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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
Score predicts surgery’s benefits for obesity, diabetes
LAS VEGAS –
The Individualized Diabetes Complications risk score “can provide personalized, evidence-based risk information for patients with type 2 diabetes and obesity about their future cardiovascular disease outcomes and mortality with and without metabolic surgery,” Ali Aminian, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Although the calculator needs validation in a prospective, randomized study to document its impact on practice, it is now available on two separate websites and as a downloadable app, said Dr. Aminian, a surgeon at the Cleveland Clinic.
The calculator inputs data for 26 distinct, “readily available” demographic and clinical entries, and based on that, estimates the patient’s 10-year risk for all-cause death, diabetic kidney disease, cerebrovascular disease, heart failure, and coronary artery disease if no surgery occurs or after some type of metabolic or bariatric surgery. The calculator does not currently have the ability to individualize predicted risks based on the specific type of metabolic surgery performed, but that is planned as a future refinement of the score.
“We validated the model in the nonsurgical patients, which showed it was very accurate. The next step is to run a randomized trial to see how useful the calculator is” for assisting in patients’ decision making, Dr. Aminian said.
The data for deriving the risk calculator, and for a preliminary validation of it, came from 13,722 patients with obesity (body mass index, 30 kg/m2 or greater) and type 2 diabetes, who were managed at the Cleveland Clinic during 1998-2017, drawn from more than 287,000 such patients in the clinic’s database. The study focused on 2,287 patients who underwent metabolic (bariatric) surgery and 11,435 patients from the same database who did not have surgery and matched by propensity scoring on a 5:1 basis with those who had surgery. The two cohorts this created matched well for age (about 54 years), sex (about two-thirds women), BMI (about 44 kg/m2), and the prevalence of various comorbidities at baseline.
Dr. Aminian and associates then analyzed the incidence of all-cause mortality and various cardiovascular disease endpoints, as well as nephropathy during follow-up, through December 2018. Patients who had undergone metabolic surgery showed statistically significant reductions in the incidence of each of those events, compared with patients who did not have surgery (JAMA. 2019;322[13]:1271-82).The investigators used these findings to create their model for calculating a patient’s risk score. For example, to calculate an estimate for the 10-year risk from all-cause mortality, the results showed that the most powerful risk factors were age, baseline body mass index, heart failure, need for insulin, and smoking status. For the endpoint of nephropathy, the most important factors were estimated glomerular filtration rate at baseline and age. Identified risk factors could account for about 80% of the 10-year risk for all-cause death and for about 75% of the risk for developing nephropathy during 10 years, based on the area-under-the-curve values the model produced.
The calculator is available at a website maintained by the Cleveland Clinic, at a site of the American Society for Metabolic and Bariatric Surgery, and in app stores, he said.
The work was partially funded by Medtronic. Dr. Aminian has received grants from Medtronic.
The AGA Practice guide on Obesity and Weight management, Education and Resources (POWER) white paper provides physicians with a comprehensive, multidisciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at www.gastro.org/obesity.
SOURCE: Aminian A et al. Obesity Week 2019, Abstract A101.
LAS VEGAS –
The Individualized Diabetes Complications risk score “can provide personalized, evidence-based risk information for patients with type 2 diabetes and obesity about their future cardiovascular disease outcomes and mortality with and without metabolic surgery,” Ali Aminian, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Although the calculator needs validation in a prospective, randomized study to document its impact on practice, it is now available on two separate websites and as a downloadable app, said Dr. Aminian, a surgeon at the Cleveland Clinic.
The calculator inputs data for 26 distinct, “readily available” demographic and clinical entries, and based on that, estimates the patient’s 10-year risk for all-cause death, diabetic kidney disease, cerebrovascular disease, heart failure, and coronary artery disease if no surgery occurs or after some type of metabolic or bariatric surgery. The calculator does not currently have the ability to individualize predicted risks based on the specific type of metabolic surgery performed, but that is planned as a future refinement of the score.
“We validated the model in the nonsurgical patients, which showed it was very accurate. The next step is to run a randomized trial to see how useful the calculator is” for assisting in patients’ decision making, Dr. Aminian said.
The data for deriving the risk calculator, and for a preliminary validation of it, came from 13,722 patients with obesity (body mass index, 30 kg/m2 or greater) and type 2 diabetes, who were managed at the Cleveland Clinic during 1998-2017, drawn from more than 287,000 such patients in the clinic’s database. The study focused on 2,287 patients who underwent metabolic (bariatric) surgery and 11,435 patients from the same database who did not have surgery and matched by propensity scoring on a 5:1 basis with those who had surgery. The two cohorts this created matched well for age (about 54 years), sex (about two-thirds women), BMI (about 44 kg/m2), and the prevalence of various comorbidities at baseline.
Dr. Aminian and associates then analyzed the incidence of all-cause mortality and various cardiovascular disease endpoints, as well as nephropathy during follow-up, through December 2018. Patients who had undergone metabolic surgery showed statistically significant reductions in the incidence of each of those events, compared with patients who did not have surgery (JAMA. 2019;322[13]:1271-82).The investigators used these findings to create their model for calculating a patient’s risk score. For example, to calculate an estimate for the 10-year risk from all-cause mortality, the results showed that the most powerful risk factors were age, baseline body mass index, heart failure, need for insulin, and smoking status. For the endpoint of nephropathy, the most important factors were estimated glomerular filtration rate at baseline and age. Identified risk factors could account for about 80% of the 10-year risk for all-cause death and for about 75% of the risk for developing nephropathy during 10 years, based on the area-under-the-curve values the model produced.
The calculator is available at a website maintained by the Cleveland Clinic, at a site of the American Society for Metabolic and Bariatric Surgery, and in app stores, he said.
The work was partially funded by Medtronic. Dr. Aminian has received grants from Medtronic.
The AGA Practice guide on Obesity and Weight management, Education and Resources (POWER) white paper provides physicians with a comprehensive, multidisciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at www.gastro.org/obesity.
SOURCE: Aminian A et al. Obesity Week 2019, Abstract A101.
LAS VEGAS –
The Individualized Diabetes Complications risk score “can provide personalized, evidence-based risk information for patients with type 2 diabetes and obesity about their future cardiovascular disease outcomes and mortality with and without metabolic surgery,” Ali Aminian, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Although the calculator needs validation in a prospective, randomized study to document its impact on practice, it is now available on two separate websites and as a downloadable app, said Dr. Aminian, a surgeon at the Cleveland Clinic.
The calculator inputs data for 26 distinct, “readily available” demographic and clinical entries, and based on that, estimates the patient’s 10-year risk for all-cause death, diabetic kidney disease, cerebrovascular disease, heart failure, and coronary artery disease if no surgery occurs or after some type of metabolic or bariatric surgery. The calculator does not currently have the ability to individualize predicted risks based on the specific type of metabolic surgery performed, but that is planned as a future refinement of the score.
“We validated the model in the nonsurgical patients, which showed it was very accurate. The next step is to run a randomized trial to see how useful the calculator is” for assisting in patients’ decision making, Dr. Aminian said.
The data for deriving the risk calculator, and for a preliminary validation of it, came from 13,722 patients with obesity (body mass index, 30 kg/m2 or greater) and type 2 diabetes, who were managed at the Cleveland Clinic during 1998-2017, drawn from more than 287,000 such patients in the clinic’s database. The study focused on 2,287 patients who underwent metabolic (bariatric) surgery and 11,435 patients from the same database who did not have surgery and matched by propensity scoring on a 5:1 basis with those who had surgery. The two cohorts this created matched well for age (about 54 years), sex (about two-thirds women), BMI (about 44 kg/m2), and the prevalence of various comorbidities at baseline.
Dr. Aminian and associates then analyzed the incidence of all-cause mortality and various cardiovascular disease endpoints, as well as nephropathy during follow-up, through December 2018. Patients who had undergone metabolic surgery showed statistically significant reductions in the incidence of each of those events, compared with patients who did not have surgery (JAMA. 2019;322[13]:1271-82).The investigators used these findings to create their model for calculating a patient’s risk score. For example, to calculate an estimate for the 10-year risk from all-cause mortality, the results showed that the most powerful risk factors were age, baseline body mass index, heart failure, need for insulin, and smoking status. For the endpoint of nephropathy, the most important factors were estimated glomerular filtration rate at baseline and age. Identified risk factors could account for about 80% of the 10-year risk for all-cause death and for about 75% of the risk for developing nephropathy during 10 years, based on the area-under-the-curve values the model produced.
The calculator is available at a website maintained by the Cleveland Clinic, at a site of the American Society for Metabolic and Bariatric Surgery, and in app stores, he said.
The work was partially funded by Medtronic. Dr. Aminian has received grants from Medtronic.
The AGA Practice guide on Obesity and Weight management, Education and Resources (POWER) white paper provides physicians with a comprehensive, multidisciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at www.gastro.org/obesity.
SOURCE: Aminian A et al. Obesity Week 2019, Abstract A101.
Catheter cryoablation effective for persistent AFib in pivotal trial
NATIONAL HARBOR, MD. – , setting the stage for the device to become the first to receive U.S. labeling for catheter ablation in this atrial fibrillation population.
The Arctic Front Advance cryoballoon, used on 165 patients with persistent atrial fibrillation (AFib) enrolled in the trial, produced a 55% rate of treatment success, including freedom from recurrent AFib during 12 months of follow-up, and produced one prespecified serious adverse event in the primary safety endpoint.
Both results easily surpassed the prespecified performance goals set by negotiation with the FDA, Hugh Calkins, MD, said at the annual International AF Symposium. The trial design included no control group and instead assessed safety and efficacy against prespecified standards set by the regulatory agency.
The cryoballoon “showed excellent performance. I don’t see how this could possibly be turned down by the FDA,” said Dr. Calkins, professor of medicine and director of the cardiac arrhythmia service at Johns Hopkins Medicine in Baltimore.
Cardiac electrophysiologists have for years routinely performed catheter ablation procedures on patients with persistent AFib even though the devices, based on ablation by radiofrequency or by chilling, have been labeled for use only in treating patients with paroxysmal AFib. Although this off-label use has not resulted in any problems with health insurance coverage, Dr. Calkins said, it has kept manufacturers from marketing their ablation devices for use in persistent AFib patients.
If the reported data result in labeling for the tested cryoballoon for persistant AFib patients, “it will have a big impact,” he predicted. “People have used cryoballoons for ablating persistent AFib for years, but this would put more fuel in the fire, both the [very positive] safety and efficacy data, and getting an FDA label, which is worth a lot,” he said in an interview.
But Dr. Calkins stopped short of anticipating that the results would convince operators experienced and focused on performing radiofrequency ablation to switch to cryo devices for treating persistent AFib patients. “People are pretty stuck in their ways,” he noted, and reports are expected soon from pivotal trials that are now testing various radiofrequency devices, as well as other types of cryo devices, in persistent AFib patients, so the range of device options labeled for this population may soon grow even more.
The STOP Persistent AF trial ran at 25 sites in the United States, Canada, and Japan during March 2017-August 2019, and included 165 adults with symptomatic, persistent AFib who had not responded to at least one antiarrhythmic drug and had a history of AFib episodes lasting at least 7 days but with no episodes persisting for 6 months or longer. The study excluded patients with prior ablation or left atrial surgery, a recent cerebrovascular event, substantially reduced left ventricular function, or substantial left atrial enlargement.
The enrolled patients were an average 65 years of age and 70% were men. Patients had been diagnosed with paroxysmal AFib an average of 5 years before study entry and with persistent AFib a little over 6 months before entry. The most recent AFib episode of enrolled patients averaged about 60 days, on average they had been unsuccessfully treated with just over one antiarrhythmic drug, and on average they had previously undergone about two cardioversions, after which their arrhythmia recurred.
The primary efficacy endpoint – a 55% rate of acute procedural success plus freedom from AFib recurrence during the 9 months following a 90-day blanking period immediately after ablation plus no added or increased antiarrhythmic drugs – significantly exceeded the prespecified performance goal of a 40% rate, Dr. Calkins reported. The study used the standard measure of recurrence as any 30-second or longer AFib episode detected during a weekly ECG telemonitoring session or during 48-hour ambulatory ECG monitoring at 6- and 12-month follow-ups or during in-office 12-lead ECG assessment at 3-, 6-, and 12-month follow-up. Twelve-month follow-up occurred for 145 of the enrolled patients.
The only prespecified primary safety event was one episode of cardiac perforation, which occurred during a repeat procedure. This rate of one safety event among 165 patients (0.6%) fell well within the prespecified safety performance goal of no more than 13%. In addition to this perforation, five additional serious adverse events (3%) occurred that were attributable to the cryoballoon treatment, including two cases of vascular pseudoaneurysm, one puncture-site hematoma, one case of pericarditis, and one episode of atrial tachycardia. Four additional serious adverse events occurred that were attributable to the ablation procedure (one acute cardiac failure, one postprocedure ileus, one respiratory failure, and one urinary tract infection), for an overall serious event rate of 5%.
During follow-up, 13% of patients had a repeat ablation procedure, following an initial ablation limited to pulmonary-vein isolation (PVI). The overall rate of 1-year efficacy, including the relatively low rate of need for redo ablation, “are an impressive endorsement of a PVI-only strategy” for initial ablation, Dr. Calkins said. “I’m a strong believer in PVI only for the first ablation for both paroxysmal and persistent AFib.”
He also noted that the 30-second threshold for scoring recurrent arrhythmia episodes following the 90-day blanking period after ablation was a very conservative measure of treatment failure, but it continues to define recurrence in this and many other current AFib ablation studies because it is the historical criteria for measuring ablation success or failure. It is especially important to maintain this criteria in a study that relied on prespecified performance criteria rather than a control arm for judging efficacy, Dr. Calkins said.
The study also included three quality-of-life measures. Patient scores on the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire rose by an average of nearly 26 points from baseline to 12 months, a statistically significant and clinically meaningful increase. Scores on both the physical and mental domains of the Short Form-12 (SF-12) improved from baseline by an average of about five points on each subscale, also statistically significant and clinically meaningful changes. Patients also reported statistically significant and in some cases substantial reductions in the prevalence rates of each of five different AFib symptoms: dizziness, dyspnea, fatigue, palpitations, and rapid heartbeat.
The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
NATIONAL HARBOR, MD. – , setting the stage for the device to become the first to receive U.S. labeling for catheter ablation in this atrial fibrillation population.
The Arctic Front Advance cryoballoon, used on 165 patients with persistent atrial fibrillation (AFib) enrolled in the trial, produced a 55% rate of treatment success, including freedom from recurrent AFib during 12 months of follow-up, and produced one prespecified serious adverse event in the primary safety endpoint.
Both results easily surpassed the prespecified performance goals set by negotiation with the FDA, Hugh Calkins, MD, said at the annual International AF Symposium. The trial design included no control group and instead assessed safety and efficacy against prespecified standards set by the regulatory agency.
The cryoballoon “showed excellent performance. I don’t see how this could possibly be turned down by the FDA,” said Dr. Calkins, professor of medicine and director of the cardiac arrhythmia service at Johns Hopkins Medicine in Baltimore.
Cardiac electrophysiologists have for years routinely performed catheter ablation procedures on patients with persistent AFib even though the devices, based on ablation by radiofrequency or by chilling, have been labeled for use only in treating patients with paroxysmal AFib. Although this off-label use has not resulted in any problems with health insurance coverage, Dr. Calkins said, it has kept manufacturers from marketing their ablation devices for use in persistent AFib patients.
If the reported data result in labeling for the tested cryoballoon for persistant AFib patients, “it will have a big impact,” he predicted. “People have used cryoballoons for ablating persistent AFib for years, but this would put more fuel in the fire, both the [very positive] safety and efficacy data, and getting an FDA label, which is worth a lot,” he said in an interview.
But Dr. Calkins stopped short of anticipating that the results would convince operators experienced and focused on performing radiofrequency ablation to switch to cryo devices for treating persistent AFib patients. “People are pretty stuck in their ways,” he noted, and reports are expected soon from pivotal trials that are now testing various radiofrequency devices, as well as other types of cryo devices, in persistent AFib patients, so the range of device options labeled for this population may soon grow even more.
The STOP Persistent AF trial ran at 25 sites in the United States, Canada, and Japan during March 2017-August 2019, and included 165 adults with symptomatic, persistent AFib who had not responded to at least one antiarrhythmic drug and had a history of AFib episodes lasting at least 7 days but with no episodes persisting for 6 months or longer. The study excluded patients with prior ablation or left atrial surgery, a recent cerebrovascular event, substantially reduced left ventricular function, or substantial left atrial enlargement.
The enrolled patients were an average 65 years of age and 70% were men. Patients had been diagnosed with paroxysmal AFib an average of 5 years before study entry and with persistent AFib a little over 6 months before entry. The most recent AFib episode of enrolled patients averaged about 60 days, on average they had been unsuccessfully treated with just over one antiarrhythmic drug, and on average they had previously undergone about two cardioversions, after which their arrhythmia recurred.
The primary efficacy endpoint – a 55% rate of acute procedural success plus freedom from AFib recurrence during the 9 months following a 90-day blanking period immediately after ablation plus no added or increased antiarrhythmic drugs – significantly exceeded the prespecified performance goal of a 40% rate, Dr. Calkins reported. The study used the standard measure of recurrence as any 30-second or longer AFib episode detected during a weekly ECG telemonitoring session or during 48-hour ambulatory ECG monitoring at 6- and 12-month follow-ups or during in-office 12-lead ECG assessment at 3-, 6-, and 12-month follow-up. Twelve-month follow-up occurred for 145 of the enrolled patients.
The only prespecified primary safety event was one episode of cardiac perforation, which occurred during a repeat procedure. This rate of one safety event among 165 patients (0.6%) fell well within the prespecified safety performance goal of no more than 13%. In addition to this perforation, five additional serious adverse events (3%) occurred that were attributable to the cryoballoon treatment, including two cases of vascular pseudoaneurysm, one puncture-site hematoma, one case of pericarditis, and one episode of atrial tachycardia. Four additional serious adverse events occurred that were attributable to the ablation procedure (one acute cardiac failure, one postprocedure ileus, one respiratory failure, and one urinary tract infection), for an overall serious event rate of 5%.
During follow-up, 13% of patients had a repeat ablation procedure, following an initial ablation limited to pulmonary-vein isolation (PVI). The overall rate of 1-year efficacy, including the relatively low rate of need for redo ablation, “are an impressive endorsement of a PVI-only strategy” for initial ablation, Dr. Calkins said. “I’m a strong believer in PVI only for the first ablation for both paroxysmal and persistent AFib.”
He also noted that the 30-second threshold for scoring recurrent arrhythmia episodes following the 90-day blanking period after ablation was a very conservative measure of treatment failure, but it continues to define recurrence in this and many other current AFib ablation studies because it is the historical criteria for measuring ablation success or failure. It is especially important to maintain this criteria in a study that relied on prespecified performance criteria rather than a control arm for judging efficacy, Dr. Calkins said.
The study also included three quality-of-life measures. Patient scores on the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire rose by an average of nearly 26 points from baseline to 12 months, a statistically significant and clinically meaningful increase. Scores on both the physical and mental domains of the Short Form-12 (SF-12) improved from baseline by an average of about five points on each subscale, also statistically significant and clinically meaningful changes. Patients also reported statistically significant and in some cases substantial reductions in the prevalence rates of each of five different AFib symptoms: dizziness, dyspnea, fatigue, palpitations, and rapid heartbeat.
The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
NATIONAL HARBOR, MD. – , setting the stage for the device to become the first to receive U.S. labeling for catheter ablation in this atrial fibrillation population.
The Arctic Front Advance cryoballoon, used on 165 patients with persistent atrial fibrillation (AFib) enrolled in the trial, produced a 55% rate of treatment success, including freedom from recurrent AFib during 12 months of follow-up, and produced one prespecified serious adverse event in the primary safety endpoint.
Both results easily surpassed the prespecified performance goals set by negotiation with the FDA, Hugh Calkins, MD, said at the annual International AF Symposium. The trial design included no control group and instead assessed safety and efficacy against prespecified standards set by the regulatory agency.
The cryoballoon “showed excellent performance. I don’t see how this could possibly be turned down by the FDA,” said Dr. Calkins, professor of medicine and director of the cardiac arrhythmia service at Johns Hopkins Medicine in Baltimore.
Cardiac electrophysiologists have for years routinely performed catheter ablation procedures on patients with persistent AFib even though the devices, based on ablation by radiofrequency or by chilling, have been labeled for use only in treating patients with paroxysmal AFib. Although this off-label use has not resulted in any problems with health insurance coverage, Dr. Calkins said, it has kept manufacturers from marketing their ablation devices for use in persistent AFib patients.
If the reported data result in labeling for the tested cryoballoon for persistant AFib patients, “it will have a big impact,” he predicted. “People have used cryoballoons for ablating persistent AFib for years, but this would put more fuel in the fire, both the [very positive] safety and efficacy data, and getting an FDA label, which is worth a lot,” he said in an interview.
But Dr. Calkins stopped short of anticipating that the results would convince operators experienced and focused on performing radiofrequency ablation to switch to cryo devices for treating persistent AFib patients. “People are pretty stuck in their ways,” he noted, and reports are expected soon from pivotal trials that are now testing various radiofrequency devices, as well as other types of cryo devices, in persistent AFib patients, so the range of device options labeled for this population may soon grow even more.
The STOP Persistent AF trial ran at 25 sites in the United States, Canada, and Japan during March 2017-August 2019, and included 165 adults with symptomatic, persistent AFib who had not responded to at least one antiarrhythmic drug and had a history of AFib episodes lasting at least 7 days but with no episodes persisting for 6 months or longer. The study excluded patients with prior ablation or left atrial surgery, a recent cerebrovascular event, substantially reduced left ventricular function, or substantial left atrial enlargement.
The enrolled patients were an average 65 years of age and 70% were men. Patients had been diagnosed with paroxysmal AFib an average of 5 years before study entry and with persistent AFib a little over 6 months before entry. The most recent AFib episode of enrolled patients averaged about 60 days, on average they had been unsuccessfully treated with just over one antiarrhythmic drug, and on average they had previously undergone about two cardioversions, after which their arrhythmia recurred.
The primary efficacy endpoint – a 55% rate of acute procedural success plus freedom from AFib recurrence during the 9 months following a 90-day blanking period immediately after ablation plus no added or increased antiarrhythmic drugs – significantly exceeded the prespecified performance goal of a 40% rate, Dr. Calkins reported. The study used the standard measure of recurrence as any 30-second or longer AFib episode detected during a weekly ECG telemonitoring session or during 48-hour ambulatory ECG monitoring at 6- and 12-month follow-ups or during in-office 12-lead ECG assessment at 3-, 6-, and 12-month follow-up. Twelve-month follow-up occurred for 145 of the enrolled patients.
The only prespecified primary safety event was one episode of cardiac perforation, which occurred during a repeat procedure. This rate of one safety event among 165 patients (0.6%) fell well within the prespecified safety performance goal of no more than 13%. In addition to this perforation, five additional serious adverse events (3%) occurred that were attributable to the cryoballoon treatment, including two cases of vascular pseudoaneurysm, one puncture-site hematoma, one case of pericarditis, and one episode of atrial tachycardia. Four additional serious adverse events occurred that were attributable to the ablation procedure (one acute cardiac failure, one postprocedure ileus, one respiratory failure, and one urinary tract infection), for an overall serious event rate of 5%.
During follow-up, 13% of patients had a repeat ablation procedure, following an initial ablation limited to pulmonary-vein isolation (PVI). The overall rate of 1-year efficacy, including the relatively low rate of need for redo ablation, “are an impressive endorsement of a PVI-only strategy” for initial ablation, Dr. Calkins said. “I’m a strong believer in PVI only for the first ablation for both paroxysmal and persistent AFib.”
He also noted that the 30-second threshold for scoring recurrent arrhythmia episodes following the 90-day blanking period after ablation was a very conservative measure of treatment failure, but it continues to define recurrence in this and many other current AFib ablation studies because it is the historical criteria for measuring ablation success or failure. It is especially important to maintain this criteria in a study that relied on prespecified performance criteria rather than a control arm for judging efficacy, Dr. Calkins said.
The study also included three quality-of-life measures. Patient scores on the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire rose by an average of nearly 26 points from baseline to 12 months, a statistically significant and clinically meaningful increase. Scores on both the physical and mental domains of the Short Form-12 (SF-12) improved from baseline by an average of about five points on each subscale, also statistically significant and clinically meaningful changes. Patients also reported statistically significant and in some cases substantial reductions in the prevalence rates of each of five different AFib symptoms: dizziness, dyspnea, fatigue, palpitations, and rapid heartbeat.
The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
REPORTING FROM THE AF SYMPOSIUM 2020
Key clinical point: Catheter ablation using a cryoballoon was safe and effective for patients with persistent atrial fibrillation in a pivotal trial.
Major finding: The rate of freedom from treatment failure after 12 months was 55%, significantly exceeding the prespecified performance goal of 40%.
Study details: A multicenter, international study with 165 enrolled patients.
Disclosures: The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
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
Carbs, fat, and mortality: Types matter more than levels
The health consequences of diet don’t largely depend on whether a person eats a high or low level of carbohydrates or a diet high or low in fat. What’s much more important is where the carbs and fats come from, according to an analysis that related diet and mortality rates in more than 37,000 American adults.
“Unhealthy low carbohydrate diet [LCD] and low-fat diet [LFD] scores were associated with higher total mortality, whereas healthy LCD and LFD scores were associated with lower total mortality,” Zhilei Shan, MD, and associates wrote in an article (JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980). The findings “suggest that the association of LCDs and LFDs with mortality may depend on the quality of food sources of macronutrients,” said the researchers, based at the Harvard T.H. Chan School of Public Health in Boston.
The analysis included follow-up of almost 300,000 person-years. It showed that, for every 20-percentile increase in a person’s unhealthy LCD score, their relative rate of total mortality increased by a statistically significant 7%; and for every 20-percentile rise in unhealthy LFD score, the relative, total mortality rate rose by a statistically significant 6%, after adjustment for several demographic and clinical measures and family and personal histories of diabetes, cancer, and heart disease. In contrast, for each 20-percentile increase in healthy LCD score relative, total mortality fell by 9%, and similar increases in healthy LFD score linked with an 11% relative drop in total mortality, also statistically significant associations in these confounder-adjusted analyses.
The findings “extend the previous evidence” for these links, and the data suggest that “the health benefits of an LCD or LFD may depend not only on the types of protein and fat or carbohydrate but also on the quality of carbohydrate or fat remaining in the diet,” the researchers wrote. They cited the documented health problems caused by eating significant amounts of low-quality carbohydrates such as refined grains and added sugars, which provide limited nutrition and introduce a high glycemic load, and can produce high levels of postprandial glucose and insulin, inflammation, insulin resistance, and dyslipidemia.
The foods people ate that produced healthy diet scores and linked with better survival were diets high in plant protein and unsaturated fat, and low in carbohydrates from refined grains, added sugar, starchy vegetables, and similar sources as part of a low carbohydrate diet. The foods that formed a healthy LFD included whole grains, whole fruit, legumes, and nonstarchy vegetables, along with higher intake of plant protein and low levels of saturated fat.
The study used data from 24-hour diet-recall surveys completed by 37,233 American adults collected by the National Health and Nutrition Examination Survey (NHANES) during 1999-2014, and linked the diet scores calculated for these people with U.S. national death records collected by the National Death Index through the end of 2015. The people included averaged about 50 years of age at the time of their dietary interview, and 53% were women. During 297,768 person-years of follow-up, 4,866 total deaths occurred, including 849 from heart disease and 1,068 from cancer. The analyses found no statistically significant links between overall LCD or LFD scores and mortality; the significant links only existed when the researchers further classified the diet scores into healthy and unhealthy subtypes.
The results also showed statistically significant links or strong trends between high or low levels of healthy or unhealthy LCD and LFD scores and cancer deaths. A 20-percentile increase in unhealthy LCD score linked with an 11% relative increase in cancer deaths, while a 20-percentile increase in the healthy LCD score linked with a 10% decrease in cancer deaths. A 20-percentile increase in the healthy LFD score linked with a 15% relative decrease in cancer mortality.
The study received no commercial fundings, and the authors had no commercial disclosures.
SOURCE: Shan Z et al. JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980.
This is an important study because the findings reinforce the already established concept that it’s the quality of the fat and carbohydrate a person eats that matters for health, rather than the relative levels of these nutrients. Eating unsaturated fats and unprocessed carbohydrates like whole grains, fruits, and legumes produces the greatest health and survival, while higher levels of saturated fats and processed carbs in the diet produce health problems. That’s much more important than whether a diet is low fat or low carb. This means sticking with the food principles advanced by the AHA diet, the DASH diet, and a Mediterranean diet.
High-fat and low-carb diets are popular because people who follow them lose weight over the short term, but those weight losses are hard to sustain longer term and create an opportunity for unhealthy effects if people eat the wrong fats, carbohydrates, and proteins. Strategies that focus on healthier food choices like the Mediterranean or AHA diets can minimize disease and produce more sustainable weight control.
Robert A. Vogel, MD , is a cardiologist in Denver affiliated with the University of Colorado School of Medicine and the VA Medical Center in Denver. He has been a consultant to the Pritikin Longevity Institute in Doral, Fla. He made these comments in an interview.
This is an important study because the findings reinforce the already established concept that it’s the quality of the fat and carbohydrate a person eats that matters for health, rather than the relative levels of these nutrients. Eating unsaturated fats and unprocessed carbohydrates like whole grains, fruits, and legumes produces the greatest health and survival, while higher levels of saturated fats and processed carbs in the diet produce health problems. That’s much more important than whether a diet is low fat or low carb. This means sticking with the food principles advanced by the AHA diet, the DASH diet, and a Mediterranean diet.
High-fat and low-carb diets are popular because people who follow them lose weight over the short term, but those weight losses are hard to sustain longer term and create an opportunity for unhealthy effects if people eat the wrong fats, carbohydrates, and proteins. Strategies that focus on healthier food choices like the Mediterranean or AHA diets can minimize disease and produce more sustainable weight control.
Robert A. Vogel, MD , is a cardiologist in Denver affiliated with the University of Colorado School of Medicine and the VA Medical Center in Denver. He has been a consultant to the Pritikin Longevity Institute in Doral, Fla. He made these comments in an interview.
This is an important study because the findings reinforce the already established concept that it’s the quality of the fat and carbohydrate a person eats that matters for health, rather than the relative levels of these nutrients. Eating unsaturated fats and unprocessed carbohydrates like whole grains, fruits, and legumes produces the greatest health and survival, while higher levels of saturated fats and processed carbs in the diet produce health problems. That’s much more important than whether a diet is low fat or low carb. This means sticking with the food principles advanced by the AHA diet, the DASH diet, and a Mediterranean diet.
High-fat and low-carb diets are popular because people who follow them lose weight over the short term, but those weight losses are hard to sustain longer term and create an opportunity for unhealthy effects if people eat the wrong fats, carbohydrates, and proteins. Strategies that focus on healthier food choices like the Mediterranean or AHA diets can minimize disease and produce more sustainable weight control.
Robert A. Vogel, MD , is a cardiologist in Denver affiliated with the University of Colorado School of Medicine and the VA Medical Center in Denver. He has been a consultant to the Pritikin Longevity Institute in Doral, Fla. He made these comments in an interview.
The health consequences of diet don’t largely depend on whether a person eats a high or low level of carbohydrates or a diet high or low in fat. What’s much more important is where the carbs and fats come from, according to an analysis that related diet and mortality rates in more than 37,000 American adults.
“Unhealthy low carbohydrate diet [LCD] and low-fat diet [LFD] scores were associated with higher total mortality, whereas healthy LCD and LFD scores were associated with lower total mortality,” Zhilei Shan, MD, and associates wrote in an article (JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980). The findings “suggest that the association of LCDs and LFDs with mortality may depend on the quality of food sources of macronutrients,” said the researchers, based at the Harvard T.H. Chan School of Public Health in Boston.
The analysis included follow-up of almost 300,000 person-years. It showed that, for every 20-percentile increase in a person’s unhealthy LCD score, their relative rate of total mortality increased by a statistically significant 7%; and for every 20-percentile rise in unhealthy LFD score, the relative, total mortality rate rose by a statistically significant 6%, after adjustment for several demographic and clinical measures and family and personal histories of diabetes, cancer, and heart disease. In contrast, for each 20-percentile increase in healthy LCD score relative, total mortality fell by 9%, and similar increases in healthy LFD score linked with an 11% relative drop in total mortality, also statistically significant associations in these confounder-adjusted analyses.
The findings “extend the previous evidence” for these links, and the data suggest that “the health benefits of an LCD or LFD may depend not only on the types of protein and fat or carbohydrate but also on the quality of carbohydrate or fat remaining in the diet,” the researchers wrote. They cited the documented health problems caused by eating significant amounts of low-quality carbohydrates such as refined grains and added sugars, which provide limited nutrition and introduce a high glycemic load, and can produce high levels of postprandial glucose and insulin, inflammation, insulin resistance, and dyslipidemia.
The foods people ate that produced healthy diet scores and linked with better survival were diets high in plant protein and unsaturated fat, and low in carbohydrates from refined grains, added sugar, starchy vegetables, and similar sources as part of a low carbohydrate diet. The foods that formed a healthy LFD included whole grains, whole fruit, legumes, and nonstarchy vegetables, along with higher intake of plant protein and low levels of saturated fat.
The study used data from 24-hour diet-recall surveys completed by 37,233 American adults collected by the National Health and Nutrition Examination Survey (NHANES) during 1999-2014, and linked the diet scores calculated for these people with U.S. national death records collected by the National Death Index through the end of 2015. The people included averaged about 50 years of age at the time of their dietary interview, and 53% were women. During 297,768 person-years of follow-up, 4,866 total deaths occurred, including 849 from heart disease and 1,068 from cancer. The analyses found no statistically significant links between overall LCD or LFD scores and mortality; the significant links only existed when the researchers further classified the diet scores into healthy and unhealthy subtypes.
The results also showed statistically significant links or strong trends between high or low levels of healthy or unhealthy LCD and LFD scores and cancer deaths. A 20-percentile increase in unhealthy LCD score linked with an 11% relative increase in cancer deaths, while a 20-percentile increase in the healthy LCD score linked with a 10% decrease in cancer deaths. A 20-percentile increase in the healthy LFD score linked with a 15% relative decrease in cancer mortality.
The study received no commercial fundings, and the authors had no commercial disclosures.
SOURCE: Shan Z et al. JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980.
The health consequences of diet don’t largely depend on whether a person eats a high or low level of carbohydrates or a diet high or low in fat. What’s much more important is where the carbs and fats come from, according to an analysis that related diet and mortality rates in more than 37,000 American adults.
“Unhealthy low carbohydrate diet [LCD] and low-fat diet [LFD] scores were associated with higher total mortality, whereas healthy LCD and LFD scores were associated with lower total mortality,” Zhilei Shan, MD, and associates wrote in an article (JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980). The findings “suggest that the association of LCDs and LFDs with mortality may depend on the quality of food sources of macronutrients,” said the researchers, based at the Harvard T.H. Chan School of Public Health in Boston.
The analysis included follow-up of almost 300,000 person-years. It showed that, for every 20-percentile increase in a person’s unhealthy LCD score, their relative rate of total mortality increased by a statistically significant 7%; and for every 20-percentile rise in unhealthy LFD score, the relative, total mortality rate rose by a statistically significant 6%, after adjustment for several demographic and clinical measures and family and personal histories of diabetes, cancer, and heart disease. In contrast, for each 20-percentile increase in healthy LCD score relative, total mortality fell by 9%, and similar increases in healthy LFD score linked with an 11% relative drop in total mortality, also statistically significant associations in these confounder-adjusted analyses.
The findings “extend the previous evidence” for these links, and the data suggest that “the health benefits of an LCD or LFD may depend not only on the types of protein and fat or carbohydrate but also on the quality of carbohydrate or fat remaining in the diet,” the researchers wrote. They cited the documented health problems caused by eating significant amounts of low-quality carbohydrates such as refined grains and added sugars, which provide limited nutrition and introduce a high glycemic load, and can produce high levels of postprandial glucose and insulin, inflammation, insulin resistance, and dyslipidemia.
The foods people ate that produced healthy diet scores and linked with better survival were diets high in plant protein and unsaturated fat, and low in carbohydrates from refined grains, added sugar, starchy vegetables, and similar sources as part of a low carbohydrate diet. The foods that formed a healthy LFD included whole grains, whole fruit, legumes, and nonstarchy vegetables, along with higher intake of plant protein and low levels of saturated fat.
The study used data from 24-hour diet-recall surveys completed by 37,233 American adults collected by the National Health and Nutrition Examination Survey (NHANES) during 1999-2014, and linked the diet scores calculated for these people with U.S. national death records collected by the National Death Index through the end of 2015. The people included averaged about 50 years of age at the time of their dietary interview, and 53% were women. During 297,768 person-years of follow-up, 4,866 total deaths occurred, including 849 from heart disease and 1,068 from cancer. The analyses found no statistically significant links between overall LCD or LFD scores and mortality; the significant links only existed when the researchers further classified the diet scores into healthy and unhealthy subtypes.
The results also showed statistically significant links or strong trends between high or low levels of healthy or unhealthy LCD and LFD scores and cancer deaths. A 20-percentile increase in unhealthy LCD score linked with an 11% relative increase in cancer deaths, while a 20-percentile increase in the healthy LCD score linked with a 10% decrease in cancer deaths. A 20-percentile increase in the healthy LFD score linked with a 15% relative decrease in cancer mortality.
The study received no commercial fundings, and the authors had no commercial disclosures.
SOURCE: Shan Z et al. JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980.
REPORTING FROM JAMA INTERNAL MEDICINE
FDA advisers set high bar for new opioids
During an opioid-addiction epidemic, can any new opioid pain drug meet prevailing safety demands to gain regulatory approval?
On Jan. 14 and 15, a Food and Drug Administration advisory committee voted virtually unanimously against two new opioid formulations and evenly split for and against a third; the 2 days of data and discussion showed how high a bar new opioids face these days for getting onto the U.S. market.
The bar’s height is very understandable given how many Americans have become addicted to opioids over the past decade, more often than not by accident while using pain medications as they believed they had been directed, said experts during the sessions held on the FDA’s campus in White Oak, Md.
Among the many upshots of the opioid crisis, the meetings held to discuss these three contender opioids highlighted the bitter irony confronting attempts to bring new, safer opioids to the U.S. market: While less abusable pain-relief medications that still harness the potent analgesic power of mu opioid receptor agonists are desperately desired, new agents in this space now receive withering scrutiny over their safeguards against misuse and abuse, and over whether they add anything meaningfully new to what’s already available. While these demands seem reasonable, perhaps even essential, it’s unclear whether any new opioid-based pain drugs will ever fully meet the safety that researchers, clinicians, and the public now seek.
A special FDA advisory committee that combined the Anesthetic and Analgesic Drug Products Advisory Committee with members of the Drug Safety and Risk Management Advisory Committee considered the application for three different opioid drugs from three separate companies. None received a clear endorsement. Oxycodegol, a new type of orally delivered opioid molecule engineered to slow brain entry and thereby delay an abuser’s high, got voted down without any votes in favor and 27 votes against agency approval. Aximris XR, an extended-release oxycodone formulation that successfully deterred intravenous abuse but had no deterrence efficacy for intranasal or oral abuse failed by a 2-24 vote against. The third agent, CTC, a novel formulation of the schedule IV opioid tramadol with the NSAID celecoxib designed to be analgesic but with limited opioid-abuse appeal, came the closest to meaningful support with a tied 13-13 vote from advisory committee members for and against agency approval. FDA staff takes advisory committee opinions and votes into account when making their final decisions about drug marketing approvals.
In each case, the committee members, mostly the same roster assembled for each of the three agents, identified specific concerns with the data purported to show each drug’s safety and efficacy. But the gathered experts and consumer representatives also consistently cited holistic challenges to approving new opioids and the stiffer criteria these agents face amid a continuing wave of opioid misuse and abuse.
“In the context of the public health issues, we don’t want to be perceived in any way of taking shortcuts,” said Linda S. Tyler, PharmD,, an advisory committee member and professor of pharmacy and chief pharmacy officer at the University of Utah in Salt Lake City. “There is no question that for a new product to come to market in this space it needs to add to what’s on the market, meet a high bar, and provide advantages compared with what’s already on the market,” she said.
Tramadol plus celecoxib gains some support
The proposed combined formulation of tramadol and celecoxib came closest to meeting that bar, as far as the advisory committee was concerned, coming away with 13 votes favoring approval to match 13 votes against. The premise behind this agent, know as CTC (cocrystal of tramadol and celecoxib), was that it combined a modest dose (44 mg) of the schedule IV opioid tramadol with a 56-mg dose of celecoxib in a twice-daily pill. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia and a speaker at the session on behalf of the applicant company, spelled out the rationale behind CTC: “We are caught in a dilemma. We need to reduce opioid use, but we also need to treat pain. We have an urgent need to have pain treatment options that are effective but have low potential for abuse and dependence. We are looking at multimodal analgesia, that uses combination of agents, recognizing that postoperative pain is a mixed pain syndrome. Multimodal pain treatments are now considered standard care. We want to minimize opioids to the lowest dose possible to produce safe analgesia. Tramadol is the least-preferred opioid for abuse,” and is rated as schedule IV, the U.S. designation for drugs considered to have a low level of potential for causing abuse or dependence. “Opioids used as stand-alone agents have contributed to the current opioid crisis,” Dr. Viscusi told the committee.
In contrast to tramadol’s schedule IV status, the mainstays of recent opioid pain therapy have been hydrocodone and oxycodone, schedule II opioids rated as having a “high potential for abuse.”
Several advisory committee members agreed that CTC minimized patient exposure to an opioid. “This drug isn’t even tramadol; it’s tramadol light. It has about as low a dose [of an opioid] as you can have and still have a drug,” said member Lee A. Hoffer, PhD, a medical anthropologist at Case Western Reserve University, Cleveland, who studies substance use disorders. “All opioids are dangerous, even at a low dose, but there is a linear relationship based on potency, so if we want to have an opioid for acute pain, I’d like it to have the lowest morphine milligram equivalent possible. The ideal is no opioids, but that is not what happens,” he said. The CTC formulation delivers 17.6 morphine milligram equivalents (MME) per pill, the manufacturer’s representatives said. The Centers for Disease Control and Prevention defines a “relatively low” daily opioid dose as 20-50 MME.
Some committee members hailed the CTC formulation as a meaningful step toward cutting opioid consumption.
“We may be very nervous about abuse of scheduled opioids, but a schedule IV opioid in an opioid-sparing formulation is as good as it gets in 2020,” said committee member Kevin L. Zacharoff, MD, a pain medicine specialist at the State University of New York at Stony Brook. “Any opioid has potential for abuse, but this is a safer alternative to the schedule II drugs. There is less public health risk with this,” said committee member Sherif Zaafran, MD, a Houston anesthesiologist. “This represents an incremental but important approach to addressing the opioid crisis, especially if used to replace schedule II opioids,” said Brandon D.L. Marshall, PhD, an epidemiologist and substance abuse researcher at Brown University in Providence, R.I.
But despite agreement that CTC represented a new low in the MME of an opioid given to patients, several committee members still saw the formulation as problematic by introducing any opioid, no matter how small the dose.
“The landscape of tramadol use and prescribing is evolving. There’s been an exponential upturn in tramadol prescribing. It’s perceived [as] safer, but it’s not completely safe. Will this change tramadol abuse and open the door to abuse of other opioids? This is what got us into trouble with opioids in the first place. Patients start with a prescription opioid that they perceive is safe. Patients don’t start with oxycodone or heroin. They start with drugs that are believed to be safe. I feel this combination has less risk for abuse, but I’m worried that it would produce a false sense of security for tolerability and safety,” said committee member Maryann E. Amirshahi, MD, a medical toxicologist at Georgetown University and MedStar Health in Washington.
Several other committee members returned to this point throughout the 2 days of discussions: The majority of Americans who have become hooked on opioids reached that point by taking an opioid pain medication for a legitimate medical reason and using the drug the way they had understood they should.
“I’m most concerned about unintentional misuse leading to addiction and abuse. Most people with an opioid addiction got it inadvertently, misusing it by mistake,” said committee member Suzanne B. Robotti, a consumer representative and executive director of DES Action USA. “I’m concerned about approving an opioid, even an opioid with a low abuse history, without a clearer picture of the human abuse potential data and what would happen if this drug were abused,” she added, referring to the proposed CTC formulation.
“All the patients I work with started [their opioid addiction] as pain patients,” Dr. Hoffer said.
“The most common use and abuse of opioids is orally. We need to avoid having patients who use the drug as prescribed and still end up addicted,” said committee member Friedhelm Sandbrink, MD, a neurologist and director of pain management at the Veterans Affairs (VA) Medical Center in Washington.
What this means, said several panelists, is functionally clamping down a class-wide lid on new opioids. “The way to reduce deaths from abuse is to reduce addiction, and to have an impact you need to reduce opioid exposure.” said committee member Sonia Hernandez-Diaz, MD, professor of epidemiology at the Harvard School of Public Health in Boston.
“In this opioid crisis, we ask for data that we wouldn’t ordinarily ask for. I feel there are unanswered questions about the abuse potential [of CTC]. We have seen a recent reduction in oxycodone use, which is great, but also an increase in tramadol use. We should not be fooled. Tramadol is an opioid, even if it’s schedule IV,” Dr. Tyler said.
Two other opioids faced greater opposition
The other two agents that the committee considered received much less support and sharper skepticism. The application for Aximris XR, an extended release form of oxycodone with a purported abuse-deterrent formulation (ADF) that relies on being difficult to extract for intravenous use as well as possibly having effective deterrence mechanisms for other forms of abuse. But FDA staffers reported that the only effective deterrence they could document was against manipulation for intravenous use, making Aximris XR the first opioid seeking ADF labeling based on deterrence to a single delivery route. This led several committee members, as well as the FDA, to comment on the clinical meaningfulness of ADF for one route. So far, the FDA approved ADF labeling for seven opioids, most notably OxyContin, an extended-release oxycodone with the biggest share of the U.S. market for opioids with ADF labeling.
“For ADF, we label based on what we expect from the premarket data. We don’t really know how that translates into what happens once the drug is on the market. Every company with an ADF in their label is required to do postmarketing studies on the abuse routes that are supposed to be deterred. We see shifts to other routes. Assessment of ADF is incredibly challenging, both scientifically and logistically, because there has not been a lot of uptake of these products, for a variety of reasons,” said Judy Staffa, PhD, associate director for Public Health Initiatives in the Office of Surveillance & Epidemiology in the FDA’s Center for Drug Evaluation and Research. The company that markets OxyContin has been the first to submit to the FDA all of its required postmarketing data on ADF efficacy, and the agency is now reviewing this filing, Dr. Staffa said.
The data presented for Aximris XR appeared to generally fail to convince committee members that it provided a meaningful addition to the range of opioids with ADF designations already available, which meant that their decision mostly came down to whether they felt it made sense to bring a me-too opioid to the U.S. market. Their answer was mostly no.
“In the end, it’s another opioid, and I’m not sure we need another opioid,” said committee member Lonnie K. Zeltzer, MD, professor of pediatrics, anesthesiology, psychiatry, and biobehavioral sciences and director of pediatric pain at the University of California, Los Angeles “There are so many options for patients and for people who abuse these drug. I don’t see this formulation as having a profound impact, but I’m very concerned about adding more prescription opioids,” said Martin Garcia-Bunuel, MD, deputy chief of staff for the VA Maryland Health Care System in Baltimore. Another concern of some committee members was that ADF remains a designation with an uncertain meaning, pending the FDA’s analysis of the OxyContin data.
“At the end of the day, we don’t know whether any of the [ADF] stuff makes a difference,” noted Steve B. Meisel, PharmD, system director of medication safety for M Health Fairview in Minneapolis and a committee member,
The third agent, oxycodegol, a molecule designed to pass more slowly across the blood-brain barrier because of an attached polyethylene glycol chain that’s supposed to prevent a rapid high after ingestion and hence cut abuse potential. It received unanimous committee rejection, primarily because its safety and efficacy evidence had so many holes, but the shadow of opioid abuse permeated the committee’s discussion.
“One dogma in the abuse world is that slowing entry into the brain reduces abuse potential, but the opioid crisis showed that this is not the only factor. Some people have become addicted to slow-acting drugs. The abuse potential of this drug, oxycodegol, needs to be considered given where we’ve been with the opioid crisis,” said Jane B. Acri, PhD, chief of the Medications Discovery and Toxicology Branch of the National Institute on Drug Abuse.
“During the opioid epidemic, do we want to approve more opioids? If the [pain] efficacy is about the same as oxycodone, is better safety or abuse potential a reason to approve it? We need guidance [from the FDA] about what is ‘better enough.’ No opioid will ever be perfect; there will always be abuse and misuse. But what is good enough to justify bringing another opioid onto the market? What is a good enough improvement? I don’t have an answer,” Dr. Hernandez-Diaz said.
Adviser comments showed that the continued threat of widespread opioid addiction has cooled prospects for new opioid approvals by making FDA advisers skittish over how to properly score the incremental value of a new opioid.
“Do we need to go back to the drawing board on how we make decisions on exposing the American public to these kinds of agents?” Dr. Garcia-Bunuel asked. “I don’t think we have the tools to make these decisions.”
During an opioid-addiction epidemic, can any new opioid pain drug meet prevailing safety demands to gain regulatory approval?
On Jan. 14 and 15, a Food and Drug Administration advisory committee voted virtually unanimously against two new opioid formulations and evenly split for and against a third; the 2 days of data and discussion showed how high a bar new opioids face these days for getting onto the U.S. market.
The bar’s height is very understandable given how many Americans have become addicted to opioids over the past decade, more often than not by accident while using pain medications as they believed they had been directed, said experts during the sessions held on the FDA’s campus in White Oak, Md.
Among the many upshots of the opioid crisis, the meetings held to discuss these three contender opioids highlighted the bitter irony confronting attempts to bring new, safer opioids to the U.S. market: While less abusable pain-relief medications that still harness the potent analgesic power of mu opioid receptor agonists are desperately desired, new agents in this space now receive withering scrutiny over their safeguards against misuse and abuse, and over whether they add anything meaningfully new to what’s already available. While these demands seem reasonable, perhaps even essential, it’s unclear whether any new opioid-based pain drugs will ever fully meet the safety that researchers, clinicians, and the public now seek.
A special FDA advisory committee that combined the Anesthetic and Analgesic Drug Products Advisory Committee with members of the Drug Safety and Risk Management Advisory Committee considered the application for three different opioid drugs from three separate companies. None received a clear endorsement. Oxycodegol, a new type of orally delivered opioid molecule engineered to slow brain entry and thereby delay an abuser’s high, got voted down without any votes in favor and 27 votes against agency approval. Aximris XR, an extended-release oxycodone formulation that successfully deterred intravenous abuse but had no deterrence efficacy for intranasal or oral abuse failed by a 2-24 vote against. The third agent, CTC, a novel formulation of the schedule IV opioid tramadol with the NSAID celecoxib designed to be analgesic but with limited opioid-abuse appeal, came the closest to meaningful support with a tied 13-13 vote from advisory committee members for and against agency approval. FDA staff takes advisory committee opinions and votes into account when making their final decisions about drug marketing approvals.
In each case, the committee members, mostly the same roster assembled for each of the three agents, identified specific concerns with the data purported to show each drug’s safety and efficacy. But the gathered experts and consumer representatives also consistently cited holistic challenges to approving new opioids and the stiffer criteria these agents face amid a continuing wave of opioid misuse and abuse.
“In the context of the public health issues, we don’t want to be perceived in any way of taking shortcuts,” said Linda S. Tyler, PharmD,, an advisory committee member and professor of pharmacy and chief pharmacy officer at the University of Utah in Salt Lake City. “There is no question that for a new product to come to market in this space it needs to add to what’s on the market, meet a high bar, and provide advantages compared with what’s already on the market,” she said.
Tramadol plus celecoxib gains some support
The proposed combined formulation of tramadol and celecoxib came closest to meeting that bar, as far as the advisory committee was concerned, coming away with 13 votes favoring approval to match 13 votes against. The premise behind this agent, know as CTC (cocrystal of tramadol and celecoxib), was that it combined a modest dose (44 mg) of the schedule IV opioid tramadol with a 56-mg dose of celecoxib in a twice-daily pill. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia and a speaker at the session on behalf of the applicant company, spelled out the rationale behind CTC: “We are caught in a dilemma. We need to reduce opioid use, but we also need to treat pain. We have an urgent need to have pain treatment options that are effective but have low potential for abuse and dependence. We are looking at multimodal analgesia, that uses combination of agents, recognizing that postoperative pain is a mixed pain syndrome. Multimodal pain treatments are now considered standard care. We want to minimize opioids to the lowest dose possible to produce safe analgesia. Tramadol is the least-preferred opioid for abuse,” and is rated as schedule IV, the U.S. designation for drugs considered to have a low level of potential for causing abuse or dependence. “Opioids used as stand-alone agents have contributed to the current opioid crisis,” Dr. Viscusi told the committee.
In contrast to tramadol’s schedule IV status, the mainstays of recent opioid pain therapy have been hydrocodone and oxycodone, schedule II opioids rated as having a “high potential for abuse.”
Several advisory committee members agreed that CTC minimized patient exposure to an opioid. “This drug isn’t even tramadol; it’s tramadol light. It has about as low a dose [of an opioid] as you can have and still have a drug,” said member Lee A. Hoffer, PhD, a medical anthropologist at Case Western Reserve University, Cleveland, who studies substance use disorders. “All opioids are dangerous, even at a low dose, but there is a linear relationship based on potency, so if we want to have an opioid for acute pain, I’d like it to have the lowest morphine milligram equivalent possible. The ideal is no opioids, but that is not what happens,” he said. The CTC formulation delivers 17.6 morphine milligram equivalents (MME) per pill, the manufacturer’s representatives said. The Centers for Disease Control and Prevention defines a “relatively low” daily opioid dose as 20-50 MME.
Some committee members hailed the CTC formulation as a meaningful step toward cutting opioid consumption.
“We may be very nervous about abuse of scheduled opioids, but a schedule IV opioid in an opioid-sparing formulation is as good as it gets in 2020,” said committee member Kevin L. Zacharoff, MD, a pain medicine specialist at the State University of New York at Stony Brook. “Any opioid has potential for abuse, but this is a safer alternative to the schedule II drugs. There is less public health risk with this,” said committee member Sherif Zaafran, MD, a Houston anesthesiologist. “This represents an incremental but important approach to addressing the opioid crisis, especially if used to replace schedule II opioids,” said Brandon D.L. Marshall, PhD, an epidemiologist and substance abuse researcher at Brown University in Providence, R.I.
But despite agreement that CTC represented a new low in the MME of an opioid given to patients, several committee members still saw the formulation as problematic by introducing any opioid, no matter how small the dose.
“The landscape of tramadol use and prescribing is evolving. There’s been an exponential upturn in tramadol prescribing. It’s perceived [as] safer, but it’s not completely safe. Will this change tramadol abuse and open the door to abuse of other opioids? This is what got us into trouble with opioids in the first place. Patients start with a prescription opioid that they perceive is safe. Patients don’t start with oxycodone or heroin. They start with drugs that are believed to be safe. I feel this combination has less risk for abuse, but I’m worried that it would produce a false sense of security for tolerability and safety,” said committee member Maryann E. Amirshahi, MD, a medical toxicologist at Georgetown University and MedStar Health in Washington.
Several other committee members returned to this point throughout the 2 days of discussions: The majority of Americans who have become hooked on opioids reached that point by taking an opioid pain medication for a legitimate medical reason and using the drug the way they had understood they should.
“I’m most concerned about unintentional misuse leading to addiction and abuse. Most people with an opioid addiction got it inadvertently, misusing it by mistake,” said committee member Suzanne B. Robotti, a consumer representative and executive director of DES Action USA. “I’m concerned about approving an opioid, even an opioid with a low abuse history, without a clearer picture of the human abuse potential data and what would happen if this drug were abused,” she added, referring to the proposed CTC formulation.
“All the patients I work with started [their opioid addiction] as pain patients,” Dr. Hoffer said.
“The most common use and abuse of opioids is orally. We need to avoid having patients who use the drug as prescribed and still end up addicted,” said committee member Friedhelm Sandbrink, MD, a neurologist and director of pain management at the Veterans Affairs (VA) Medical Center in Washington.
What this means, said several panelists, is functionally clamping down a class-wide lid on new opioids. “The way to reduce deaths from abuse is to reduce addiction, and to have an impact you need to reduce opioid exposure.” said committee member Sonia Hernandez-Diaz, MD, professor of epidemiology at the Harvard School of Public Health in Boston.
“In this opioid crisis, we ask for data that we wouldn’t ordinarily ask for. I feel there are unanswered questions about the abuse potential [of CTC]. We have seen a recent reduction in oxycodone use, which is great, but also an increase in tramadol use. We should not be fooled. Tramadol is an opioid, even if it’s schedule IV,” Dr. Tyler said.
Two other opioids faced greater opposition
The other two agents that the committee considered received much less support and sharper skepticism. The application for Aximris XR, an extended release form of oxycodone with a purported abuse-deterrent formulation (ADF) that relies on being difficult to extract for intravenous use as well as possibly having effective deterrence mechanisms for other forms of abuse. But FDA staffers reported that the only effective deterrence they could document was against manipulation for intravenous use, making Aximris XR the first opioid seeking ADF labeling based on deterrence to a single delivery route. This led several committee members, as well as the FDA, to comment on the clinical meaningfulness of ADF for one route. So far, the FDA approved ADF labeling for seven opioids, most notably OxyContin, an extended-release oxycodone with the biggest share of the U.S. market for opioids with ADF labeling.
“For ADF, we label based on what we expect from the premarket data. We don’t really know how that translates into what happens once the drug is on the market. Every company with an ADF in their label is required to do postmarketing studies on the abuse routes that are supposed to be deterred. We see shifts to other routes. Assessment of ADF is incredibly challenging, both scientifically and logistically, because there has not been a lot of uptake of these products, for a variety of reasons,” said Judy Staffa, PhD, associate director for Public Health Initiatives in the Office of Surveillance & Epidemiology in the FDA’s Center for Drug Evaluation and Research. The company that markets OxyContin has been the first to submit to the FDA all of its required postmarketing data on ADF efficacy, and the agency is now reviewing this filing, Dr. Staffa said.
The data presented for Aximris XR appeared to generally fail to convince committee members that it provided a meaningful addition to the range of opioids with ADF designations already available, which meant that their decision mostly came down to whether they felt it made sense to bring a me-too opioid to the U.S. market. Their answer was mostly no.
“In the end, it’s another opioid, and I’m not sure we need another opioid,” said committee member Lonnie K. Zeltzer, MD, professor of pediatrics, anesthesiology, psychiatry, and biobehavioral sciences and director of pediatric pain at the University of California, Los Angeles “There are so many options for patients and for people who abuse these drug. I don’t see this formulation as having a profound impact, but I’m very concerned about adding more prescription opioids,” said Martin Garcia-Bunuel, MD, deputy chief of staff for the VA Maryland Health Care System in Baltimore. Another concern of some committee members was that ADF remains a designation with an uncertain meaning, pending the FDA’s analysis of the OxyContin data.
“At the end of the day, we don’t know whether any of the [ADF] stuff makes a difference,” noted Steve B. Meisel, PharmD, system director of medication safety for M Health Fairview in Minneapolis and a committee member,
The third agent, oxycodegol, a molecule designed to pass more slowly across the blood-brain barrier because of an attached polyethylene glycol chain that’s supposed to prevent a rapid high after ingestion and hence cut abuse potential. It received unanimous committee rejection, primarily because its safety and efficacy evidence had so many holes, but the shadow of opioid abuse permeated the committee’s discussion.
“One dogma in the abuse world is that slowing entry into the brain reduces abuse potential, but the opioid crisis showed that this is not the only factor. Some people have become addicted to slow-acting drugs. The abuse potential of this drug, oxycodegol, needs to be considered given where we’ve been with the opioid crisis,” said Jane B. Acri, PhD, chief of the Medications Discovery and Toxicology Branch of the National Institute on Drug Abuse.
“During the opioid epidemic, do we want to approve more opioids? If the [pain] efficacy is about the same as oxycodone, is better safety or abuse potential a reason to approve it? We need guidance [from the FDA] about what is ‘better enough.’ No opioid will ever be perfect; there will always be abuse and misuse. But what is good enough to justify bringing another opioid onto the market? What is a good enough improvement? I don’t have an answer,” Dr. Hernandez-Diaz said.
Adviser comments showed that the continued threat of widespread opioid addiction has cooled prospects for new opioid approvals by making FDA advisers skittish over how to properly score the incremental value of a new opioid.
“Do we need to go back to the drawing board on how we make decisions on exposing the American public to these kinds of agents?” Dr. Garcia-Bunuel asked. “I don’t think we have the tools to make these decisions.”
During an opioid-addiction epidemic, can any new opioid pain drug meet prevailing safety demands to gain regulatory approval?
On Jan. 14 and 15, a Food and Drug Administration advisory committee voted virtually unanimously against two new opioid formulations and evenly split for and against a third; the 2 days of data and discussion showed how high a bar new opioids face these days for getting onto the U.S. market.
The bar’s height is very understandable given how many Americans have become addicted to opioids over the past decade, more often than not by accident while using pain medications as they believed they had been directed, said experts during the sessions held on the FDA’s campus in White Oak, Md.
Among the many upshots of the opioid crisis, the meetings held to discuss these three contender opioids highlighted the bitter irony confronting attempts to bring new, safer opioids to the U.S. market: While less abusable pain-relief medications that still harness the potent analgesic power of mu opioid receptor agonists are desperately desired, new agents in this space now receive withering scrutiny over their safeguards against misuse and abuse, and over whether they add anything meaningfully new to what’s already available. While these demands seem reasonable, perhaps even essential, it’s unclear whether any new opioid-based pain drugs will ever fully meet the safety that researchers, clinicians, and the public now seek.
A special FDA advisory committee that combined the Anesthetic and Analgesic Drug Products Advisory Committee with members of the Drug Safety and Risk Management Advisory Committee considered the application for three different opioid drugs from three separate companies. None received a clear endorsement. Oxycodegol, a new type of orally delivered opioid molecule engineered to slow brain entry and thereby delay an abuser’s high, got voted down without any votes in favor and 27 votes against agency approval. Aximris XR, an extended-release oxycodone formulation that successfully deterred intravenous abuse but had no deterrence efficacy for intranasal or oral abuse failed by a 2-24 vote against. The third agent, CTC, a novel formulation of the schedule IV opioid tramadol with the NSAID celecoxib designed to be analgesic but with limited opioid-abuse appeal, came the closest to meaningful support with a tied 13-13 vote from advisory committee members for and against agency approval. FDA staff takes advisory committee opinions and votes into account when making their final decisions about drug marketing approvals.
In each case, the committee members, mostly the same roster assembled for each of the three agents, identified specific concerns with the data purported to show each drug’s safety and efficacy. But the gathered experts and consumer representatives also consistently cited holistic challenges to approving new opioids and the stiffer criteria these agents face amid a continuing wave of opioid misuse and abuse.
“In the context of the public health issues, we don’t want to be perceived in any way of taking shortcuts,” said Linda S. Tyler, PharmD,, an advisory committee member and professor of pharmacy and chief pharmacy officer at the University of Utah in Salt Lake City. “There is no question that for a new product to come to market in this space it needs to add to what’s on the market, meet a high bar, and provide advantages compared with what’s already on the market,” she said.
Tramadol plus celecoxib gains some support
The proposed combined formulation of tramadol and celecoxib came closest to meeting that bar, as far as the advisory committee was concerned, coming away with 13 votes favoring approval to match 13 votes against. The premise behind this agent, know as CTC (cocrystal of tramadol and celecoxib), was that it combined a modest dose (44 mg) of the schedule IV opioid tramadol with a 56-mg dose of celecoxib in a twice-daily pill. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia and a speaker at the session on behalf of the applicant company, spelled out the rationale behind CTC: “We are caught in a dilemma. We need to reduce opioid use, but we also need to treat pain. We have an urgent need to have pain treatment options that are effective but have low potential for abuse and dependence. We are looking at multimodal analgesia, that uses combination of agents, recognizing that postoperative pain is a mixed pain syndrome. Multimodal pain treatments are now considered standard care. We want to minimize opioids to the lowest dose possible to produce safe analgesia. Tramadol is the least-preferred opioid for abuse,” and is rated as schedule IV, the U.S. designation for drugs considered to have a low level of potential for causing abuse or dependence. “Opioids used as stand-alone agents have contributed to the current opioid crisis,” Dr. Viscusi told the committee.
In contrast to tramadol’s schedule IV status, the mainstays of recent opioid pain therapy have been hydrocodone and oxycodone, schedule II opioids rated as having a “high potential for abuse.”
Several advisory committee members agreed that CTC minimized patient exposure to an opioid. “This drug isn’t even tramadol; it’s tramadol light. It has about as low a dose [of an opioid] as you can have and still have a drug,” said member Lee A. Hoffer, PhD, a medical anthropologist at Case Western Reserve University, Cleveland, who studies substance use disorders. “All opioids are dangerous, even at a low dose, but there is a linear relationship based on potency, so if we want to have an opioid for acute pain, I’d like it to have the lowest morphine milligram equivalent possible. The ideal is no opioids, but that is not what happens,” he said. The CTC formulation delivers 17.6 morphine milligram equivalents (MME) per pill, the manufacturer’s representatives said. The Centers for Disease Control and Prevention defines a “relatively low” daily opioid dose as 20-50 MME.
Some committee members hailed the CTC formulation as a meaningful step toward cutting opioid consumption.
“We may be very nervous about abuse of scheduled opioids, but a schedule IV opioid in an opioid-sparing formulation is as good as it gets in 2020,” said committee member Kevin L. Zacharoff, MD, a pain medicine specialist at the State University of New York at Stony Brook. “Any opioid has potential for abuse, but this is a safer alternative to the schedule II drugs. There is less public health risk with this,” said committee member Sherif Zaafran, MD, a Houston anesthesiologist. “This represents an incremental but important approach to addressing the opioid crisis, especially if used to replace schedule II opioids,” said Brandon D.L. Marshall, PhD, an epidemiologist and substance abuse researcher at Brown University in Providence, R.I.
But despite agreement that CTC represented a new low in the MME of an opioid given to patients, several committee members still saw the formulation as problematic by introducing any opioid, no matter how small the dose.
“The landscape of tramadol use and prescribing is evolving. There’s been an exponential upturn in tramadol prescribing. It’s perceived [as] safer, but it’s not completely safe. Will this change tramadol abuse and open the door to abuse of other opioids? This is what got us into trouble with opioids in the first place. Patients start with a prescription opioid that they perceive is safe. Patients don’t start with oxycodone or heroin. They start with drugs that are believed to be safe. I feel this combination has less risk for abuse, but I’m worried that it would produce a false sense of security for tolerability and safety,” said committee member Maryann E. Amirshahi, MD, a medical toxicologist at Georgetown University and MedStar Health in Washington.
Several other committee members returned to this point throughout the 2 days of discussions: The majority of Americans who have become hooked on opioids reached that point by taking an opioid pain medication for a legitimate medical reason and using the drug the way they had understood they should.
“I’m most concerned about unintentional misuse leading to addiction and abuse. Most people with an opioid addiction got it inadvertently, misusing it by mistake,” said committee member Suzanne B. Robotti, a consumer representative and executive director of DES Action USA. “I’m concerned about approving an opioid, even an opioid with a low abuse history, without a clearer picture of the human abuse potential data and what would happen if this drug were abused,” she added, referring to the proposed CTC formulation.
“All the patients I work with started [their opioid addiction] as pain patients,” Dr. Hoffer said.
“The most common use and abuse of opioids is orally. We need to avoid having patients who use the drug as prescribed and still end up addicted,” said committee member Friedhelm Sandbrink, MD, a neurologist and director of pain management at the Veterans Affairs (VA) Medical Center in Washington.
What this means, said several panelists, is functionally clamping down a class-wide lid on new opioids. “The way to reduce deaths from abuse is to reduce addiction, and to have an impact you need to reduce opioid exposure.” said committee member Sonia Hernandez-Diaz, MD, professor of epidemiology at the Harvard School of Public Health in Boston.
“In this opioid crisis, we ask for data that we wouldn’t ordinarily ask for. I feel there are unanswered questions about the abuse potential [of CTC]. We have seen a recent reduction in oxycodone use, which is great, but also an increase in tramadol use. We should not be fooled. Tramadol is an opioid, even if it’s schedule IV,” Dr. Tyler said.
Two other opioids faced greater opposition
The other two agents that the committee considered received much less support and sharper skepticism. The application for Aximris XR, an extended release form of oxycodone with a purported abuse-deterrent formulation (ADF) that relies on being difficult to extract for intravenous use as well as possibly having effective deterrence mechanisms for other forms of abuse. But FDA staffers reported that the only effective deterrence they could document was against manipulation for intravenous use, making Aximris XR the first opioid seeking ADF labeling based on deterrence to a single delivery route. This led several committee members, as well as the FDA, to comment on the clinical meaningfulness of ADF for one route. So far, the FDA approved ADF labeling for seven opioids, most notably OxyContin, an extended-release oxycodone with the biggest share of the U.S. market for opioids with ADF labeling.
“For ADF, we label based on what we expect from the premarket data. We don’t really know how that translates into what happens once the drug is on the market. Every company with an ADF in their label is required to do postmarketing studies on the abuse routes that are supposed to be deterred. We see shifts to other routes. Assessment of ADF is incredibly challenging, both scientifically and logistically, because there has not been a lot of uptake of these products, for a variety of reasons,” said Judy Staffa, PhD, associate director for Public Health Initiatives in the Office of Surveillance & Epidemiology in the FDA’s Center for Drug Evaluation and Research. The company that markets OxyContin has been the first to submit to the FDA all of its required postmarketing data on ADF efficacy, and the agency is now reviewing this filing, Dr. Staffa said.
The data presented for Aximris XR appeared to generally fail to convince committee members that it provided a meaningful addition to the range of opioids with ADF designations already available, which meant that their decision mostly came down to whether they felt it made sense to bring a me-too opioid to the U.S. market. Their answer was mostly no.
“In the end, it’s another opioid, and I’m not sure we need another opioid,” said committee member Lonnie K. Zeltzer, MD, professor of pediatrics, anesthesiology, psychiatry, and biobehavioral sciences and director of pediatric pain at the University of California, Los Angeles “There are so many options for patients and for people who abuse these drug. I don’t see this formulation as having a profound impact, but I’m very concerned about adding more prescription opioids,” said Martin Garcia-Bunuel, MD, deputy chief of staff for the VA Maryland Health Care System in Baltimore. Another concern of some committee members was that ADF remains a designation with an uncertain meaning, pending the FDA’s analysis of the OxyContin data.
“At the end of the day, we don’t know whether any of the [ADF] stuff makes a difference,” noted Steve B. Meisel, PharmD, system director of medication safety for M Health Fairview in Minneapolis and a committee member,
The third agent, oxycodegol, a molecule designed to pass more slowly across the blood-brain barrier because of an attached polyethylene glycol chain that’s supposed to prevent a rapid high after ingestion and hence cut abuse potential. It received unanimous committee rejection, primarily because its safety and efficacy evidence had so many holes, but the shadow of opioid abuse permeated the committee’s discussion.
“One dogma in the abuse world is that slowing entry into the brain reduces abuse potential, but the opioid crisis showed that this is not the only factor. Some people have become addicted to slow-acting drugs. The abuse potential of this drug, oxycodegol, needs to be considered given where we’ve been with the opioid crisis,” said Jane B. Acri, PhD, chief of the Medications Discovery and Toxicology Branch of the National Institute on Drug Abuse.
“During the opioid epidemic, do we want to approve more opioids? If the [pain] efficacy is about the same as oxycodone, is better safety or abuse potential a reason to approve it? We need guidance [from the FDA] about what is ‘better enough.’ No opioid will ever be perfect; there will always be abuse and misuse. But what is good enough to justify bringing another opioid onto the market? What is a good enough improvement? I don’t have an answer,” Dr. Hernandez-Diaz said.
Adviser comments showed that the continued threat of widespread opioid addiction has cooled prospects for new opioid approvals by making FDA advisers skittish over how to properly score the incremental value of a new opioid.
“Do we need to go back to the drawing board on how we make decisions on exposing the American public to these kinds of agents?” Dr. Garcia-Bunuel asked. “I don’t think we have the tools to make these decisions.”
Coronary function testing during angiography boosts 1-year angina outcomes
PHILADELPHIA – Longer and more extensive follow-up of the positive CorMicA trial confirmed that clinicians who receive added information on the presence or absence of microvascular coronary disease or coronary vasospasm in patients with chronic, stable angina but without detectable coronary obstruction adjust patient treatment in ways that produce better outcomes.
For example, expanded 1-year follow-up of the 151-patient, multicenter, CorMicA randomized study showed that stable angina patients without coronary obstruction treated by clinicians aware of microvascular or vasospastic coronary disease had blood pressures that averaged about 12/5 mm Hg lower than those of patients in the control arm, in which this information was kept blinded.
Clinicians in the study who received information about diagnoses of microvascular angina, vasospastic angina, both, or neither, generally better tailored the treatments they gave these patients, were more likely to prescribe cardiac rehabilitation to these patients, and successfully capped increases in blood pressure that occurred in the control patients, Colin Berry, MD, said at the American Heart Association scientific sessions. The investigators made the diagnoses of microvascular and vasospastic angina using an “invasive diagnostic procedure” that involved placing a wire with pressure and temperature sensors in a selected coronary artery and measuring flow patterns that resulted from a systemic infusion of adenosine and from incremental, intracoronary infusions of acetylcholine.
The CorMicA results “tell us that, if we use existing drugs and nonpharmacologic treatments, we can improve patients’ quality of life,” said Dr. Berry, co-lead investigator of the study and professor of cardiology and imaging at the University of Glasgow. “There were probably two drivers of change in treatment” between the intervention arm where clinicians learned whether their patients had microvascular angina or vasospasm, and the control arm where this information was kept blinded. Some patients reclassified as having microvascular disease or vasospasm were restarted on standard agents for treatment of coronary artery disease such as statins and ACE inhibitors that had previously been stopped, noted Dr. Berry. The identification of a specific type of vascular disorder also helped guide treatment. For example, patients identified as having vasospasm were taken off of beta-blockers, which are contraindicated in these patients, and instead began treatment with a calcium channel antagonist, he said.
“CorMicA was a landmark trial. The interventional cardiologists at my center believe that the testing [for microvascular and vasospastic angina] should be used routinely, based on the reported data,” said Harmony R. Reynolds, MD, a cardiologist at NYU Langone Health in New York.
The CorMicA (Coronary Microvascular Angina) trial enrolled 391 patients at either of two hospitals in Scotland during November 2016–November 2017. All patients were scheduled for clinically indicated, elective diagnostic angiography for suspected stable angina. Clinicians identified a coronary obstruction in 206 patients that excluded them from the main CorMicA analysis. They focused on the 181 without coronary obstruction visible by angiography, and specifically the 151 of these patients who underwent the invasive diagnostic procedure, with 76 randomized to have their diagnostic-procedure results relayed to their treating physicians and 75 patients whose diagnostic results remained blinded. The study’s primary endpoint was the mean difference in angina severity at 6 months after treatment assessed by the Seattle Angina Questionnaire (SAQ) summary score. After 6 months, the between-group difference in average SAQ summary scores was 11.7 units, a statistically significant as well as clinically meaningful benefit that linked with knowledge of the coronary function of patients based on invasive testing (J Am Coll Cardiol. 2018 Dec 11;72[23 Part A]:2841-55).
The prespecified 1-year follow-up with another SAQ took place for 142 of the 151 randomized patients, and showed ongoing separation of SAQ scores between the intervention and control patients, reaching a statistically significant mean difference of 13.6 units, Dr. Berry reported. Other benefits that linked with dissemination of results from the invasive diagnostic procedure included maintenance of the quality-of-life benefit seen after 6 months, an incremental further reduction in illness perception from 6 to 12 months, and a substantial further improvement in global treatment satisfaction, which grew from a 30% higher level in the intervention group compared with controls at 6 months to a 44% between-group difference after 12 months. Concurrently with Dr. Berry’s report, the results appeared online (JACC: Cardiovasc Interv. 2020 Jan 13;13[1] 33-45).
Additional findings for various clinical measures that were not part of the 6-month findings provided further insight into the impact that clinician knowledge about microvascular disease or vasospasm had on patients. These metrics suggested that the benefits in the intervention patients may have largely resulted from their avoiding elevations in risk markers that occurred among controls who received routine care.
For example, after 12 months, average 12/5 mm Hg differences in systolic and diastolic blood pressures between the two arms was nearly all because of pressure increases from baseline in the control patients with only very small drops in pressure from baseline among the intervention patients. Weight measurements after 1 year showed that the control patients were on average 1.3 kg heavier than the intervention patients, again mostly because of weight increases among the controls. Enrollment in a cardiac rehabilitation program at 12 months had occurred for 40% of the intervention patients and 16% of the controls, a 73% relative increase in the intervention arm, Dr. Berry reported.
The invasive, coronary, physiological assessments used in CorMicA led to stratified medical therapy and created an opportunity for better long-term angina treatment in patients without obstructive coronary disease, Dr. Berry concluded. He stressed the need to further test this hypothesis in larger, prospective studies, and to assess its cost effectiveness. But the proof-of-concept demonstrated by the CorMicA results indicate a role for more thorough investigation of coronary dysfunction when obstructive disease is absent, with the opportunity to use this information to better tailor treatment. The findings also highlight the potential for new drug development that can address nonobstructive microvascular or vasospastic coronary disease, he said.
Dr. Berry has been a speaker on behalf of Abbott Vascular, and he has received research funding from AstraZeneca, GlaxoSmithKline, HeartFlow, Novartis, and Siemens Healthcare. Dr. Reynolds had no disclosures.
SOURCE: Ford TJ. AHA 2019, session FS.AOS.03 abstract.
PHILADELPHIA – Longer and more extensive follow-up of the positive CorMicA trial confirmed that clinicians who receive added information on the presence or absence of microvascular coronary disease or coronary vasospasm in patients with chronic, stable angina but without detectable coronary obstruction adjust patient treatment in ways that produce better outcomes.
For example, expanded 1-year follow-up of the 151-patient, multicenter, CorMicA randomized study showed that stable angina patients without coronary obstruction treated by clinicians aware of microvascular or vasospastic coronary disease had blood pressures that averaged about 12/5 mm Hg lower than those of patients in the control arm, in which this information was kept blinded.
Clinicians in the study who received information about diagnoses of microvascular angina, vasospastic angina, both, or neither, generally better tailored the treatments they gave these patients, were more likely to prescribe cardiac rehabilitation to these patients, and successfully capped increases in blood pressure that occurred in the control patients, Colin Berry, MD, said at the American Heart Association scientific sessions. The investigators made the diagnoses of microvascular and vasospastic angina using an “invasive diagnostic procedure” that involved placing a wire with pressure and temperature sensors in a selected coronary artery and measuring flow patterns that resulted from a systemic infusion of adenosine and from incremental, intracoronary infusions of acetylcholine.
The CorMicA results “tell us that, if we use existing drugs and nonpharmacologic treatments, we can improve patients’ quality of life,” said Dr. Berry, co-lead investigator of the study and professor of cardiology and imaging at the University of Glasgow. “There were probably two drivers of change in treatment” between the intervention arm where clinicians learned whether their patients had microvascular angina or vasospasm, and the control arm where this information was kept blinded. Some patients reclassified as having microvascular disease or vasospasm were restarted on standard agents for treatment of coronary artery disease such as statins and ACE inhibitors that had previously been stopped, noted Dr. Berry. The identification of a specific type of vascular disorder also helped guide treatment. For example, patients identified as having vasospasm were taken off of beta-blockers, which are contraindicated in these patients, and instead began treatment with a calcium channel antagonist, he said.
“CorMicA was a landmark trial. The interventional cardiologists at my center believe that the testing [for microvascular and vasospastic angina] should be used routinely, based on the reported data,” said Harmony R. Reynolds, MD, a cardiologist at NYU Langone Health in New York.
The CorMicA (Coronary Microvascular Angina) trial enrolled 391 patients at either of two hospitals in Scotland during November 2016–November 2017. All patients were scheduled for clinically indicated, elective diagnostic angiography for suspected stable angina. Clinicians identified a coronary obstruction in 206 patients that excluded them from the main CorMicA analysis. They focused on the 181 without coronary obstruction visible by angiography, and specifically the 151 of these patients who underwent the invasive diagnostic procedure, with 76 randomized to have their diagnostic-procedure results relayed to their treating physicians and 75 patients whose diagnostic results remained blinded. The study’s primary endpoint was the mean difference in angina severity at 6 months after treatment assessed by the Seattle Angina Questionnaire (SAQ) summary score. After 6 months, the between-group difference in average SAQ summary scores was 11.7 units, a statistically significant as well as clinically meaningful benefit that linked with knowledge of the coronary function of patients based on invasive testing (J Am Coll Cardiol. 2018 Dec 11;72[23 Part A]:2841-55).
The prespecified 1-year follow-up with another SAQ took place for 142 of the 151 randomized patients, and showed ongoing separation of SAQ scores between the intervention and control patients, reaching a statistically significant mean difference of 13.6 units, Dr. Berry reported. Other benefits that linked with dissemination of results from the invasive diagnostic procedure included maintenance of the quality-of-life benefit seen after 6 months, an incremental further reduction in illness perception from 6 to 12 months, and a substantial further improvement in global treatment satisfaction, which grew from a 30% higher level in the intervention group compared with controls at 6 months to a 44% between-group difference after 12 months. Concurrently with Dr. Berry’s report, the results appeared online (JACC: Cardiovasc Interv. 2020 Jan 13;13[1] 33-45).
Additional findings for various clinical measures that were not part of the 6-month findings provided further insight into the impact that clinician knowledge about microvascular disease or vasospasm had on patients. These metrics suggested that the benefits in the intervention patients may have largely resulted from their avoiding elevations in risk markers that occurred among controls who received routine care.
For example, after 12 months, average 12/5 mm Hg differences in systolic and diastolic blood pressures between the two arms was nearly all because of pressure increases from baseline in the control patients with only very small drops in pressure from baseline among the intervention patients. Weight measurements after 1 year showed that the control patients were on average 1.3 kg heavier than the intervention patients, again mostly because of weight increases among the controls. Enrollment in a cardiac rehabilitation program at 12 months had occurred for 40% of the intervention patients and 16% of the controls, a 73% relative increase in the intervention arm, Dr. Berry reported.
The invasive, coronary, physiological assessments used in CorMicA led to stratified medical therapy and created an opportunity for better long-term angina treatment in patients without obstructive coronary disease, Dr. Berry concluded. He stressed the need to further test this hypothesis in larger, prospective studies, and to assess its cost effectiveness. But the proof-of-concept demonstrated by the CorMicA results indicate a role for more thorough investigation of coronary dysfunction when obstructive disease is absent, with the opportunity to use this information to better tailor treatment. The findings also highlight the potential for new drug development that can address nonobstructive microvascular or vasospastic coronary disease, he said.
Dr. Berry has been a speaker on behalf of Abbott Vascular, and he has received research funding from AstraZeneca, GlaxoSmithKline, HeartFlow, Novartis, and Siemens Healthcare. Dr. Reynolds had no disclosures.
SOURCE: Ford TJ. AHA 2019, session FS.AOS.03 abstract.
PHILADELPHIA – Longer and more extensive follow-up of the positive CorMicA trial confirmed that clinicians who receive added information on the presence or absence of microvascular coronary disease or coronary vasospasm in patients with chronic, stable angina but without detectable coronary obstruction adjust patient treatment in ways that produce better outcomes.
For example, expanded 1-year follow-up of the 151-patient, multicenter, CorMicA randomized study showed that stable angina patients without coronary obstruction treated by clinicians aware of microvascular or vasospastic coronary disease had blood pressures that averaged about 12/5 mm Hg lower than those of patients in the control arm, in which this information was kept blinded.
Clinicians in the study who received information about diagnoses of microvascular angina, vasospastic angina, both, or neither, generally better tailored the treatments they gave these patients, were more likely to prescribe cardiac rehabilitation to these patients, and successfully capped increases in blood pressure that occurred in the control patients, Colin Berry, MD, said at the American Heart Association scientific sessions. The investigators made the diagnoses of microvascular and vasospastic angina using an “invasive diagnostic procedure” that involved placing a wire with pressure and temperature sensors in a selected coronary artery and measuring flow patterns that resulted from a systemic infusion of adenosine and from incremental, intracoronary infusions of acetylcholine.
The CorMicA results “tell us that, if we use existing drugs and nonpharmacologic treatments, we can improve patients’ quality of life,” said Dr. Berry, co-lead investigator of the study and professor of cardiology and imaging at the University of Glasgow. “There were probably two drivers of change in treatment” between the intervention arm where clinicians learned whether their patients had microvascular angina or vasospasm, and the control arm where this information was kept blinded. Some patients reclassified as having microvascular disease or vasospasm were restarted on standard agents for treatment of coronary artery disease such as statins and ACE inhibitors that had previously been stopped, noted Dr. Berry. The identification of a specific type of vascular disorder also helped guide treatment. For example, patients identified as having vasospasm were taken off of beta-blockers, which are contraindicated in these patients, and instead began treatment with a calcium channel antagonist, he said.
“CorMicA was a landmark trial. The interventional cardiologists at my center believe that the testing [for microvascular and vasospastic angina] should be used routinely, based on the reported data,” said Harmony R. Reynolds, MD, a cardiologist at NYU Langone Health in New York.
The CorMicA (Coronary Microvascular Angina) trial enrolled 391 patients at either of two hospitals in Scotland during November 2016–November 2017. All patients were scheduled for clinically indicated, elective diagnostic angiography for suspected stable angina. Clinicians identified a coronary obstruction in 206 patients that excluded them from the main CorMicA analysis. They focused on the 181 without coronary obstruction visible by angiography, and specifically the 151 of these patients who underwent the invasive diagnostic procedure, with 76 randomized to have their diagnostic-procedure results relayed to their treating physicians and 75 patients whose diagnostic results remained blinded. The study’s primary endpoint was the mean difference in angina severity at 6 months after treatment assessed by the Seattle Angina Questionnaire (SAQ) summary score. After 6 months, the between-group difference in average SAQ summary scores was 11.7 units, a statistically significant as well as clinically meaningful benefit that linked with knowledge of the coronary function of patients based on invasive testing (J Am Coll Cardiol. 2018 Dec 11;72[23 Part A]:2841-55).
The prespecified 1-year follow-up with another SAQ took place for 142 of the 151 randomized patients, and showed ongoing separation of SAQ scores between the intervention and control patients, reaching a statistically significant mean difference of 13.6 units, Dr. Berry reported. Other benefits that linked with dissemination of results from the invasive diagnostic procedure included maintenance of the quality-of-life benefit seen after 6 months, an incremental further reduction in illness perception from 6 to 12 months, and a substantial further improvement in global treatment satisfaction, which grew from a 30% higher level in the intervention group compared with controls at 6 months to a 44% between-group difference after 12 months. Concurrently with Dr. Berry’s report, the results appeared online (JACC: Cardiovasc Interv. 2020 Jan 13;13[1] 33-45).
Additional findings for various clinical measures that were not part of the 6-month findings provided further insight into the impact that clinician knowledge about microvascular disease or vasospasm had on patients. These metrics suggested that the benefits in the intervention patients may have largely resulted from their avoiding elevations in risk markers that occurred among controls who received routine care.
For example, after 12 months, average 12/5 mm Hg differences in systolic and diastolic blood pressures between the two arms was nearly all because of pressure increases from baseline in the control patients with only very small drops in pressure from baseline among the intervention patients. Weight measurements after 1 year showed that the control patients were on average 1.3 kg heavier than the intervention patients, again mostly because of weight increases among the controls. Enrollment in a cardiac rehabilitation program at 12 months had occurred for 40% of the intervention patients and 16% of the controls, a 73% relative increase in the intervention arm, Dr. Berry reported.
The invasive, coronary, physiological assessments used in CorMicA led to stratified medical therapy and created an opportunity for better long-term angina treatment in patients without obstructive coronary disease, Dr. Berry concluded. He stressed the need to further test this hypothesis in larger, prospective studies, and to assess its cost effectiveness. But the proof-of-concept demonstrated by the CorMicA results indicate a role for more thorough investigation of coronary dysfunction when obstructive disease is absent, with the opportunity to use this information to better tailor treatment. The findings also highlight the potential for new drug development that can address nonobstructive microvascular or vasospastic coronary disease, he said.
Dr. Berry has been a speaker on behalf of Abbott Vascular, and he has received research funding from AstraZeneca, GlaxoSmithKline, HeartFlow, Novartis, and Siemens Healthcare. Dr. Reynolds had no disclosures.
SOURCE: Ford TJ. AHA 2019, session FS.AOS.03 abstract.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
FDA committee rejects oxycodegol, new opioid designed for less abuse
A Food and Drug Administration advisory committee voted 27-0 on Jan. 14 against recommending agency approval of oxycodegol, a new type of opioid molecule designed to slow passage of the drug through the blood-brain barrier and hence cause less of a “high” and potentially blunt the drug’s abuse potential.
But the panel, which includes members from both the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, unanimously shared the opinion that the data submitted by the drug developer, Nektar, failed to clearly demonstrate the drug’s safety and efficacy.
“There was a lot of ambiguity [in the data] about safety and efficacy, and this is too important an issue to have so much ambiguity,” summed up Ronald S. Litman, DO, professor of anesthesiology and critical care at the University of Pennsylvania in Philadelphia and chair of the combined committee.
“The subliminal message” that would surround oxycodegol if it received FDA approval would be that it is a “safer” opioid, “and that would make it a blockbuster drug, and for that to happen you need data that [prove] the benefits outweigh risks, but we didn’t see those data. It was all speculation, and we can’t approve a potential blockbuster opioid in the middle of a public health opioid crisis based on speculation,” commented Steve B. Meisel, PharmD, system director of medication safety for Fairview Health Services in Minneapolis and a committee member.
According to Nektar, oxycodegol is a new molecular entity that combines a morphinan pharmacophore, oxycodol, with a six-unit chain of polyethylene glycol, a design that slows movement of the drug into the brain by about an hour after an oral dose when compared with oxycodone. It works as a full mu opioid receptor agonist that inhibits the nociceptive pathways while it reduces reinforcing or euphoric effects and other negative CNS-mediated side effects because of its slowed entry into the central nervous system.
But, as became apparent during the course of the day’s presentations and questions, while the clinical evidence in general supported this mechanism, the data were flawed by many limitations and caveats. FDA staffers critiqued the company’s data set for a variety of issues, including testing dosages that were “arbitrary and flawed,” evidence for “high oral abuse potential” in one study, including “a high rate of euphoria” of 17% even at the recommended dosage level (and a higher euphoria incidence at a higher dosage), limited information on additional pain medications that enrolled patients had used both before enrollment and during the study, and possible enrollment bias. Many panel members also raised concerns that included the efficacy data coming from a single randomized study, incomplete data on possible hepatic toxicity, no data to address potential abuse via injection or inhalation, a very modest demonstrated increment in pain relief, and abuse potential studies that relied on a single dose of the drug.
On the other hand, many committee members, and others in the pain field, applauded the general concept behind oxycodegol and urged the developer to run additional studies and collect more data for a future FDA application.
There has been “a lot of controversy” about oxycodegol, often centered on the question “why do we need another opioid,” commented Steven P. Cohen, MD, professor of anesthesiology, neurology, and pain medicine and chief of pain medicine at Johns Hopkins Health in Baltimore. “Having another opioid on the market with a different pain indication and possibly lower abuse potential” would be welcome and “almost certainly would not result in more prescriptions or abuse,” said Dr. Cohen, who was not a committee member but addressed in an interview the need for new and effective pain medications that offer an alternative to conventional opioids. “Patients who might otherwise be prescribed a different opioid might receive oxycodegol instead,” he suggested. But first, the developing company will need to collect a lot more clinical data than it has reported so far.
A Food and Drug Administration advisory committee voted 27-0 on Jan. 14 against recommending agency approval of oxycodegol, a new type of opioid molecule designed to slow passage of the drug through the blood-brain barrier and hence cause less of a “high” and potentially blunt the drug’s abuse potential.
But the panel, which includes members from both the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, unanimously shared the opinion that the data submitted by the drug developer, Nektar, failed to clearly demonstrate the drug’s safety and efficacy.
“There was a lot of ambiguity [in the data] about safety and efficacy, and this is too important an issue to have so much ambiguity,” summed up Ronald S. Litman, DO, professor of anesthesiology and critical care at the University of Pennsylvania in Philadelphia and chair of the combined committee.
“The subliminal message” that would surround oxycodegol if it received FDA approval would be that it is a “safer” opioid, “and that would make it a blockbuster drug, and for that to happen you need data that [prove] the benefits outweigh risks, but we didn’t see those data. It was all speculation, and we can’t approve a potential blockbuster opioid in the middle of a public health opioid crisis based on speculation,” commented Steve B. Meisel, PharmD, system director of medication safety for Fairview Health Services in Minneapolis and a committee member.
According to Nektar, oxycodegol is a new molecular entity that combines a morphinan pharmacophore, oxycodol, with a six-unit chain of polyethylene glycol, a design that slows movement of the drug into the brain by about an hour after an oral dose when compared with oxycodone. It works as a full mu opioid receptor agonist that inhibits the nociceptive pathways while it reduces reinforcing or euphoric effects and other negative CNS-mediated side effects because of its slowed entry into the central nervous system.
But, as became apparent during the course of the day’s presentations and questions, while the clinical evidence in general supported this mechanism, the data were flawed by many limitations and caveats. FDA staffers critiqued the company’s data set for a variety of issues, including testing dosages that were “arbitrary and flawed,” evidence for “high oral abuse potential” in one study, including “a high rate of euphoria” of 17% even at the recommended dosage level (and a higher euphoria incidence at a higher dosage), limited information on additional pain medications that enrolled patients had used both before enrollment and during the study, and possible enrollment bias. Many panel members also raised concerns that included the efficacy data coming from a single randomized study, incomplete data on possible hepatic toxicity, no data to address potential abuse via injection or inhalation, a very modest demonstrated increment in pain relief, and abuse potential studies that relied on a single dose of the drug.
On the other hand, many committee members, and others in the pain field, applauded the general concept behind oxycodegol and urged the developer to run additional studies and collect more data for a future FDA application.
There has been “a lot of controversy” about oxycodegol, often centered on the question “why do we need another opioid,” commented Steven P. Cohen, MD, professor of anesthesiology, neurology, and pain medicine and chief of pain medicine at Johns Hopkins Health in Baltimore. “Having another opioid on the market with a different pain indication and possibly lower abuse potential” would be welcome and “almost certainly would not result in more prescriptions or abuse,” said Dr. Cohen, who was not a committee member but addressed in an interview the need for new and effective pain medications that offer an alternative to conventional opioids. “Patients who might otherwise be prescribed a different opioid might receive oxycodegol instead,” he suggested. But first, the developing company will need to collect a lot more clinical data than it has reported so far.
A Food and Drug Administration advisory committee voted 27-0 on Jan. 14 against recommending agency approval of oxycodegol, a new type of opioid molecule designed to slow passage of the drug through the blood-brain barrier and hence cause less of a “high” and potentially blunt the drug’s abuse potential.
But the panel, which includes members from both the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, unanimously shared the opinion that the data submitted by the drug developer, Nektar, failed to clearly demonstrate the drug’s safety and efficacy.
“There was a lot of ambiguity [in the data] about safety and efficacy, and this is too important an issue to have so much ambiguity,” summed up Ronald S. Litman, DO, professor of anesthesiology and critical care at the University of Pennsylvania in Philadelphia and chair of the combined committee.
“The subliminal message” that would surround oxycodegol if it received FDA approval would be that it is a “safer” opioid, “and that would make it a blockbuster drug, and for that to happen you need data that [prove] the benefits outweigh risks, but we didn’t see those data. It was all speculation, and we can’t approve a potential blockbuster opioid in the middle of a public health opioid crisis based on speculation,” commented Steve B. Meisel, PharmD, system director of medication safety for Fairview Health Services in Minneapolis and a committee member.
According to Nektar, oxycodegol is a new molecular entity that combines a morphinan pharmacophore, oxycodol, with a six-unit chain of polyethylene glycol, a design that slows movement of the drug into the brain by about an hour after an oral dose when compared with oxycodone. It works as a full mu opioid receptor agonist that inhibits the nociceptive pathways while it reduces reinforcing or euphoric effects and other negative CNS-mediated side effects because of its slowed entry into the central nervous system.
But, as became apparent during the course of the day’s presentations and questions, while the clinical evidence in general supported this mechanism, the data were flawed by many limitations and caveats. FDA staffers critiqued the company’s data set for a variety of issues, including testing dosages that were “arbitrary and flawed,” evidence for “high oral abuse potential” in one study, including “a high rate of euphoria” of 17% even at the recommended dosage level (and a higher euphoria incidence at a higher dosage), limited information on additional pain medications that enrolled patients had used both before enrollment and during the study, and possible enrollment bias. Many panel members also raised concerns that included the efficacy data coming from a single randomized study, incomplete data on possible hepatic toxicity, no data to address potential abuse via injection or inhalation, a very modest demonstrated increment in pain relief, and abuse potential studies that relied on a single dose of the drug.
On the other hand, many committee members, and others in the pain field, applauded the general concept behind oxycodegol and urged the developer to run additional studies and collect more data for a future FDA application.
There has been “a lot of controversy” about oxycodegol, often centered on the question “why do we need another opioid,” commented Steven P. Cohen, MD, professor of anesthesiology, neurology, and pain medicine and chief of pain medicine at Johns Hopkins Health in Baltimore. “Having another opioid on the market with a different pain indication and possibly lower abuse potential” would be welcome and “almost certainly would not result in more prescriptions or abuse,” said Dr. Cohen, who was not a committee member but addressed in an interview the need for new and effective pain medications that offer an alternative to conventional opioids. “Patients who might otherwise be prescribed a different opioid might receive oxycodegol instead,” he suggested. But first, the developing company will need to collect a lot more clinical data than it has reported so far.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
Half of SLE patients have incident neuropsychiatric events
Neuropsychiatric events occurred in just over half of all patients recently diagnosed with systemic lupus erythematosus and followed for an average of nearly 8 years in an international study of more than 1,800 patients.
Up to 30% of these neuropsychiatric (NP) events in up to 20% of the followed cohort were directly attributable to systemic lupus erythematosus (SLE) in a representative patient population, wrote John G. Hanly, MD, and associates in Annals of the Rheumatic Diseases. Their findings were consistent with prior reports, they added.
Another notable finding from follow-up of these 1,827 SLE patients was that among those without a history of SLE-related NP events at baseline, 74% remained free of NP events during the subsequent 10 years, wrote Dr. Hanly, professor of medicine and director of the lupus clinic at Dalhousie University, Halifax, N.S., and coauthors. Among patients free from SLE-associated NP events after 2 years, 84% remained event free during their remaining follow-up. SLE patients with a history of an NP event that subsequently resolved had a 72% rate of freedom from another NP event during 10 years of follow-up.
These findings came from patients recently diagnosed with SLE (within the preceding 15 months) and enrolled at any of 31 participating academic medical centers in North America, Europe, and Asia. The investigators considered preenrollment NP events to include those starting from 6 months prior to diagnosis of SLE until the time patients entered the study. They used case definitions for 19 SLE-associated NP events published by the American College of Rheumatology (Arthritis Rheum. 1999 Apr;42[4]:599-608). All enrolled patients underwent annual assessment for NP events, with follow-up continuing as long as 18 years.
The researchers identified NP events in 955 of the 1,827 enrolled patients, a 52% incidence, including 1,910 unique NP events that included episodes from each of the 19 NP event types, with 92% involving the central nervous system and 8% involving the peripheral nervous system. The percentage of NP events attributable to SLE ranged from 17% to 31%, and they occurred in 14%-21% of the studied patients, with the range reflecting various attribution models used in the analyses. Some patients remained in the same NP state, while others progressed through more than one state.
The study did not receive commercial funding. Dr. Hanly had no disclosures.
SOURCE: Hanly JG et al. Ann Rheum Dis. 2020 Jan 8. doi: 10.1136/annrheumdis-2019-216150.
Neuropsychiatric events occurred in just over half of all patients recently diagnosed with systemic lupus erythematosus and followed for an average of nearly 8 years in an international study of more than 1,800 patients.
Up to 30% of these neuropsychiatric (NP) events in up to 20% of the followed cohort were directly attributable to systemic lupus erythematosus (SLE) in a representative patient population, wrote John G. Hanly, MD, and associates in Annals of the Rheumatic Diseases. Their findings were consistent with prior reports, they added.
Another notable finding from follow-up of these 1,827 SLE patients was that among those without a history of SLE-related NP events at baseline, 74% remained free of NP events during the subsequent 10 years, wrote Dr. Hanly, professor of medicine and director of the lupus clinic at Dalhousie University, Halifax, N.S., and coauthors. Among patients free from SLE-associated NP events after 2 years, 84% remained event free during their remaining follow-up. SLE patients with a history of an NP event that subsequently resolved had a 72% rate of freedom from another NP event during 10 years of follow-up.
These findings came from patients recently diagnosed with SLE (within the preceding 15 months) and enrolled at any of 31 participating academic medical centers in North America, Europe, and Asia. The investigators considered preenrollment NP events to include those starting from 6 months prior to diagnosis of SLE until the time patients entered the study. They used case definitions for 19 SLE-associated NP events published by the American College of Rheumatology (Arthritis Rheum. 1999 Apr;42[4]:599-608). All enrolled patients underwent annual assessment for NP events, with follow-up continuing as long as 18 years.
The researchers identified NP events in 955 of the 1,827 enrolled patients, a 52% incidence, including 1,910 unique NP events that included episodes from each of the 19 NP event types, with 92% involving the central nervous system and 8% involving the peripheral nervous system. The percentage of NP events attributable to SLE ranged from 17% to 31%, and they occurred in 14%-21% of the studied patients, with the range reflecting various attribution models used in the analyses. Some patients remained in the same NP state, while others progressed through more than one state.
The study did not receive commercial funding. Dr. Hanly had no disclosures.
SOURCE: Hanly JG et al. Ann Rheum Dis. 2020 Jan 8. doi: 10.1136/annrheumdis-2019-216150.
Neuropsychiatric events occurred in just over half of all patients recently diagnosed with systemic lupus erythematosus and followed for an average of nearly 8 years in an international study of more than 1,800 patients.
Up to 30% of these neuropsychiatric (NP) events in up to 20% of the followed cohort were directly attributable to systemic lupus erythematosus (SLE) in a representative patient population, wrote John G. Hanly, MD, and associates in Annals of the Rheumatic Diseases. Their findings were consistent with prior reports, they added.
Another notable finding from follow-up of these 1,827 SLE patients was that among those without a history of SLE-related NP events at baseline, 74% remained free of NP events during the subsequent 10 years, wrote Dr. Hanly, professor of medicine and director of the lupus clinic at Dalhousie University, Halifax, N.S., and coauthors. Among patients free from SLE-associated NP events after 2 years, 84% remained event free during their remaining follow-up. SLE patients with a history of an NP event that subsequently resolved had a 72% rate of freedom from another NP event during 10 years of follow-up.
These findings came from patients recently diagnosed with SLE (within the preceding 15 months) and enrolled at any of 31 participating academic medical centers in North America, Europe, and Asia. The investigators considered preenrollment NP events to include those starting from 6 months prior to diagnosis of SLE until the time patients entered the study. They used case definitions for 19 SLE-associated NP events published by the American College of Rheumatology (Arthritis Rheum. 1999 Apr;42[4]:599-608). All enrolled patients underwent annual assessment for NP events, with follow-up continuing as long as 18 years.
The researchers identified NP events in 955 of the 1,827 enrolled patients, a 52% incidence, including 1,910 unique NP events that included episodes from each of the 19 NP event types, with 92% involving the central nervous system and 8% involving the peripheral nervous system. The percentage of NP events attributable to SLE ranged from 17% to 31%, and they occurred in 14%-21% of the studied patients, with the range reflecting various attribution models used in the analyses. Some patients remained in the same NP state, while others progressed through more than one state.
The study did not receive commercial funding. Dr. Hanly had no disclosures.
SOURCE: Hanly JG et al. Ann Rheum Dis. 2020 Jan 8. doi: 10.1136/annrheumdis-2019-216150.
FROM ANNALS OF THE RHEUMATIC DISEASES
Diabetes boosts bariatric surgery complications
LAS VEGAS – compared with patients without diabetes, in an analysis of more than 550,000 patients who underwent this surgery.
The analysis also showed that among patients with diabetes undergoing bariatric surgery, those with insulin-dependent diabetes had significantly higher rates of these and other complications, compared with patients with diabetes but no insulin dependence, Andrew A. Wheeler, MD, said at a meeting presented by The Obesity Society and the American Society for Metabolic and Bariatric Surgery.
The specific factors driving these observations remain unknown, but may relate at least in part to the efficacy of glycemic control in patients during the months and weeks before surgery, said Dr. Wheeler, chief of metabolic and bariatric surgery at the University of Missouri in Columbia.
“Perioperative blood glucose control reflected in hemoglobin A1c may help us understand if certain patients with diabetes are at increased risk of surgical complications,” Dr. Wheeler said during his talk. “We need to see whether preoperative hemoglobin A1c tracks with the rate of complications,” he added in an interview. “Some surgeons will defer surgery until the level goes down, but right now, everyone uses a different level.”
The study by Dr. Wheeler and associates used data collected from essentially all the bariatric surgeries done at the roughly 840 U.S. centers accredited to do the surgery during 2015-2017 – a total of 555,239 patients – in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program run by the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery. The cohort included 413,239 patients without diabetes and 136,010 with diabetes, with the remainder having an unknown status. Nearly all patients underwent either sleeve gastrectomy or gastric bypass, with significantly more patients, 74%, having sleeve gastrectomy in the group without diabetes, and 62% of those with diabetes undergoing sleeve gastrectomy.
Patients with diabetes uniformly had significantly higher rates of complications as measured by several parameters, and among those with diabetes, the complication rates were highest in those with insulin dependence. The researchers ran a multivariate analysis that controlled for many demographic and clinical variables, and found that despite these corrections, patients with diabetes, and especially those with insulin dependence, had higher relative rates of many complications that were statistically significant. In addition to the increased rates of deep surgical-site infections and 30-day ICU admissions, patients with diabetes had a 54% relatively increased rate of wound disruption, and a 29% increased relative rate of superficial surgical-site infections, compared with those without diabetes. And among patients with diabetes, those with insulin dependence had a 40% increased rate of surgical-site infections, a 74% increase in progressive renal failure, and a 39% increased rate of hospital readmission relative to patients with diabetes that was not insulin dependent, Dr. Wheeler reported.
The absolute complication rates were, in general, low. For example, the total rate of superficial plus deep surgical-site infections was less than 1% both in patients with diabetes and those without, although the rate rose above 1% in patients with insulin-dependent diabetes. The most common complication reported by Dr. Wheeler was 30-day hospital readmission, which was 4.0% in patients without diabetes, 4.8% in those with diabetes, and 6.4% in patients with insulin-dependent diabetes. The data also showed that gastric bypass led to more complications than did sleeve gastrectomy, but complications with both types of surgeries increased in patients with diabetes, compared with those without diabetes.
Dr. Wheeler had no disclosures.
SOURCE: Wheeler AA et al. Obesity Week 2019, Abstract A133.
Most bariatric surgeons believe that patients with diabetes who undergo this surgery will have more complications than will patients without diabetes, based on their anecdotal experience and findings from previous, smaller studies. But in Dr. Wheeler’s report, we see this demonstrated in an incredibly large number of patients. This is one of the first studies to use 3 years of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, which included more than half a million patients.
A randomized study involving more than 18,000 cases showed that putting bariatric surgery patients on an “enhanced recovery program” before surgery and including measures that minimized insulin resistance and catabolism perioperatively led to a substantial reduction in extended length of stay (Surg Obes Relat Dis. 2019 Nov;15[11]:1977-89). In routine care, bariatric surgeons are now often routinely using “prehabilitation” to prepare patients for surgery.
Corrigan McBride, MD , is professor of surgery and director of bariatric surgery at the University of Nebraska Medical Center in Omaha. She had no disclosures. She made these comments in an interview.
Most bariatric surgeons believe that patients with diabetes who undergo this surgery will have more complications than will patients without diabetes, based on their anecdotal experience and findings from previous, smaller studies. But in Dr. Wheeler’s report, we see this demonstrated in an incredibly large number of patients. This is one of the first studies to use 3 years of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, which included more than half a million patients.
A randomized study involving more than 18,000 cases showed that putting bariatric surgery patients on an “enhanced recovery program” before surgery and including measures that minimized insulin resistance and catabolism perioperatively led to a substantial reduction in extended length of stay (Surg Obes Relat Dis. 2019 Nov;15[11]:1977-89). In routine care, bariatric surgeons are now often routinely using “prehabilitation” to prepare patients for surgery.
Corrigan McBride, MD , is professor of surgery and director of bariatric surgery at the University of Nebraska Medical Center in Omaha. She had no disclosures. She made these comments in an interview.
Most bariatric surgeons believe that patients with diabetes who undergo this surgery will have more complications than will patients without diabetes, based on their anecdotal experience and findings from previous, smaller studies. But in Dr. Wheeler’s report, we see this demonstrated in an incredibly large number of patients. This is one of the first studies to use 3 years of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, which included more than half a million patients.
A randomized study involving more than 18,000 cases showed that putting bariatric surgery patients on an “enhanced recovery program” before surgery and including measures that minimized insulin resistance and catabolism perioperatively led to a substantial reduction in extended length of stay (Surg Obes Relat Dis. 2019 Nov;15[11]:1977-89). In routine care, bariatric surgeons are now often routinely using “prehabilitation” to prepare patients for surgery.
Corrigan McBride, MD , is professor of surgery and director of bariatric surgery at the University of Nebraska Medical Center in Omaha. She had no disclosures. She made these comments in an interview.
LAS VEGAS – compared with patients without diabetes, in an analysis of more than 550,000 patients who underwent this surgery.
The analysis also showed that among patients with diabetes undergoing bariatric surgery, those with insulin-dependent diabetes had significantly higher rates of these and other complications, compared with patients with diabetes but no insulin dependence, Andrew A. Wheeler, MD, said at a meeting presented by The Obesity Society and the American Society for Metabolic and Bariatric Surgery.
The specific factors driving these observations remain unknown, but may relate at least in part to the efficacy of glycemic control in patients during the months and weeks before surgery, said Dr. Wheeler, chief of metabolic and bariatric surgery at the University of Missouri in Columbia.
“Perioperative blood glucose control reflected in hemoglobin A1c may help us understand if certain patients with diabetes are at increased risk of surgical complications,” Dr. Wheeler said during his talk. “We need to see whether preoperative hemoglobin A1c tracks with the rate of complications,” he added in an interview. “Some surgeons will defer surgery until the level goes down, but right now, everyone uses a different level.”
The study by Dr. Wheeler and associates used data collected from essentially all the bariatric surgeries done at the roughly 840 U.S. centers accredited to do the surgery during 2015-2017 – a total of 555,239 patients – in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program run by the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery. The cohort included 413,239 patients without diabetes and 136,010 with diabetes, with the remainder having an unknown status. Nearly all patients underwent either sleeve gastrectomy or gastric bypass, with significantly more patients, 74%, having sleeve gastrectomy in the group without diabetes, and 62% of those with diabetes undergoing sleeve gastrectomy.
Patients with diabetes uniformly had significantly higher rates of complications as measured by several parameters, and among those with diabetes, the complication rates were highest in those with insulin dependence. The researchers ran a multivariate analysis that controlled for many demographic and clinical variables, and found that despite these corrections, patients with diabetes, and especially those with insulin dependence, had higher relative rates of many complications that were statistically significant. In addition to the increased rates of deep surgical-site infections and 30-day ICU admissions, patients with diabetes had a 54% relatively increased rate of wound disruption, and a 29% increased relative rate of superficial surgical-site infections, compared with those without diabetes. And among patients with diabetes, those with insulin dependence had a 40% increased rate of surgical-site infections, a 74% increase in progressive renal failure, and a 39% increased rate of hospital readmission relative to patients with diabetes that was not insulin dependent, Dr. Wheeler reported.
The absolute complication rates were, in general, low. For example, the total rate of superficial plus deep surgical-site infections was less than 1% both in patients with diabetes and those without, although the rate rose above 1% in patients with insulin-dependent diabetes. The most common complication reported by Dr. Wheeler was 30-day hospital readmission, which was 4.0% in patients without diabetes, 4.8% in those with diabetes, and 6.4% in patients with insulin-dependent diabetes. The data also showed that gastric bypass led to more complications than did sleeve gastrectomy, but complications with both types of surgeries increased in patients with diabetes, compared with those without diabetes.
Dr. Wheeler had no disclosures.
SOURCE: Wheeler AA et al. Obesity Week 2019, Abstract A133.
LAS VEGAS – compared with patients without diabetes, in an analysis of more than 550,000 patients who underwent this surgery.
The analysis also showed that among patients with diabetes undergoing bariatric surgery, those with insulin-dependent diabetes had significantly higher rates of these and other complications, compared with patients with diabetes but no insulin dependence, Andrew A. Wheeler, MD, said at a meeting presented by The Obesity Society and the American Society for Metabolic and Bariatric Surgery.
The specific factors driving these observations remain unknown, but may relate at least in part to the efficacy of glycemic control in patients during the months and weeks before surgery, said Dr. Wheeler, chief of metabolic and bariatric surgery at the University of Missouri in Columbia.
“Perioperative blood glucose control reflected in hemoglobin A1c may help us understand if certain patients with diabetes are at increased risk of surgical complications,” Dr. Wheeler said during his talk. “We need to see whether preoperative hemoglobin A1c tracks with the rate of complications,” he added in an interview. “Some surgeons will defer surgery until the level goes down, but right now, everyone uses a different level.”
The study by Dr. Wheeler and associates used data collected from essentially all the bariatric surgeries done at the roughly 840 U.S. centers accredited to do the surgery during 2015-2017 – a total of 555,239 patients – in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program run by the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery. The cohort included 413,239 patients without diabetes and 136,010 with diabetes, with the remainder having an unknown status. Nearly all patients underwent either sleeve gastrectomy or gastric bypass, with significantly more patients, 74%, having sleeve gastrectomy in the group without diabetes, and 62% of those with diabetes undergoing sleeve gastrectomy.
Patients with diabetes uniformly had significantly higher rates of complications as measured by several parameters, and among those with diabetes, the complication rates were highest in those with insulin dependence. The researchers ran a multivariate analysis that controlled for many demographic and clinical variables, and found that despite these corrections, patients with diabetes, and especially those with insulin dependence, had higher relative rates of many complications that were statistically significant. In addition to the increased rates of deep surgical-site infections and 30-day ICU admissions, patients with diabetes had a 54% relatively increased rate of wound disruption, and a 29% increased relative rate of superficial surgical-site infections, compared with those without diabetes. And among patients with diabetes, those with insulin dependence had a 40% increased rate of surgical-site infections, a 74% increase in progressive renal failure, and a 39% increased rate of hospital readmission relative to patients with diabetes that was not insulin dependent, Dr. Wheeler reported.
The absolute complication rates were, in general, low. For example, the total rate of superficial plus deep surgical-site infections was less than 1% both in patients with diabetes and those without, although the rate rose above 1% in patients with insulin-dependent diabetes. The most common complication reported by Dr. Wheeler was 30-day hospital readmission, which was 4.0% in patients without diabetes, 4.8% in those with diabetes, and 6.4% in patients with insulin-dependent diabetes. The data also showed that gastric bypass led to more complications than did sleeve gastrectomy, but complications with both types of surgeries increased in patients with diabetes, compared with those without diabetes.
Dr. Wheeler had no disclosures.
SOURCE: Wheeler AA et al. Obesity Week 2019, Abstract A133.
REPORTING FROM OBESITY WEEK 2019
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,