said at the American Heart Association scientific sessions. This suggested that the genetic test had roughly the same association with an increased stroke risk as several components of the CHA2DS2-VASc score, such as female sex, an age of 65-74 years old, or having heart failure as a comorbidity, each of which links with an increased risk for ischemic stroke of about 31%-38%, Dr. Marston noted.
The genetic test produced even sharper discrimination among the patients with the lowest stroke risk as measured by their CHA2DS2-VASc score (Circulation. 2012 Aug 14;126[7]: 860-5). Among the slightly more than 3,000 patients in the study with a CHA2DS2-VASc score of three or less, those in the subgroup with the highest risk by the 32-loci screen had a stroke rate during follow-up that was 76% higher than those in the low or intermediate tertile for their genetic score. Among the 796 patients with a CHA2DS2-VASc score of just 1 or 2, those who also fell into the highest level of risk on the 32-loci screen had a stroke rate 3.5-fold higher than those with a similar CHA2DS2-VASc score but in the low and intermediate tertiles by the 32-loci screen.
The additional risk prediction provided by the 32-loci test was statistically significant in the analysis of the 3,071 patients with a CHA2DS2-VASc score of 3 or less after adjustment for age, sex, ancestry, and the individual components of the CHA2DS2-VASc score, which includes factors such as hypertension, diabetes, and heart failure, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. The 3.5-fold elevation among patients with a high genetic-risk score in the cohort of 796 patients with a CHA2DS2-VASc score of 1 or 2 just missed statistical significance (P = .06), possibly because the number of patients in the analysis was relatively low. Future research should explore the predictive value of the genetic risk score in patients with a CHA2DS2-VASc score of 0 or 1, the “group where therapeutic decisions could be altered” depending on the genetic risk score, he explained.
Dr. Marston and his associates used data collected in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial, which was designed to assess the safety and efficacy of the direct-acting oral anticoagulant edoxaban in patients with AFib (New Engl J Med. 2013 Nov 28; 369[21]: 2091-2104). The 32-loci panel to measure a person’s genetic risk for stroke came from a 2018 report by a multinational team of researchers (Nature Genetics. 2018 Apr;50[4]: 524-37). The new analysis applied this 32-loci genetic test panel to 11.164 unrelated AFib patients with European ancestry from the ENGAGE AF-TIMIT 48 database. They divided this cohort into tertiles based on having a low, intermediate, or high stroke risk as assessed by the 32-loci genetic test. The analysis focused on patients enrolled in the trial who had European ancestry because the 32-loci screening test relied predominantly on data collected from people with this genetic background, Dr. Marston said.
SOURCE: Marston NA et al. AHA 2019, Abstract 336.
REPORTING FROM AHA 2019
Uncertain generalizability limits AFib ablation in HFrEF
Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.
Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.
The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.
“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”
CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.
“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.
During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).
Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).
“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.
Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.
“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.
The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.
The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.
This is part 2 of a 2-part story. See part 1 here.
Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.
Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.
The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.
“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”
CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.
“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.
During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).
Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).
“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.
Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.
“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.
The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.
The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.
This is part 2 of a 2-part story. See part 1 here.
Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.
Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.
The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.
“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”
CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.
“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.
During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).
Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).
“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.
Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.
“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.
The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.
The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.
This is part 2 of a 2-part story. See part 1 here.
Cardiac arrests peak with pollution in Japan
PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.
“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.
The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).
“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.
What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.
From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).
“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”
The average daily concentration for PM2.5 was 13.9/m3 across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m3). A 10-mcg/m3 increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.
“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.
The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m3 day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.
PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.
“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.
Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.
SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.
“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.
The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).
“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.
What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.
From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).
“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”
The average daily concentration for PM2.5 was 13.9/m3 across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m3). A 10-mcg/m3 increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.
“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.
The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m3 day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.
PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.
“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.
Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.
SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.
“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.
The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).
“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.
What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.
From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).
“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”
The average daily concentration for PM2.5 was 13.9/m3 across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m3). A 10-mcg/m3 increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.
“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.
The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m3 day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.
PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.
“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.
Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.
SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.
REPORTING FROM AHA 2019