Conference Coverage

In patients with stable chest pain, the burden of low-attenuation noncalcified plaque on coronary CT angiography is a better predictor of future myocardial infarction risk than a cardiovascular risk score, an Agatson coronary artery calcium score, or angiographic severity of coronary stenoses, Michelle C. Williams, MBChB, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

These findings from a post hoc analysis of the large multicenter SCOT-HEART trial challenge current concepts regarding the supposed superiority of the classic tools for MI risk prediction, noted Dr. Williams, a senior clinical research fellow at the University of Edinburgh.

Indeed, it’s likely that the current established predictors of risk – that is, coronary artery calcium, severity of stenosis, and cardiovascular risk score – are associated with clinical events only indirectly through their correlation with low-attenuated calcified plaque burden, which is the real driver of future MI, she continued.

Histologically, low-attenuated noncalcified plaque on coronary CT angiography (CCTA) is defined by a thin fibrous cap, a large, inflamed, lipid-rich necrotic core, and microcalcification. Previously, Dr. Williams and her coinvestigators demonstrated that visual identification of this unstable plaque subtype is of benefit in predicting future risk of MI (J Am Coll Cardiol. 2019 Jan 29;73[3]:291-301).

But visual identification of plaque subtypes is a crude and laborious process. In her current study, she and her coworkers have taken things a giant step further, using commercially available CCTA software to semiautomatically quantify the burden of this highest-risk plaque subtype as well as all the other subtypes.

This post hoc analysis of the previously reported main SCOT-HEART trial (N Engl J Med. 2018 Sep 6;379[10]:924-933) included 1,769 patients with stable chest pain randomized to standard care with or without CCTA guidance and followed for a median of 4.7 years, during which 41 patients had a fatal or nonfatal MI. At enrollment, 37% of participants had normal coronary arteries, 38% had nonobstructive coronary artery disease (CAD), and the remainder had obstructive CAD.

In a multivariate analysis, low-attenuation noncalcified plaque burden was the strongest predictor of future MI, with an adjusted hazard ratio of 1.6 per doubling. This metric was strongly correlated with coronary artery calcium score, underscoring the limited value of doing noncontrast CT in order to determine a coronary artery calcium score when CCTA is performed.

Low-attenuation plaque burden correlated very strongly with angiographic severity of stenosis, and only weakly with cardiovascular risk score, perhaps explaining the poor prognostic performance of cardiovascular risk scores in SCOT-HEART and other studies, according to Dr. Williams.

Patients with a low-attenuation noncalcified plaque burden greater than 4% in their coronary tree were 4.7 times more likely to have a subsequent MI than were those with a lesser burden. The predictive power was even greater in patients with nonobstructive CAD, where a low-attenuation noncalcified plaque burden in excess of 4% conferred a 6.6-fold greater likelihood of fatal or nonfatal MI, she observed.

Two things need to happen before measurement of low-attenuation noncalcified plaque via CCTA to predict MI risk is ready to be adopted in routine clinical practice, according to Dr. Williams. These SCOT-HEART results need to be validated in other cohorts, a process now underway in the SCOT-HEART 2 trial and other studies. Also, improved software incorporating machine learning is needed in order to speed up the semiautomated analysis of plaque subtypes, which now takes 20-30 minutes.

Dr. Williams reported having no financial conflicts regarding her study, funded by the National Health Service.

In conjunction with her virtual presentation at ACC 2020, the SCOT-HEART study results were published online (Circulation. 2020 Mar 16. doi: 10.1161/CIRCULATIONAHA.119.044720. [Epub ahead of print]).

bjancin@mdedge.com

SOURCE: Williams MC et al. ACC 2020, Abstract 909-06.

In patients with stable chest pain, the burden of low-attenuation noncalcified plaque on coronary CT angiography is a better predictor of future myocardial infarction risk than a cardiovascular risk score, an Agatson coronary artery calcium score, or angiographic severity of coronary stenoses, Michelle C. Williams, MBChB, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

These findings from a post hoc analysis of the large multicenter SCOT-HEART trial challenge current concepts regarding the supposed superiority of the classic tools for MI risk prediction, noted Dr. Williams, a senior clinical research fellow at the University of Edinburgh.

Indeed, it’s likely that the current established predictors of risk – that is, coronary artery calcium, severity of stenosis, and cardiovascular risk score – are associated with clinical events only indirectly through their correlation with low-attenuated calcified plaque burden, which is the real driver of future MI, she continued.

Histologically, low-attenuated noncalcified plaque on coronary CT angiography (CCTA) is defined by a thin fibrous cap, a large, inflamed, lipid-rich necrotic core, and microcalcification. Previously, Dr. Williams and her coinvestigators demonstrated that visual identification of this unstable plaque subtype is of benefit in predicting future risk of MI (J Am Coll Cardiol. 2019 Jan 29;73[3]:291-301).

But visual identification of plaque subtypes is a crude and laborious process. In her current study, she and her coworkers have taken things a giant step further, using commercially available CCTA software to semiautomatically quantify the burden of this highest-risk plaque subtype as well as all the other subtypes.

This post hoc analysis of the previously reported main SCOT-HEART trial (N Engl J Med. 2018 Sep 6;379[10]:924-933) included 1,769 patients with stable chest pain randomized to standard care with or without CCTA guidance and followed for a median of 4.7 years, during which 41 patients had a fatal or nonfatal MI. At enrollment, 37% of participants had normal coronary arteries, 38% had nonobstructive coronary artery disease (CAD), and the remainder had obstructive CAD.

In a multivariate analysis, low-attenuation noncalcified plaque burden was the strongest predictor of future MI, with an adjusted hazard ratio of 1.6 per doubling. This metric was strongly correlated with coronary artery calcium score, underscoring the limited value of doing noncontrast CT in order to determine a coronary artery calcium score when CCTA is performed.

Low-attenuation plaque burden correlated very strongly with angiographic severity of stenosis, and only weakly with cardiovascular risk score, perhaps explaining the poor prognostic performance of cardiovascular risk scores in SCOT-HEART and other studies, according to Dr. Williams.

Patients with a low-attenuation noncalcified plaque burden greater than 4% in their coronary tree were 4.7 times more likely to have a subsequent MI than were those with a lesser burden. The predictive power was even greater in patients with nonobstructive CAD, where a low-attenuation noncalcified plaque burden in excess of 4% conferred a 6.6-fold greater likelihood of fatal or nonfatal MI, she observed.

Two things need to happen before measurement of low-attenuation noncalcified plaque via CCTA to predict MI risk is ready to be adopted in routine clinical practice, according to Dr. Williams. These SCOT-HEART results need to be validated in other cohorts, a process now underway in the SCOT-HEART 2 trial and other studies. Also, improved software incorporating machine learning is needed in order to speed up the semiautomated analysis of plaque subtypes, which now takes 20-30 minutes.

Dr. Williams reported having no financial conflicts regarding her study, funded by the National Health Service.

In conjunction with her virtual presentation at ACC 2020, the SCOT-HEART study results were published online (Circulation. 2020 Mar 16. doi: 10.1161/CIRCULATIONAHA.119.044720. [Epub ahead of print]).

bjancin@mdedge.com

SOURCE: Williams MC et al. ACC 2020, Abstract 909-06.

In patients with stable chest pain, the burden of low-attenuation noncalcified plaque on coronary CT angiography is a better predictor of future myocardial infarction risk than a cardiovascular risk score, an Agatson coronary artery calcium score, or angiographic severity of coronary stenoses, Michelle C. Williams, MBChB, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

These findings from a post hoc analysis of the large multicenter SCOT-HEART trial challenge current concepts regarding the supposed superiority of the classic tools for MI risk prediction, noted Dr. Williams, a senior clinical research fellow at the University of Edinburgh.

Indeed, it’s likely that the current established predictors of risk – that is, coronary artery calcium, severity of stenosis, and cardiovascular risk score – are associated with clinical events only indirectly through their correlation with low-attenuated calcified plaque burden, which is the real driver of future MI, she continued.

Histologically, low-attenuated noncalcified plaque on coronary CT angiography (CCTA) is defined by a thin fibrous cap, a large, inflamed, lipid-rich necrotic core, and microcalcification. Previously, Dr. Williams and her coinvestigators demonstrated that visual identification of this unstable plaque subtype is of benefit in predicting future risk of MI (J Am Coll Cardiol. 2019 Jan 29;73[3]:291-301).

But visual identification of plaque subtypes is a crude and laborious process. In her current study, she and her coworkers have taken things a giant step further, using commercially available CCTA software to semiautomatically quantify the burden of this highest-risk plaque subtype as well as all the other subtypes.

This post hoc analysis of the previously reported main SCOT-HEART trial (N Engl J Med. 2018 Sep 6;379[10]:924-933) included 1,769 patients with stable chest pain randomized to standard care with or without CCTA guidance and followed for a median of 4.7 years, during which 41 patients had a fatal or nonfatal MI. At enrollment, 37% of participants had normal coronary arteries, 38% had nonobstructive coronary artery disease (CAD), and the remainder had obstructive CAD.

In a multivariate analysis, low-attenuation noncalcified plaque burden was the strongest predictor of future MI, with an adjusted hazard ratio of 1.6 per doubling. This metric was strongly correlated with coronary artery calcium score, underscoring the limited value of doing noncontrast CT in order to determine a coronary artery calcium score when CCTA is performed.

Low-attenuation plaque burden correlated very strongly with angiographic severity of stenosis, and only weakly with cardiovascular risk score, perhaps explaining the poor prognostic performance of cardiovascular risk scores in SCOT-HEART and other studies, according to Dr. Williams.

Patients with a low-attenuation noncalcified plaque burden greater than 4% in their coronary tree were 4.7 times more likely to have a subsequent MI than were those with a lesser burden. The predictive power was even greater in patients with nonobstructive CAD, where a low-attenuation noncalcified plaque burden in excess of 4% conferred a 6.6-fold greater likelihood of fatal or nonfatal MI, she observed.

Two things need to happen before measurement of low-attenuation noncalcified plaque via CCTA to predict MI risk is ready to be adopted in routine clinical practice, according to Dr. Williams. These SCOT-HEART results need to be validated in other cohorts, a process now underway in the SCOT-HEART 2 trial and other studies. Also, improved software incorporating machine learning is needed in order to speed up the semiautomated analysis of plaque subtypes, which now takes 20-30 minutes.

Dr. Williams reported having no financial conflicts regarding her study, funded by the National Health Service.

In conjunction with her virtual presentation at ACC 2020, the SCOT-HEART study results were published online (Circulation. 2020 Mar 16. doi: 10.1161/CIRCULATIONAHA.119.044720. [Epub ahead of print]).

bjancin@mdedge.com

SOURCE: Williams MC et al. ACC 2020, Abstract 909-06.

Adults given propofol as part of an elective outpatient endoscopy procedure showed similar driving skills after postsedation recovery and prior to the procedure, based on simulation data from an open-label study of 41 patients.

Although current guidelines recommend that patients refrain from driving for 24 hours after propofol sedation and be accompanied by a responsible adult, data on the driving skills of patients after postsedation recovery are limited, Pooja Lal, MD, of the Cleveland Clinic Foundation and colleagues wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“We assessed psychomotor recovery using a driving simulator which mimics real-life driving in outpatients undergoing gastrointestinal endoscopy with propofol,” they wrote.

The researchers enrolled 41 outpatients who were given propofol for various elective procedures at an endoscopy unit of a single center. Patients’ driving skills were tested at baseline and after postsedation recovery using a driving simulator. Postsedation recovery was defined as Aldrete score of 9 in the recovery room. Patients were excluded from the study if they demonstrated altered mental status of any type including dementia, delirium, and hepatic encephalopathy; if they were legally blind; or were currently inpatients.

Overall, driving skills were not significantly different between preprocedure and postsedation recovery on measures of number of times over the speed limit (3.2 vs. 3.4), number of times drivers went off the road (0.37 vs. 0.54), and total pedal reaction time (6.1 seconds vs. 7.6 seconds).

“The two variables including gas pedal reaction time and the total number of collisions did not follow normal distribution,” with medians of 0.70 for gas pedal reaction time in both groups and medians of 0 collisions for both groups, the investigators noted.

The study findings were limited by the small sample size and open-label design. However, the results suggest that driving skills were similar for patients at baseline and after achieving a postsedation Aldrete score of 9, the researchers wrote. Based on these findings, “current recommendations that patients should refrain from driving and unescorted use of public transport for 24 hours after sedation may need to be reconsidered in patients who receive propofol sedation.”

“With this study, we are aiming to identify the correct patient population who could potentially drive themselves home after their procedure rather than having to arrange for transportation,” Dr. Lal said in an interview.

“The significant cost associated with the daylong interruption of the activities of daily living, having a family member accompany them for their procedures, or not being able to use public transport unescorted may deter some patients from complying with colonoscopy screenings and other important endoscopic procedures,” she explained.

“There are patients who arrive for their procedure without any accompanying family members and we have to admit them to an observation unit overnight or reschedule their procedures. The expense and inconvenience associated with the extended recovery potentially could be an impediment to many important screening exams,” she noted. “In the setting of increased awareness regarding the need for these screening exams, this study is important to highlight these barriers and propose a solution for them.”

The potential costs of lost salaries is extremely high, she said. “If we assume that the 24-hour recovery period necessitates taking a day off from work, the value of lost salary per patient would be $183.68 as per the 2019 national hourly average wage. With an estimated 19 million colonoscopies performed annually in the United States, the aggregate cost of lost wages with the 24-hour guideline would be $3.5 billion. This amount does not account for the lost wages of the accompanying family member.”

Dr. Lal said she and her colleagues were not surprised by the findings. “The endoscopists in our endoscopy unit have noted that patients recover much more rapidly after sedation with propofol compared with other sedative agents. This observation led to the hypothesis that those patients receiving propofol should have a speedy psychomotor recovery and should be able to drive the same day. Our findings are in accordance with our observations.” However, “larger and preferably multicenter studies are needed to validate these findings and add to our knowledge about the postsedation psychomotor recovery,” said Dr. Lal. She added that the study is ongoing and the researchers have collected data from a total of 63 patients, which increases the power of the results.

The researchers had no financial conflicts to disclose.

*This story was updated on 5/8/2020.

SOURCE: Lal P et al. DDW 2020, Abstract 295.

Adults given propofol as part of an elective outpatient endoscopy procedure showed similar driving skills after postsedation recovery and prior to the procedure, based on simulation data from an open-label study of 41 patients.

Although current guidelines recommend that patients refrain from driving for 24 hours after propofol sedation and be accompanied by a responsible adult, data on the driving skills of patients after postsedation recovery are limited, Pooja Lal, MD, of the Cleveland Clinic Foundation and colleagues wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“We assessed psychomotor recovery using a driving simulator which mimics real-life driving in outpatients undergoing gastrointestinal endoscopy with propofol,” they wrote.

The researchers enrolled 41 outpatients who were given propofol for various elective procedures at an endoscopy unit of a single center. Patients’ driving skills were tested at baseline and after postsedation recovery using a driving simulator. Postsedation recovery was defined as Aldrete score of 9 in the recovery room. Patients were excluded from the study if they demonstrated altered mental status of any type including dementia, delirium, and hepatic encephalopathy; if they were legally blind; or were currently inpatients.

Overall, driving skills were not significantly different between preprocedure and postsedation recovery on measures of number of times over the speed limit (3.2 vs. 3.4), number of times drivers went off the road (0.37 vs. 0.54), and total pedal reaction time (6.1 seconds vs. 7.6 seconds).

“The two variables including gas pedal reaction time and the total number of collisions did not follow normal distribution,” with medians of 0.70 for gas pedal reaction time in both groups and medians of 0 collisions for both groups, the investigators noted.

The study findings were limited by the small sample size and open-label design. However, the results suggest that driving skills were similar for patients at baseline and after achieving a postsedation Aldrete score of 9, the researchers wrote. Based on these findings, “current recommendations that patients should refrain from driving and unescorted use of public transport for 24 hours after sedation may need to be reconsidered in patients who receive propofol sedation.”

“With this study, we are aiming to identify the correct patient population who could potentially drive themselves home after their procedure rather than having to arrange for transportation,” Dr. Lal said in an interview.

“The significant cost associated with the daylong interruption of the activities of daily living, having a family member accompany them for their procedures, or not being able to use public transport unescorted may deter some patients from complying with colonoscopy screenings and other important endoscopic procedures,” she explained.

“There are patients who arrive for their procedure without any accompanying family members and we have to admit them to an observation unit overnight or reschedule their procedures. The expense and inconvenience associated with the extended recovery potentially could be an impediment to many important screening exams,” she noted. “In the setting of increased awareness regarding the need for these screening exams, this study is important to highlight these barriers and propose a solution for them.”

The potential costs of lost salaries is extremely high, she said. “If we assume that the 24-hour recovery period necessitates taking a day off from work, the value of lost salary per patient would be $183.68 as per the 2019 national hourly average wage. With an estimated 19 million colonoscopies performed annually in the United States, the aggregate cost of lost wages with the 24-hour guideline would be $3.5 billion. This amount does not account for the lost wages of the accompanying family member.”

Dr. Lal said she and her colleagues were not surprised by the findings. “The endoscopists in our endoscopy unit have noted that patients recover much more rapidly after sedation with propofol compared with other sedative agents. This observation led to the hypothesis that those patients receiving propofol should have a speedy psychomotor recovery and should be able to drive the same day. Our findings are in accordance with our observations.” However, “larger and preferably multicenter studies are needed to validate these findings and add to our knowledge about the postsedation psychomotor recovery,” said Dr. Lal. She added that the study is ongoing and the researchers have collected data from a total of 63 patients, which increases the power of the results.

The researchers had no financial conflicts to disclose.

*This story was updated on 5/8/2020.

SOURCE: Lal P et al. DDW 2020, Abstract 295.

Adults given propofol as part of an elective outpatient endoscopy procedure showed similar driving skills after postsedation recovery and prior to the procedure, based on simulation data from an open-label study of 41 patients.

Although current guidelines recommend that patients refrain from driving for 24 hours after propofol sedation and be accompanied by a responsible adult, data on the driving skills of patients after postsedation recovery are limited, Pooja Lal, MD, of the Cleveland Clinic Foundation and colleagues wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“We assessed psychomotor recovery using a driving simulator which mimics real-life driving in outpatients undergoing gastrointestinal endoscopy with propofol,” they wrote.

The researchers enrolled 41 outpatients who were given propofol for various elective procedures at an endoscopy unit of a single center. Patients’ driving skills were tested at baseline and after postsedation recovery using a driving simulator. Postsedation recovery was defined as Aldrete score of 9 in the recovery room. Patients were excluded from the study if they demonstrated altered mental status of any type including dementia, delirium, and hepatic encephalopathy; if they were legally blind; or were currently inpatients.

Overall, driving skills were not significantly different between preprocedure and postsedation recovery on measures of number of times over the speed limit (3.2 vs. 3.4), number of times drivers went off the road (0.37 vs. 0.54), and total pedal reaction time (6.1 seconds vs. 7.6 seconds).

“The two variables including gas pedal reaction time and the total number of collisions did not follow normal distribution,” with medians of 0.70 for gas pedal reaction time in both groups and medians of 0 collisions for both groups, the investigators noted.

The study findings were limited by the small sample size and open-label design. However, the results suggest that driving skills were similar for patients at baseline and after achieving a postsedation Aldrete score of 9, the researchers wrote. Based on these findings, “current recommendations that patients should refrain from driving and unescorted use of public transport for 24 hours after sedation may need to be reconsidered in patients who receive propofol sedation.”

“With this study, we are aiming to identify the correct patient population who could potentially drive themselves home after their procedure rather than having to arrange for transportation,” Dr. Lal said in an interview.

“The significant cost associated with the daylong interruption of the activities of daily living, having a family member accompany them for their procedures, or not being able to use public transport unescorted may deter some patients from complying with colonoscopy screenings and other important endoscopic procedures,” she explained.

“There are patients who arrive for their procedure without any accompanying family members and we have to admit them to an observation unit overnight or reschedule their procedures. The expense and inconvenience associated with the extended recovery potentially could be an impediment to many important screening exams,” she noted. “In the setting of increased awareness regarding the need for these screening exams, this study is important to highlight these barriers and propose a solution for them.”

The potential costs of lost salaries is extremely high, she said. “If we assume that the 24-hour recovery period necessitates taking a day off from work, the value of lost salary per patient would be $183.68 as per the 2019 national hourly average wage. With an estimated 19 million colonoscopies performed annually in the United States, the aggregate cost of lost wages with the 24-hour guideline would be $3.5 billion. This amount does not account for the lost wages of the accompanying family member.”

Dr. Lal said she and her colleagues were not surprised by the findings. “The endoscopists in our endoscopy unit have noted that patients recover much more rapidly after sedation with propofol compared with other sedative agents. This observation led to the hypothesis that those patients receiving propofol should have a speedy psychomotor recovery and should be able to drive the same day. Our findings are in accordance with our observations.” However, “larger and preferably multicenter studies are needed to validate these findings and add to our knowledge about the postsedation psychomotor recovery,” said Dr. Lal. She added that the study is ongoing and the researchers have collected data from a total of 63 patients, which increases the power of the results.

The researchers had no financial conflicts to disclose.

*This story was updated on 5/8/2020.

SOURCE: Lal P et al. DDW 2020, Abstract 295.

Patients with an indication for an implantable cardiac defibrillator for primary prevention of sudden cardiac death and a sharply reduced left ventricular ejection fraction of 35% or less safely received treatment from a refined, subcutaneous device that produced one of the lowest rates of inappropriate cardiac shocks ever seen in a reported ICD study, in a single-arm trial with 1,111 patients followed for 18 months.

The results showed “high efficacy and safety with contemporary devices and programming” despite being “the ‘sickest’ cohort studied to date” for use of a subcutaneous ICD (S-ICD), Michael R. Gold, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. The 3.1% 1-year rate of patients who received at least one inappropriate shock was “the lowest reported for the S-ICD, and lower than in many transvenous ICD device studies,” and was also “the lowest 1-year rate reported to date for a multicenter ICD trial,” said Dr. Gold, a cardiac electrophysiologist and professor of medicine at the Medical University of South Carolina, Charleston. The upshot is that these data may help convince clinicians to be more liberal about offering a S-ICD device to patients with left ventricular function in this low range who need an ICD and do not need pacing.

The study’s primary endpoint was the rate of freedom from inappropriate shocks during 18 months of follow-up, which happened in 95.9% of patients and was highly statistically significant for meeting the prespecified performance goal of 91.6% that had been set using “standard Food and Drug Administration benchmarks,” with particular reliance on the performance shown in the MADIT-RIT trial (N Engl J Med. 2012 Dec 13;367[24]:2275-83).
 

S-ICDs maintain ‘niche’ status despite advantages

The S-ICD first received Food and Drug Administration clearance for U.S. use in 2012, but despite not requiring placement of a transvenous lead and thus eliminating the possibility for lead complications and deterioration, it so far has had very modest penetration into American practice. Recently, roughly 4% of U.S. patients who’ve received an ICD have had a subcutaneous model placed, relegating the S-ICD to “niche device” status, noted Andrea M. Russo, MD, director of electrophysiology and arrhythmia services at Cooper University Health Care in Camden, N.J. A major limitation of S-ICD devices is that they cannot provide chronic pacing and so aren’t an option for the many patients who also need this function in addition to protection from life-threatening ventricular arrhythmias.

“We have had a bias for whom we place an S-ICD,” explained Dr. Gold. “They have mostly been used in younger patients with less heart disease,” but when used in the current study cohort with markedly depressed heart function, the results showed that “we didn’t appear to harm patients in any way,” including no episodes of syncope because of an arrhythmia. Compared with other S-ICD studies, the patients in the new study, UNTOUCHED, had “lower ejection fractions, more heart failure diagnoses, and a higher rate of ischemic etiology.”

The tested S-ICD device appears to have safety and efficacy that is “just as good, and perhaps better” than many ICDs that use transvenous leads, “which was very surprising to us,” said Dr. Gold during a press briefing. “I think it will change practice” for ICD placement in patients who do not need pacing. “We found the device works even in the sickest patients.”

“This was a classic ICD population, with a low ejection fraction, and the results showed that the device performed well,” commented Dr. Russo, who served on the steering committee for the study. “I agree that the results will help” increase use of this device, but she added that other factors in addition to concerns about the inappropriate shock rate and the lack of most pacing functions have hobbled uptake since the device came on the market. These notably include a somewhat different placement approach than operators need to learn. The device is not always offered as an option to patients by their clinicians “in part because of their lack of familiarity, and concern about inappropriate shocks,” she said in an interview. That’s despite the clear attractions of a leaderless device, which obviates issues of lead deterioration, lead placement complications like perforations and pneumothorax, and sizing issues that can come up for women with narrower veins, as well as cutting the risk both for infections overall and for infections that progress to bacteremia, noted Dr. Russo, who is president of the Heart Rhythm Society.
 

Device improvements boost performance

The low 1-year and 18-month rates of inappropriate shocks likely occurred because of new filtering and programming incorporated into the tested device. “By changing the filter, we could make it more like a transvenous device” that is not fooled by T wave over sensing. The programing also included a high beat threshold, with a conditional zone above 200 beats per minute and an “aggressive shock zone” of 250 bpm, Dr. Gold said. This helped make the tested S-ICD more immune to inappropriately shocking a supraventricular arrhythmia; the study recorded no inappropriate shocks of this type, he reported.

The UNTOUCHED study enrolled 1,116 patients at any of 110 sites in the United States and elsewhere who had a need for primary prevention of sudden cardiac death, a left ventricular ejection fraction of 35% or less, no need for pacing, and had successfully passed an S-ICD screening test. The investigators were able to include 1,111 of these patients in their endpoint analysis. Patients averaged 56 years of age, a quarter were women, and their average ejection fraction was 26%.

In addition to the primary endpoint and the 1-year inappropriate-shock rate, the results also showed an all-cause shock-free rate of 90.6% during 18-months’ follow-up, which significantly surpassed the prespecified performance goal for this metric of 85.8%. The tested device also appeared to successfully apply appropriate shocks when needed, delivering a total of 64 of these with just 1 shock failure, a case where the patient spontaneously reverted to normal rhythm. During the study period, 53 patients died (5%), including 3 arrhythmia-related deaths: 1 caused by asystole and 2 from pulseless electrical activity.

“The data show that in a standard ICD population, the device worked well, and was safe and effective,” Dr. Russo said. “These data say, at least consider this device along with a transvenous device” for appropriate patients. “It’s a great option for some patients. I’ve seen so may lead problems, and this avoids them.”

UNTOUCHED was sponsored by Boston Scientific, the company that markets the tested S-ICD. Dr. Gold has been a consultant to Boston Scientific and Medtronic and has been an investigator for trials sponsored by each of these companies. Dr. Russo served on the steering committee for UNTOUCHED but received no compensation and has no financial disclosures.

mzoler@mdedge.com

Patients with an indication for an implantable cardiac defibrillator for primary prevention of sudden cardiac death and a sharply reduced left ventricular ejection fraction of 35% or less safely received treatment from a refined, subcutaneous device that produced one of the lowest rates of inappropriate cardiac shocks ever seen in a reported ICD study, in a single-arm trial with 1,111 patients followed for 18 months.

The results showed “high efficacy and safety with contemporary devices and programming” despite being “the ‘sickest’ cohort studied to date” for use of a subcutaneous ICD (S-ICD), Michael R. Gold, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. The 3.1% 1-year rate of patients who received at least one inappropriate shock was “the lowest reported for the S-ICD, and lower than in many transvenous ICD device studies,” and was also “the lowest 1-year rate reported to date for a multicenter ICD trial,” said Dr. Gold, a cardiac electrophysiologist and professor of medicine at the Medical University of South Carolina, Charleston. The upshot is that these data may help convince clinicians to be more liberal about offering a S-ICD device to patients with left ventricular function in this low range who need an ICD and do not need pacing.

The study’s primary endpoint was the rate of freedom from inappropriate shocks during 18 months of follow-up, which happened in 95.9% of patients and was highly statistically significant for meeting the prespecified performance goal of 91.6% that had been set using “standard Food and Drug Administration benchmarks,” with particular reliance on the performance shown in the MADIT-RIT trial (N Engl J Med. 2012 Dec 13;367[24]:2275-83).
 

S-ICDs maintain ‘niche’ status despite advantages

The S-ICD first received Food and Drug Administration clearance for U.S. use in 2012, but despite not requiring placement of a transvenous lead and thus eliminating the possibility for lead complications and deterioration, it so far has had very modest penetration into American practice. Recently, roughly 4% of U.S. patients who’ve received an ICD have had a subcutaneous model placed, relegating the S-ICD to “niche device” status, noted Andrea M. Russo, MD, director of electrophysiology and arrhythmia services at Cooper University Health Care in Camden, N.J. A major limitation of S-ICD devices is that they cannot provide chronic pacing and so aren’t an option for the many patients who also need this function in addition to protection from life-threatening ventricular arrhythmias.

“We have had a bias for whom we place an S-ICD,” explained Dr. Gold. “They have mostly been used in younger patients with less heart disease,” but when used in the current study cohort with markedly depressed heart function, the results showed that “we didn’t appear to harm patients in any way,” including no episodes of syncope because of an arrhythmia. Compared with other S-ICD studies, the patients in the new study, UNTOUCHED, had “lower ejection fractions, more heart failure diagnoses, and a higher rate of ischemic etiology.”

The tested S-ICD device appears to have safety and efficacy that is “just as good, and perhaps better” than many ICDs that use transvenous leads, “which was very surprising to us,” said Dr. Gold during a press briefing. “I think it will change practice” for ICD placement in patients who do not need pacing. “We found the device works even in the sickest patients.”

“This was a classic ICD population, with a low ejection fraction, and the results showed that the device performed well,” commented Dr. Russo, who served on the steering committee for the study. “I agree that the results will help” increase use of this device, but she added that other factors in addition to concerns about the inappropriate shock rate and the lack of most pacing functions have hobbled uptake since the device came on the market. These notably include a somewhat different placement approach than operators need to learn. The device is not always offered as an option to patients by their clinicians “in part because of their lack of familiarity, and concern about inappropriate shocks,” she said in an interview. That’s despite the clear attractions of a leaderless device, which obviates issues of lead deterioration, lead placement complications like perforations and pneumothorax, and sizing issues that can come up for women with narrower veins, as well as cutting the risk both for infections overall and for infections that progress to bacteremia, noted Dr. Russo, who is president of the Heart Rhythm Society.
 

Device improvements boost performance

The low 1-year and 18-month rates of inappropriate shocks likely occurred because of new filtering and programming incorporated into the tested device. “By changing the filter, we could make it more like a transvenous device” that is not fooled by T wave over sensing. The programing also included a high beat threshold, with a conditional zone above 200 beats per minute and an “aggressive shock zone” of 250 bpm, Dr. Gold said. This helped make the tested S-ICD more immune to inappropriately shocking a supraventricular arrhythmia; the study recorded no inappropriate shocks of this type, he reported.

The UNTOUCHED study enrolled 1,116 patients at any of 110 sites in the United States and elsewhere who had a need for primary prevention of sudden cardiac death, a left ventricular ejection fraction of 35% or less, no need for pacing, and had successfully passed an S-ICD screening test. The investigators were able to include 1,111 of these patients in their endpoint analysis. Patients averaged 56 years of age, a quarter were women, and their average ejection fraction was 26%.

In addition to the primary endpoint and the 1-year inappropriate-shock rate, the results also showed an all-cause shock-free rate of 90.6% during 18-months’ follow-up, which significantly surpassed the prespecified performance goal for this metric of 85.8%. The tested device also appeared to successfully apply appropriate shocks when needed, delivering a total of 64 of these with just 1 shock failure, a case where the patient spontaneously reverted to normal rhythm. During the study period, 53 patients died (5%), including 3 arrhythmia-related deaths: 1 caused by asystole and 2 from pulseless electrical activity.

“The data show that in a standard ICD population, the device worked well, and was safe and effective,” Dr. Russo said. “These data say, at least consider this device along with a transvenous device” for appropriate patients. “It’s a great option for some patients. I’ve seen so may lead problems, and this avoids them.”

UNTOUCHED was sponsored by Boston Scientific, the company that markets the tested S-ICD. Dr. Gold has been a consultant to Boston Scientific and Medtronic and has been an investigator for trials sponsored by each of these companies. Dr. Russo served on the steering committee for UNTOUCHED but received no compensation and has no financial disclosures.

mzoler@mdedge.com

Patients with an indication for an implantable cardiac defibrillator for primary prevention of sudden cardiac death and a sharply reduced left ventricular ejection fraction of 35% or less safely received treatment from a refined, subcutaneous device that produced one of the lowest rates of inappropriate cardiac shocks ever seen in a reported ICD study, in a single-arm trial with 1,111 patients followed for 18 months.

The results showed “high efficacy and safety with contemporary devices and programming” despite being “the ‘sickest’ cohort studied to date” for use of a subcutaneous ICD (S-ICD), Michael R. Gold, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. The 3.1% 1-year rate of patients who received at least one inappropriate shock was “the lowest reported for the S-ICD, and lower than in many transvenous ICD device studies,” and was also “the lowest 1-year rate reported to date for a multicenter ICD trial,” said Dr. Gold, a cardiac electrophysiologist and professor of medicine at the Medical University of South Carolina, Charleston. The upshot is that these data may help convince clinicians to be more liberal about offering a S-ICD device to patients with left ventricular function in this low range who need an ICD and do not need pacing.

The study’s primary endpoint was the rate of freedom from inappropriate shocks during 18 months of follow-up, which happened in 95.9% of patients and was highly statistically significant for meeting the prespecified performance goal of 91.6% that had been set using “standard Food and Drug Administration benchmarks,” with particular reliance on the performance shown in the MADIT-RIT trial (N Engl J Med. 2012 Dec 13;367[24]:2275-83).
 

S-ICDs maintain ‘niche’ status despite advantages

The S-ICD first received Food and Drug Administration clearance for U.S. use in 2012, but despite not requiring placement of a transvenous lead and thus eliminating the possibility for lead complications and deterioration, it so far has had very modest penetration into American practice. Recently, roughly 4% of U.S. patients who’ve received an ICD have had a subcutaneous model placed, relegating the S-ICD to “niche device” status, noted Andrea M. Russo, MD, director of electrophysiology and arrhythmia services at Cooper University Health Care in Camden, N.J. A major limitation of S-ICD devices is that they cannot provide chronic pacing and so aren’t an option for the many patients who also need this function in addition to protection from life-threatening ventricular arrhythmias.

“We have had a bias for whom we place an S-ICD,” explained Dr. Gold. “They have mostly been used in younger patients with less heart disease,” but when used in the current study cohort with markedly depressed heart function, the results showed that “we didn’t appear to harm patients in any way,” including no episodes of syncope because of an arrhythmia. Compared with other S-ICD studies, the patients in the new study, UNTOUCHED, had “lower ejection fractions, more heart failure diagnoses, and a higher rate of ischemic etiology.”

The tested S-ICD device appears to have safety and efficacy that is “just as good, and perhaps better” than many ICDs that use transvenous leads, “which was very surprising to us,” said Dr. Gold during a press briefing. “I think it will change practice” for ICD placement in patients who do not need pacing. “We found the device works even in the sickest patients.”

“This was a classic ICD population, with a low ejection fraction, and the results showed that the device performed well,” commented Dr. Russo, who served on the steering committee for the study. “I agree that the results will help” increase use of this device, but she added that other factors in addition to concerns about the inappropriate shock rate and the lack of most pacing functions have hobbled uptake since the device came on the market. These notably include a somewhat different placement approach than operators need to learn. The device is not always offered as an option to patients by their clinicians “in part because of their lack of familiarity, and concern about inappropriate shocks,” she said in an interview. That’s despite the clear attractions of a leaderless device, which obviates issues of lead deterioration, lead placement complications like perforations and pneumothorax, and sizing issues that can come up for women with narrower veins, as well as cutting the risk both for infections overall and for infections that progress to bacteremia, noted Dr. Russo, who is president of the Heart Rhythm Society.
 

Device improvements boost performance

The low 1-year and 18-month rates of inappropriate shocks likely occurred because of new filtering and programming incorporated into the tested device. “By changing the filter, we could make it more like a transvenous device” that is not fooled by T wave over sensing. The programing also included a high beat threshold, with a conditional zone above 200 beats per minute and an “aggressive shock zone” of 250 bpm, Dr. Gold said. This helped make the tested S-ICD more immune to inappropriately shocking a supraventricular arrhythmia; the study recorded no inappropriate shocks of this type, he reported.

The UNTOUCHED study enrolled 1,116 patients at any of 110 sites in the United States and elsewhere who had a need for primary prevention of sudden cardiac death, a left ventricular ejection fraction of 35% or less, no need for pacing, and had successfully passed an S-ICD screening test. The investigators were able to include 1,111 of these patients in their endpoint analysis. Patients averaged 56 years of age, a quarter were women, and their average ejection fraction was 26%.

In addition to the primary endpoint and the 1-year inappropriate-shock rate, the results also showed an all-cause shock-free rate of 90.6% during 18-months’ follow-up, which significantly surpassed the prespecified performance goal for this metric of 85.8%. The tested device also appeared to successfully apply appropriate shocks when needed, delivering a total of 64 of these with just 1 shock failure, a case where the patient spontaneously reverted to normal rhythm. During the study period, 53 patients died (5%), including 3 arrhythmia-related deaths: 1 caused by asystole and 2 from pulseless electrical activity.

“The data show that in a standard ICD population, the device worked well, and was safe and effective,” Dr. Russo said. “These data say, at least consider this device along with a transvenous device” for appropriate patients. “It’s a great option for some patients. I’ve seen so may lead problems, and this avoids them.”

UNTOUCHED was sponsored by Boston Scientific, the company that markets the tested S-ICD. Dr. Gold has been a consultant to Boston Scientific and Medtronic and has been an investigator for trials sponsored by each of these companies. Dr. Russo served on the steering committee for UNTOUCHED but received no compensation and has no financial disclosures.

mzoler@mdedge.com

Moderate, daily coffee consumption had no apparent adverse effect for triggering incident heart arrhythmias, and even linked with a small but statistically significant drop in arrhythmias in an analysis of prospectively collected data from nearly 300,000 U.K. residents.

“In this large, population-based, prospective study, moderate habitual coffee drinking was associated with a lower risk of arrhythmia,” EunJeong Kim, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19.

Her analysis found that on average each additional daily cup of coffee that people said they drank reduced the incidence of arrhythmic episodes by a statistically significant 3%, compared with those who drank fewer daily cups. The relationship held for people who reported drinking as many as five or six cups of coffee daily.

“The main message of our study is that it does not appear to be deleterious to continue with moderate amounts of habitual coffee intake regarding a risk of overall arrhythmia,” said Dr. Kim, a cardiac electrophysiologist at the University of California, San Francisco.

Evidence builds for coffee’s safety

The finding adds to a substantial existing evidence base documenting the safety of moderate, habitual coffee drinking when it comes to heart rhythms. For example, a recent report from the Physicians Health Study of nearly 19,000 American men showed a statistically significant decrease in the incidence of atrial fibrillation during an average follow-up of 9 years among men who reported drinking one to three cups of coffee daily (J Am Heart Assoc. 2019 Aug 6;8[15]:e011346). In addition, a recent review of several reports found that “mild-to-moderate habitual consumption of caffeinated beverages, particularly a daily intake of 2-3 cups of coffee or tea, appears to be safe across a broad range of cardiovascular conditions, and may even be beneficial with respect to diabetes mellitus, atherosclerosis, heart failure, arrhythmia and total mortality,” but also concluded that “acute consumption of high doses of caffeine, particularly in the form of energy drinks, is best avoided”(Trends Cardiovasc Med. 2019 Aug;29[6]:345-50). Specifically about cardiac arrhythmias, the review said “while caffeine is commonly considered a trigger for arrhythmias by physicians and patients alike there is minimal evidence to support this misconception. Rather caffeine is associated with a mild reduction in the incidence of atrial fibrillation in observational studies.”

“There has been a lot of public interest about a possible association of caffeine and arrhythmias,” but an adverse effect from daily consumption of a moderate amount of coffee “is more legend and anecdote than fact based,” commented Andrew D. Krahn, MD, an electrophysiologist, professor of medicine, and head of cardiology at the University of British Columbia and St. Paul’s Hospital in Vancouver. “Increasingly we’re finding that there really is nothing here” when the proarrhythmic effects of moderate coffee undergo detailed assessment, he said in an interview.
 

What the study did

The study run by Dr. Kim and her associates used prospectively collected data from 296,227 participants in the UK Biobank during 2006-2016 who had complete data on their coffee intake and for the other covariables used in the analysis. During an average 5.25 years of follow-up, these people had more than 13,000 incident arrhythmic events, including 4,748 episodes of atrial fibrillation or flutter and 798 supraventricular tachycardia events, as well as fewer numbers of ventricular arrhythmias and many episodes of less clinically relevant events like skipped beats.

The multivariate analysis the researchers ran controlled for more than 20 demographic, lifestyle, and clinical variables, including adjustment for tea intake but not for consumption of other caffeine-containing drinks.

The adjusted analysis showed an average, statistically significant 3% incremental drop in both all incident arrhythmias and in incident atrial fibrillation episodes for each additional cup of coffee drunk a day, for up to 6 daily cups.

A strength of this study is that it included a large number of people, Dr. Krahn noted, and “the UK Biobank includes a very diverse, community-based sample” of people, said Dr. Kim. The analysis excluded people with prevalent arrhythmia at baseline, so the study couldn’t address the impact of coffee consumption in this setting. A limitation of the study is that participants in the UK Biobank are all volunteers, which could result in a selection bias, Dr. Krahn said.
 

What it tells us

While the main message from the results is that moderate daily coffee drinking is not arrhythmogenic, “it is also possible that coffee is beneficial” based on the small but statistically significant decline in new-onset events, Dr. Kim added. “Multiple studies revealed that caffeine and potentially other constituents in coffee have antioxidant and anti-inflammatory properties. Multiple studies have reported the potential benefit of coffee in multiple chronic medical conditions such as cardiovascular disease, diabetes, and certain types of cancers, as well as for all-cause mortality.”

“It’s plausible that a moderate amount of coffee intake a day will not cause big physiologic changes, and moderate coffee intake may link with other characteristics” of moderate behavior that result in average or better than average outcomes, Dr. Krahn commented. “These results add to the existing data in a different and large population,” which strengthens the case that moderate coffee intake isn’t harmful, he said.

The study received no commercial funding. Dr. Kim and Dr. Krahn had no disclosures. The senior author on Dr. Kim’s study, Gregory M. Marcus, MD, has been a consultant to Johnson & Johnson and Incardia, has an equity interest in Incardia, and has received research funding from Baylis, Eight Sleep, and Medtronic.

mzoler@mdedge.com

SOURCE: Kim EJ et al. Heart Rhythm 2020, abstract D-PO01-032.

Moderate, daily coffee consumption had no apparent adverse effect for triggering incident heart arrhythmias, and even linked with a small but statistically significant drop in arrhythmias in an analysis of prospectively collected data from nearly 300,000 U.K. residents.

“In this large, population-based, prospective study, moderate habitual coffee drinking was associated with a lower risk of arrhythmia,” EunJeong Kim, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19.

Her analysis found that on average each additional daily cup of coffee that people said they drank reduced the incidence of arrhythmic episodes by a statistically significant 3%, compared with those who drank fewer daily cups. The relationship held for people who reported drinking as many as five or six cups of coffee daily.

“The main message of our study is that it does not appear to be deleterious to continue with moderate amounts of habitual coffee intake regarding a risk of overall arrhythmia,” said Dr. Kim, a cardiac electrophysiologist at the University of California, San Francisco.

Evidence builds for coffee’s safety

The finding adds to a substantial existing evidence base documenting the safety of moderate, habitual coffee drinking when it comes to heart rhythms. For example, a recent report from the Physicians Health Study of nearly 19,000 American men showed a statistically significant decrease in the incidence of atrial fibrillation during an average follow-up of 9 years among men who reported drinking one to three cups of coffee daily (J Am Heart Assoc. 2019 Aug 6;8[15]:e011346). In addition, a recent review of several reports found that “mild-to-moderate habitual consumption of caffeinated beverages, particularly a daily intake of 2-3 cups of coffee or tea, appears to be safe across a broad range of cardiovascular conditions, and may even be beneficial with respect to diabetes mellitus, atherosclerosis, heart failure, arrhythmia and total mortality,” but also concluded that “acute consumption of high doses of caffeine, particularly in the form of energy drinks, is best avoided”(Trends Cardiovasc Med. 2019 Aug;29[6]:345-50). Specifically about cardiac arrhythmias, the review said “while caffeine is commonly considered a trigger for arrhythmias by physicians and patients alike there is minimal evidence to support this misconception. Rather caffeine is associated with a mild reduction in the incidence of atrial fibrillation in observational studies.”

“There has been a lot of public interest about a possible association of caffeine and arrhythmias,” but an adverse effect from daily consumption of a moderate amount of coffee “is more legend and anecdote than fact based,” commented Andrew D. Krahn, MD, an electrophysiologist, professor of medicine, and head of cardiology at the University of British Columbia and St. Paul’s Hospital in Vancouver. “Increasingly we’re finding that there really is nothing here” when the proarrhythmic effects of moderate coffee undergo detailed assessment, he said in an interview.
 

What the study did

The study run by Dr. Kim and her associates used prospectively collected data from 296,227 participants in the UK Biobank during 2006-2016 who had complete data on their coffee intake and for the other covariables used in the analysis. During an average 5.25 years of follow-up, these people had more than 13,000 incident arrhythmic events, including 4,748 episodes of atrial fibrillation or flutter and 798 supraventricular tachycardia events, as well as fewer numbers of ventricular arrhythmias and many episodes of less clinically relevant events like skipped beats.

The multivariate analysis the researchers ran controlled for more than 20 demographic, lifestyle, and clinical variables, including adjustment for tea intake but not for consumption of other caffeine-containing drinks.

The adjusted analysis showed an average, statistically significant 3% incremental drop in both all incident arrhythmias and in incident atrial fibrillation episodes for each additional cup of coffee drunk a day, for up to 6 daily cups.

A strength of this study is that it included a large number of people, Dr. Krahn noted, and “the UK Biobank includes a very diverse, community-based sample” of people, said Dr. Kim. The analysis excluded people with prevalent arrhythmia at baseline, so the study couldn’t address the impact of coffee consumption in this setting. A limitation of the study is that participants in the UK Biobank are all volunteers, which could result in a selection bias, Dr. Krahn said.
 

What it tells us

While the main message from the results is that moderate daily coffee drinking is not arrhythmogenic, “it is also possible that coffee is beneficial” based on the small but statistically significant decline in new-onset events, Dr. Kim added. “Multiple studies revealed that caffeine and potentially other constituents in coffee have antioxidant and anti-inflammatory properties. Multiple studies have reported the potential benefit of coffee in multiple chronic medical conditions such as cardiovascular disease, diabetes, and certain types of cancers, as well as for all-cause mortality.”

“It’s plausible that a moderate amount of coffee intake a day will not cause big physiologic changes, and moderate coffee intake may link with other characteristics” of moderate behavior that result in average or better than average outcomes, Dr. Krahn commented. “These results add to the existing data in a different and large population,” which strengthens the case that moderate coffee intake isn’t harmful, he said.

The study received no commercial funding. Dr. Kim and Dr. Krahn had no disclosures. The senior author on Dr. Kim’s study, Gregory M. Marcus, MD, has been a consultant to Johnson & Johnson and Incardia, has an equity interest in Incardia, and has received research funding from Baylis, Eight Sleep, and Medtronic.

mzoler@mdedge.com

SOURCE: Kim EJ et al. Heart Rhythm 2020, abstract D-PO01-032.

Moderate, daily coffee consumption had no apparent adverse effect for triggering incident heart arrhythmias, and even linked with a small but statistically significant drop in arrhythmias in an analysis of prospectively collected data from nearly 300,000 U.K. residents.

“In this large, population-based, prospective study, moderate habitual coffee drinking was associated with a lower risk of arrhythmia,” EunJeong Kim, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19.

Her analysis found that on average each additional daily cup of coffee that people said they drank reduced the incidence of arrhythmic episodes by a statistically significant 3%, compared with those who drank fewer daily cups. The relationship held for people who reported drinking as many as five or six cups of coffee daily.

“The main message of our study is that it does not appear to be deleterious to continue with moderate amounts of habitual coffee intake regarding a risk of overall arrhythmia,” said Dr. Kim, a cardiac electrophysiologist at the University of California, San Francisco.

Evidence builds for coffee’s safety

The finding adds to a substantial existing evidence base documenting the safety of moderate, habitual coffee drinking when it comes to heart rhythms. For example, a recent report from the Physicians Health Study of nearly 19,000 American men showed a statistically significant decrease in the incidence of atrial fibrillation during an average follow-up of 9 years among men who reported drinking one to three cups of coffee daily (J Am Heart Assoc. 2019 Aug 6;8[15]:e011346). In addition, a recent review of several reports found that “mild-to-moderate habitual consumption of caffeinated beverages, particularly a daily intake of 2-3 cups of coffee or tea, appears to be safe across a broad range of cardiovascular conditions, and may even be beneficial with respect to diabetes mellitus, atherosclerosis, heart failure, arrhythmia and total mortality,” but also concluded that “acute consumption of high doses of caffeine, particularly in the form of energy drinks, is best avoided”(Trends Cardiovasc Med. 2019 Aug;29[6]:345-50). Specifically about cardiac arrhythmias, the review said “while caffeine is commonly considered a trigger for arrhythmias by physicians and patients alike there is minimal evidence to support this misconception. Rather caffeine is associated with a mild reduction in the incidence of atrial fibrillation in observational studies.”

“There has been a lot of public interest about a possible association of caffeine and arrhythmias,” but an adverse effect from daily consumption of a moderate amount of coffee “is more legend and anecdote than fact based,” commented Andrew D. Krahn, MD, an electrophysiologist, professor of medicine, and head of cardiology at the University of British Columbia and St. Paul’s Hospital in Vancouver. “Increasingly we’re finding that there really is nothing here” when the proarrhythmic effects of moderate coffee undergo detailed assessment, he said in an interview.
 

What the study did

The study run by Dr. Kim and her associates used prospectively collected data from 296,227 participants in the UK Biobank during 2006-2016 who had complete data on their coffee intake and for the other covariables used in the analysis. During an average 5.25 years of follow-up, these people had more than 13,000 incident arrhythmic events, including 4,748 episodes of atrial fibrillation or flutter and 798 supraventricular tachycardia events, as well as fewer numbers of ventricular arrhythmias and many episodes of less clinically relevant events like skipped beats.

The multivariate analysis the researchers ran controlled for more than 20 demographic, lifestyle, and clinical variables, including adjustment for tea intake but not for consumption of other caffeine-containing drinks.

The adjusted analysis showed an average, statistically significant 3% incremental drop in both all incident arrhythmias and in incident atrial fibrillation episodes for each additional cup of coffee drunk a day, for up to 6 daily cups.

A strength of this study is that it included a large number of people, Dr. Krahn noted, and “the UK Biobank includes a very diverse, community-based sample” of people, said Dr. Kim. The analysis excluded people with prevalent arrhythmia at baseline, so the study couldn’t address the impact of coffee consumption in this setting. A limitation of the study is that participants in the UK Biobank are all volunteers, which could result in a selection bias, Dr. Krahn said.
 

What it tells us

While the main message from the results is that moderate daily coffee drinking is not arrhythmogenic, “it is also possible that coffee is beneficial” based on the small but statistically significant decline in new-onset events, Dr. Kim added. “Multiple studies revealed that caffeine and potentially other constituents in coffee have antioxidant and anti-inflammatory properties. Multiple studies have reported the potential benefit of coffee in multiple chronic medical conditions such as cardiovascular disease, diabetes, and certain types of cancers, as well as for all-cause mortality.”

“It’s plausible that a moderate amount of coffee intake a day will not cause big physiologic changes, and moderate coffee intake may link with other characteristics” of moderate behavior that result in average or better than average outcomes, Dr. Krahn commented. “These results add to the existing data in a different and large population,” which strengthens the case that moderate coffee intake isn’t harmful, he said.

The study received no commercial funding. Dr. Kim and Dr. Krahn had no disclosures. The senior author on Dr. Kim’s study, Gregory M. Marcus, MD, has been a consultant to Johnson & Johnson and Incardia, has an equity interest in Incardia, and has received research funding from Baylis, Eight Sleep, and Medtronic.

mzoler@mdedge.com

SOURCE: Kim EJ et al. Heart Rhythm 2020, abstract D-PO01-032.

The serum level of neurofilament light chain (sNfL) around the time of multiple sclerosis (MS) diagnosis is associated with long-term clinical disease progression, with higher baseline levels a sensitive marker of subsequent poor clinical outcomes, research suggests. The study showed that patients with higher sNfL within 5 years of MS diagnosis had a higher risk of long term-clinical disability and higher risk of developing progressive MS. The level of sNfL also predicted the rate of increase over time in the Expanded Disability Status Scale (EDSS).

Serum NfL levels can provide “useful information in both directions, adding to both an overall reassuring picture or worrying picture both at first presentation and then on subsequent visits,” said Simon Thebault, MBBCh, a neurology resident at the University of Ottawa and the Ottawa Hospital Research Institute, Canada.

This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
 

Prognostication from day one

Many studies have shown a correlation between MS disease activity (clinical relapses, EDSS progression, MRI lesions) and elevated sNfL. Other studies have also looked at the prognostic value of NfL in serum and cerebrospinal fluid (CSF), but the data are limited by the lack of long-term biobanked samples and subsequent follow-up, Dr. Thebault explained.

The new study took advantage of the Ottawa MS biobank, which contains carefully frozen and stored samples from more than 3,000 patients with MS going back up to 25 years.

The team identified patients with serum collected within 5 years of first MS symptom onset (baseline) who were followed for a median of 18.9 years (range 15.0 to 27.0 years). They quantified levels of sNfL in 67 patients and 37 matched controls.

In patients with MS, the median baseline sNfL level was 10.1 pg/mL – 38.5% higher than the median level in controls (7.26 pg/mL, P = 0.004).

The baseline sNfL level was “most helpful as a sensitive predictive marker to rule out disease progression,” the researchers reported in their meeting abstract.

Patients with baseline sNfL levels less than 7.62 pg/mL were 4.3 times less likely to develop significant disability (EDSS score ≥ 4; P = 0.001) and 7.1 times less likely to develop progressive MS by end of follow-up (P = 0.054).

The most rapid disease progression was seen in patients with the highest baseline NfL levels (3rd-tertile, > 13.2 pg/mL). Higher baseline sNfL level was associated with faster rate of EDSS progression even after adjusting for confounders of age, sex, and disease-modifying treatment.

“We were able to show that serum neurofilament levels collected very early in the disease, usually at the time of first diagnosis, were predictive of the clinical progression [by EDSS score] and the risk of evolving to secondary progressive MS on average 19 years later,” Dr. Thebault said. A baseline level less than 7.6 pg/mL was “reassuring.”

“Prognostication in MS from day one is important,” he emphasized.

“If we know someone is on a bad trajectory, neurologists might recommend more aggressive therapies up front. Equally, if a patient has a very reassuring picture, then maybe it is more appropriate to start with safer treatments [the so called ‘platform therapies’] that may serve a patient well for many years, as they did for many in the years before higher-efficacy therapies were available,” Dr. Thebault said.

“In the hands of an expert MS neurologist who understands both the pearls and pitfalls of this test ... serum neurofilament is already a useful clinical tool, and we have implemented it in our daily practice in Ottawa,” he concluded.
 

Noteworthy study

Commenting on the study, Asaff Harel, MD, neurologist at Lenox Hill Hospital in New York City, said the findings in this study are “noteworthy, as there is a relative lack of effective prognostic biomarkers in the field of MS.”

“It remains to be seen whether this improves risk stratification of patients above what can be achieved by looking at other prognostic factors, such as age, gender, baseline EDSS, and severity and frequency of relapses during early disease course,” Dr. Harel cautioned.

“This was a relatively small study and further research is necessary,” Dr. Harel added. It’s also worth noting, he said, that out of the 67 patients who met criteria to be included in the study (i.e., those with blood samples taken during “early MS,” more than 15 years ago), almost half were lost to follow-up, which could potentially open the study to error.

It is also “unclear whether early NfL level is a better prognostic marker than severity of early disease course and baseline EDSS, both of which were not addressed in the study, and this will be interesting to determine in the future,” Dr. Harel commented.

Funding for the study was provided by The Ottawa Hospital Pilot Project Grant. Thebault and Harel have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The serum level of neurofilament light chain (sNfL) around the time of multiple sclerosis (MS) diagnosis is associated with long-term clinical disease progression, with higher baseline levels a sensitive marker of subsequent poor clinical outcomes, research suggests. The study showed that patients with higher sNfL within 5 years of MS diagnosis had a higher risk of long term-clinical disability and higher risk of developing progressive MS. The level of sNfL also predicted the rate of increase over time in the Expanded Disability Status Scale (EDSS).

Serum NfL levels can provide “useful information in both directions, adding to both an overall reassuring picture or worrying picture both at first presentation and then on subsequent visits,” said Simon Thebault, MBBCh, a neurology resident at the University of Ottawa and the Ottawa Hospital Research Institute, Canada.

This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
 

Prognostication from day one

Many studies have shown a correlation between MS disease activity (clinical relapses, EDSS progression, MRI lesions) and elevated sNfL. Other studies have also looked at the prognostic value of NfL in serum and cerebrospinal fluid (CSF), but the data are limited by the lack of long-term biobanked samples and subsequent follow-up, Dr. Thebault explained.

The new study took advantage of the Ottawa MS biobank, which contains carefully frozen and stored samples from more than 3,000 patients with MS going back up to 25 years.

The team identified patients with serum collected within 5 years of first MS symptom onset (baseline) who were followed for a median of 18.9 years (range 15.0 to 27.0 years). They quantified levels of sNfL in 67 patients and 37 matched controls.

In patients with MS, the median baseline sNfL level was 10.1 pg/mL – 38.5% higher than the median level in controls (7.26 pg/mL, P = 0.004).

The baseline sNfL level was “most helpful as a sensitive predictive marker to rule out disease progression,” the researchers reported in their meeting abstract.

Patients with baseline sNfL levels less than 7.62 pg/mL were 4.3 times less likely to develop significant disability (EDSS score ≥ 4; P = 0.001) and 7.1 times less likely to develop progressive MS by end of follow-up (P = 0.054).

The most rapid disease progression was seen in patients with the highest baseline NfL levels (3rd-tertile, > 13.2 pg/mL). Higher baseline sNfL level was associated with faster rate of EDSS progression even after adjusting for confounders of age, sex, and disease-modifying treatment.

“We were able to show that serum neurofilament levels collected very early in the disease, usually at the time of first diagnosis, were predictive of the clinical progression [by EDSS score] and the risk of evolving to secondary progressive MS on average 19 years later,” Dr. Thebault said. A baseline level less than 7.6 pg/mL was “reassuring.”

“Prognostication in MS from day one is important,” he emphasized.

“If we know someone is on a bad trajectory, neurologists might recommend more aggressive therapies up front. Equally, if a patient has a very reassuring picture, then maybe it is more appropriate to start with safer treatments [the so called ‘platform therapies’] that may serve a patient well for many years, as they did for many in the years before higher-efficacy therapies were available,” Dr. Thebault said.

“In the hands of an expert MS neurologist who understands both the pearls and pitfalls of this test ... serum neurofilament is already a useful clinical tool, and we have implemented it in our daily practice in Ottawa,” he concluded.
 

Noteworthy study

Commenting on the study, Asaff Harel, MD, neurologist at Lenox Hill Hospital in New York City, said the findings in this study are “noteworthy, as there is a relative lack of effective prognostic biomarkers in the field of MS.”

“It remains to be seen whether this improves risk stratification of patients above what can be achieved by looking at other prognostic factors, such as age, gender, baseline EDSS, and severity and frequency of relapses during early disease course,” Dr. Harel cautioned.

“This was a relatively small study and further research is necessary,” Dr. Harel added. It’s also worth noting, he said, that out of the 67 patients who met criteria to be included in the study (i.e., those with blood samples taken during “early MS,” more than 15 years ago), almost half were lost to follow-up, which could potentially open the study to error.

It is also “unclear whether early NfL level is a better prognostic marker than severity of early disease course and baseline EDSS, both of which were not addressed in the study, and this will be interesting to determine in the future,” Dr. Harel commented.

Funding for the study was provided by The Ottawa Hospital Pilot Project Grant. Thebault and Harel have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The serum level of neurofilament light chain (sNfL) around the time of multiple sclerosis (MS) diagnosis is associated with long-term clinical disease progression, with higher baseline levels a sensitive marker of subsequent poor clinical outcomes, research suggests. The study showed that patients with higher sNfL within 5 years of MS diagnosis had a higher risk of long term-clinical disability and higher risk of developing progressive MS. The level of sNfL also predicted the rate of increase over time in the Expanded Disability Status Scale (EDSS).

Serum NfL levels can provide “useful information in both directions, adding to both an overall reassuring picture or worrying picture both at first presentation and then on subsequent visits,” said Simon Thebault, MBBCh, a neurology resident at the University of Ottawa and the Ottawa Hospital Research Institute, Canada.

This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
 

Prognostication from day one

Many studies have shown a correlation between MS disease activity (clinical relapses, EDSS progression, MRI lesions) and elevated sNfL. Other studies have also looked at the prognostic value of NfL in serum and cerebrospinal fluid (CSF), but the data are limited by the lack of long-term biobanked samples and subsequent follow-up, Dr. Thebault explained.

The new study took advantage of the Ottawa MS biobank, which contains carefully frozen and stored samples from more than 3,000 patients with MS going back up to 25 years.

The team identified patients with serum collected within 5 years of first MS symptom onset (baseline) who were followed for a median of 18.9 years (range 15.0 to 27.0 years). They quantified levels of sNfL in 67 patients and 37 matched controls.

In patients with MS, the median baseline sNfL level was 10.1 pg/mL – 38.5% higher than the median level in controls (7.26 pg/mL, P = 0.004).

The baseline sNfL level was “most helpful as a sensitive predictive marker to rule out disease progression,” the researchers reported in their meeting abstract.

Patients with baseline sNfL levels less than 7.62 pg/mL were 4.3 times less likely to develop significant disability (EDSS score ≥ 4; P = 0.001) and 7.1 times less likely to develop progressive MS by end of follow-up (P = 0.054).

The most rapid disease progression was seen in patients with the highest baseline NfL levels (3rd-tertile, > 13.2 pg/mL). Higher baseline sNfL level was associated with faster rate of EDSS progression even after adjusting for confounders of age, sex, and disease-modifying treatment.

“We were able to show that serum neurofilament levels collected very early in the disease, usually at the time of first diagnosis, were predictive of the clinical progression [by EDSS score] and the risk of evolving to secondary progressive MS on average 19 years later,” Dr. Thebault said. A baseline level less than 7.6 pg/mL was “reassuring.”

“Prognostication in MS from day one is important,” he emphasized.

“If we know someone is on a bad trajectory, neurologists might recommend more aggressive therapies up front. Equally, if a patient has a very reassuring picture, then maybe it is more appropriate to start with safer treatments [the so called ‘platform therapies’] that may serve a patient well for many years, as they did for many in the years before higher-efficacy therapies were available,” Dr. Thebault said.

“In the hands of an expert MS neurologist who understands both the pearls and pitfalls of this test ... serum neurofilament is already a useful clinical tool, and we have implemented it in our daily practice in Ottawa,” he concluded.
 

Noteworthy study

Commenting on the study, Asaff Harel, MD, neurologist at Lenox Hill Hospital in New York City, said the findings in this study are “noteworthy, as there is a relative lack of effective prognostic biomarkers in the field of MS.”

“It remains to be seen whether this improves risk stratification of patients above what can be achieved by looking at other prognostic factors, such as age, gender, baseline EDSS, and severity and frequency of relapses during early disease course,” Dr. Harel cautioned.

“This was a relatively small study and further research is necessary,” Dr. Harel added. It’s also worth noting, he said, that out of the 67 patients who met criteria to be included in the study (i.e., those with blood samples taken during “early MS,” more than 15 years ago), almost half were lost to follow-up, which could potentially open the study to error.

It is also “unclear whether early NfL level is a better prognostic marker than severity of early disease course and baseline EDSS, both of which were not addressed in the study, and this will be interesting to determine in the future,” Dr. Harel commented.

Funding for the study was provided by The Ottawa Hospital Pilot Project Grant. Thebault and Harel have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with epilepsy may report less than half of their seizures to clinicians, according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.

Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.

jremaly@mdedge.com

SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.

Patients with epilepsy may report less than half of their seizures to clinicians, according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.

Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.

jremaly@mdedge.com

SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.

Patients with epilepsy may report less than half of their seizures to clinicians, according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.

Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.

jremaly@mdedge.com

SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.

Capmatinib produced rapid, deep responses in patients with advanced non–small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations, according to a presentation at the AACR virtual meeting I.

The duration of response was impressive in both treatment-naive and previously treated patients, according to presenter Edward B. Garon, MD, of the University of California, Los Angeles.

In view of these responses, Dr. Garon urged early molecular testing in NSCLC.

He also noted that capmatinib produced responses in patients with brain metastases. However, because of small patient numbers, additional study is needed to validate the intracranial efficacy of capmatinib and ascertain mechanisms of resistance.

Study rationale and details

METex14 mutations are reported in up to 4% of patients with NSCLC and portend poor outcomes with chemotherapy and immune checkpoint inhibitors (PLoS One 2014; 9:e107677; Ann Oncol 2018;29:2085-91).

Capmatinib is a highly selective, reversible, and potent inhibitor of MET tyrosine kinase that crosses the blood-brain barrier.

In the phase 2 GEOMETRY mono-1 study, Dr. Garon and colleagues tested capmatinib, given at 400 mg orally twice a day, in patients with METex14-mutated, ALK and EGFR wild-type, stage IIIB/IV NSCLC. Patients with neurologically stable or asymptomatic brain metastases were eligible.

Dr. Garon presented safety data for all patients enrolled in this study and efficacy data for patients in cohorts 4 and 5b. Cohort 4 enrolled patients who received prior systemic therapy for advanced disease, and cohort 5b enrolled treatment-naive patients. Both cohorts had METex14 gene mutations but not amplification.

Efficacy

There were 97 patients evaluable for efficacy – 69 previously treated and 28 treatment naive. The median age in both cohorts was 71 years, most patients were female (58% of previously treated and 64.3% of treatment-naive patients), and most were never-smokers (58% and 64.3%, respectively). Adenocarcinoma was the predominant histology.

The overall response rate, per an independent review committee, was 40.6% in previously treated patients and 67.9% in treatment-naive patients.

Waterfall plots showed deep responses, with only four cases of disease progression in the previously treated cohort and none in the treatment-naive cohort.

Responses occurred rapidly. Many responses exceeded 1 year and were ongoing at the data cut-off. The median response duration was 9.72 months in previously treated patients and 11.14 months in treatment-naive patients.

There were 13 patients with evaluable baseline brain metastases (3.3 brain lesions per patient [range, 1-8]). Twelve patients had intracranial disease control, and seven patients (54%) had intracranial response. Four patients had complete resolution of all brain lesions.

Intracranial responses were generally seen by the first radiologic evaluation and occurred as rapidly as systemic responses.

Safety

With safety data on all 334 patients in the trial, the GEOMETRY mono-1 study is the largest reported experience with capmatinib in NSCLC patients. The median treatment exposure time was 14.9 weeks.

Overall, 35.6% of patients experienced a grade 3/4 adverse event (AE). Grade 4 AEs were observed in 4.5% of patients, and there were no treatment-related deaths.

Peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%) were the most frequent AEs of any grade.

In all, 21.9% of patients required dose adjustments due to treatment-related AEs, and 11.1% of patients stopped treatment because of an AE.

This study was sponsored by Novartis. Dr. Garon disclosed relationships with Novartis, AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Eli Lilly, EMD Serono, Genentech, GSK, Iovance, Merck, Mirati, and Neon.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Garon EB et al. AACR 2020, Abstract CT082.

Capmatinib produced rapid, deep responses in patients with advanced non–small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations, according to a presentation at the AACR virtual meeting I.

The duration of response was impressive in both treatment-naive and previously treated patients, according to presenter Edward B. Garon, MD, of the University of California, Los Angeles.

In view of these responses, Dr. Garon urged early molecular testing in NSCLC.

He also noted that capmatinib produced responses in patients with brain metastases. However, because of small patient numbers, additional study is needed to validate the intracranial efficacy of capmatinib and ascertain mechanisms of resistance.

Study rationale and details

METex14 mutations are reported in up to 4% of patients with NSCLC and portend poor outcomes with chemotherapy and immune checkpoint inhibitors (PLoS One 2014; 9:e107677; Ann Oncol 2018;29:2085-91).

Capmatinib is a highly selective, reversible, and potent inhibitor of MET tyrosine kinase that crosses the blood-brain barrier.

In the phase 2 GEOMETRY mono-1 study, Dr. Garon and colleagues tested capmatinib, given at 400 mg orally twice a day, in patients with METex14-mutated, ALK and EGFR wild-type, stage IIIB/IV NSCLC. Patients with neurologically stable or asymptomatic brain metastases were eligible.

Dr. Garon presented safety data for all patients enrolled in this study and efficacy data for patients in cohorts 4 and 5b. Cohort 4 enrolled patients who received prior systemic therapy for advanced disease, and cohort 5b enrolled treatment-naive patients. Both cohorts had METex14 gene mutations but not amplification.

Efficacy

There were 97 patients evaluable for efficacy – 69 previously treated and 28 treatment naive. The median age in both cohorts was 71 years, most patients were female (58% of previously treated and 64.3% of treatment-naive patients), and most were never-smokers (58% and 64.3%, respectively). Adenocarcinoma was the predominant histology.

The overall response rate, per an independent review committee, was 40.6% in previously treated patients and 67.9% in treatment-naive patients.

Waterfall plots showed deep responses, with only four cases of disease progression in the previously treated cohort and none in the treatment-naive cohort.

Responses occurred rapidly. Many responses exceeded 1 year and were ongoing at the data cut-off. The median response duration was 9.72 months in previously treated patients and 11.14 months in treatment-naive patients.

There were 13 patients with evaluable baseline brain metastases (3.3 brain lesions per patient [range, 1-8]). Twelve patients had intracranial disease control, and seven patients (54%) had intracranial response. Four patients had complete resolution of all brain lesions.

Intracranial responses were generally seen by the first radiologic evaluation and occurred as rapidly as systemic responses.

Safety

With safety data on all 334 patients in the trial, the GEOMETRY mono-1 study is the largest reported experience with capmatinib in NSCLC patients. The median treatment exposure time was 14.9 weeks.

Overall, 35.6% of patients experienced a grade 3/4 adverse event (AE). Grade 4 AEs were observed in 4.5% of patients, and there were no treatment-related deaths.

Peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%) were the most frequent AEs of any grade.

In all, 21.9% of patients required dose adjustments due to treatment-related AEs, and 11.1% of patients stopped treatment because of an AE.

This study was sponsored by Novartis. Dr. Garon disclosed relationships with Novartis, AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Eli Lilly, EMD Serono, Genentech, GSK, Iovance, Merck, Mirati, and Neon.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Garon EB et al. AACR 2020, Abstract CT082.

Capmatinib produced rapid, deep responses in patients with advanced non–small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations, according to a presentation at the AACR virtual meeting I.

The duration of response was impressive in both treatment-naive and previously treated patients, according to presenter Edward B. Garon, MD, of the University of California, Los Angeles.

In view of these responses, Dr. Garon urged early molecular testing in NSCLC.

He also noted that capmatinib produced responses in patients with brain metastases. However, because of small patient numbers, additional study is needed to validate the intracranial efficacy of capmatinib and ascertain mechanisms of resistance.

Study rationale and details

METex14 mutations are reported in up to 4% of patients with NSCLC and portend poor outcomes with chemotherapy and immune checkpoint inhibitors (PLoS One 2014; 9:e107677; Ann Oncol 2018;29:2085-91).

Capmatinib is a highly selective, reversible, and potent inhibitor of MET tyrosine kinase that crosses the blood-brain barrier.

In the phase 2 GEOMETRY mono-1 study, Dr. Garon and colleagues tested capmatinib, given at 400 mg orally twice a day, in patients with METex14-mutated, ALK and EGFR wild-type, stage IIIB/IV NSCLC. Patients with neurologically stable or asymptomatic brain metastases were eligible.

Dr. Garon presented safety data for all patients enrolled in this study and efficacy data for patients in cohorts 4 and 5b. Cohort 4 enrolled patients who received prior systemic therapy for advanced disease, and cohort 5b enrolled treatment-naive patients. Both cohorts had METex14 gene mutations but not amplification.

Efficacy

There were 97 patients evaluable for efficacy – 69 previously treated and 28 treatment naive. The median age in both cohorts was 71 years, most patients were female (58% of previously treated and 64.3% of treatment-naive patients), and most were never-smokers (58% and 64.3%, respectively). Adenocarcinoma was the predominant histology.

The overall response rate, per an independent review committee, was 40.6% in previously treated patients and 67.9% in treatment-naive patients.

Waterfall plots showed deep responses, with only four cases of disease progression in the previously treated cohort and none in the treatment-naive cohort.

Responses occurred rapidly. Many responses exceeded 1 year and were ongoing at the data cut-off. The median response duration was 9.72 months in previously treated patients and 11.14 months in treatment-naive patients.

There were 13 patients with evaluable baseline brain metastases (3.3 brain lesions per patient [range, 1-8]). Twelve patients had intracranial disease control, and seven patients (54%) had intracranial response. Four patients had complete resolution of all brain lesions.

Intracranial responses were generally seen by the first radiologic evaluation and occurred as rapidly as systemic responses.

Safety

With safety data on all 334 patients in the trial, the GEOMETRY mono-1 study is the largest reported experience with capmatinib in NSCLC patients. The median treatment exposure time was 14.9 weeks.

Overall, 35.6% of patients experienced a grade 3/4 adverse event (AE). Grade 4 AEs were observed in 4.5% of patients, and there were no treatment-related deaths.

Peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%) were the most frequent AEs of any grade.

In all, 21.9% of patients required dose adjustments due to treatment-related AEs, and 11.1% of patients stopped treatment because of an AE.

This study was sponsored by Novartis. Dr. Garon disclosed relationships with Novartis, AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Eli Lilly, EMD Serono, Genentech, GSK, Iovance, Merck, Mirati, and Neon.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Garon EB et al. AACR 2020, Abstract CT082.

A new meta-analysis has concluded that the benefit of statin therapy in the prevention of ischemic stroke “greatly exceeds” the risk for intracerebral hemorrhage (ICH). The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.

Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.

To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.

Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).

“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
 

Increased secondary ICH?

However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).

“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.

Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”

Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.

“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.

Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.

“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.

“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.

Dr. Pandhi has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.

A new meta-analysis has concluded that the benefit of statin therapy in the prevention of ischemic stroke “greatly exceeds” the risk for intracerebral hemorrhage (ICH). The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.

Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.

To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.

Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).

“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
 

Increased secondary ICH?

However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).

“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.

Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”

Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.

“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.

Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.

“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.

“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.

Dr. Pandhi has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.

A new meta-analysis has concluded that the benefit of statin therapy in the prevention of ischemic stroke “greatly exceeds” the risk for intracerebral hemorrhage (ICH). The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.

Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.

To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.

Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).

“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
 

Increased secondary ICH?

However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).

“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.

Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”

Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.

“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.

Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.

“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.

“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.

Dr. Pandhi has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.

The autologous tumor cell vaccine gemogenovatucel-T (Vigil Ovarian) is well tolerated as maintenance therapy in stage III-IV ovarian cancer patients and may improve relapse-free survival, particularly in BRCA wild-type disease, according to findings from the ongoing VITAL study.

In patients with and without BRCA1/2 mutations, the median relapse-free survival was longer with gemogenovatucel-T maintenance than with placebo, but the difference did not reach statistical significance (P = .065).

However, among patients with wild-type BRCA, the median relapse-free survival was significantly longer with gemogenovatucel-T (P = .0007).

Rodney P. Rocconi, MD, of the Mitchell Cancer Institute at University of South Alabama, Mobile, reported these results in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancers. The meeting was canceled because of the COVID-19 pandemic. Some data have been updated from the abstract.
 

Study rationale

Gemogenovatucel-T (formerly called FANG) is an autologous tumor cell vaccine transfected with a plasmid encoding granulocyte-macrophage colony–stimulating factor and a novel bifunctional short hairpin interfering RNA targeting furin convertase.

“In the era of personalized, targeted medicine, I think this is about as personalized as you can get, this type of vaccine,” Dr. Rocconi said. “Essentially, we harvest patients’ own cancer cells and create a vaccine that is targeted to the antigens on their cells so that it recognizes only that patient’s cancer.”

The vaccine also helps recruit immune cells to the area and has a very limited off-target effect, Dr. Rocconi added.

He noted that gemogenovatucel-T previously demonstrated promising efficacy and limited side effects in a phase 1 study that included patients with advanced ovarian cancer (Mol Ther. 2012 Mar;20[3]:679-86).

“So we thought that, in ovarian cancer, as a maintenance therapy, it made a lot of sense,” Dr. Rocconi said, noting that the overall prognosis for advanced epithelial ovarian cancer remains limited.
 

Treatment and toxicity

Dr. Rocconi and colleagues reported data on 91 patients in the VITAL study. The patients had achieved a complete response after frontline surgery and chemotherapy, and they were randomized to maintenance with gemogenovatucel-T or placebo.

Patients had a median time from surgery to randomization of 208.5 days in the gemogenovatucel-T group and 200 days in the control group. The patients were treated with 1 x 10⁷ cells/mL of gemogenovatucel-T or placebo intradermally once a month for up to 12 doses.

Gemogenovatucel-T was well tolerated. No added overall toxicity was noted in the gemogenovatucel-T group versus the control group, and no grade 4/5 toxicities were observed, Dr. Rocconi said. Grade 2/3 toxic events were observed in 8% of patients in the gemogenovatucel-T group, compared with 18% in the control group. The most common events were nausea and musculoskeletal pain in the gemogenovatucel-T group, and were bone pain and fatigue in the control group.
 

Relapse-free and overall survival

In the entire cohort, the median relapse-free survival was longer with gemogenovatucel-T maintenance – 12.6 months versus 8.4 months with placebo (hazard ratio, 0.69) – but the difference did not reach statistical significance (P = .065).

However, in the 67 patients with wild-type BRCA, the median relapse-free survival was 19.4 months with gemogenovatucel-T and 14.8 months with placebo, a statistically significant difference (HR, 0.459; P = .0007).

The median overall survival was not reached in the BRCA wild-type patients treated with gemogenovatucel-T, and it was 41.4 months from the time of randomization in those who received placebo (HR, 0.417; P = .02).

No benefit was seen with gemogenovatucel-T in patients with known BRCA1/2 mutations, Dr. Rocconi said.
 

‘Encouraging’ results

The overall improvement in the gemogenovatucel-T group was encouraging, particularly in a maintenance-type trial, Dr. Rocconi said. He noted that prior treatments for maintenance have received approval based on shorter survival gains, and the finding of particular benefit in BRCA wild-type disease could have important implications for a population that usually has lesser benefit from treatments, compared with patients who have BRCA mutations.

“So this result is very unique,” Dr. Rocconi said, explaining that about 85% of ovarian cancer patients have BRCA wild-type disease; with this treatment, patients with wild-type BRCA may achieve similar survival rates as those seen in BRCA-mutant disease.

“I think, in general, immunotherapy has been somewhat disappointing in ovarian cancer, so to have a targeted vaccine work in ovarian cancer, just broadly ... is pretty noteworthy,” he said. “We’re really excited, obviously, about the overall success we’ve seen for all patients, but most importantly in those with BRCA wild type. This is a pretty marked significance in recurrence-free intervals and overall survival, and we’re definitely pleased with that.”
 

Next steps

The findings from this trial have been submitted for publication, and efforts are underway to determine next steps through communication with the Food and Drug Administration, Dr. Rocconi said.

Additionally, other studies are underway to assess gemogenovatucel-T in patients who fall in “the middle ground” – that is, patients who have BRCA wild-type disease but have “some homologous recombination deficiency where the tumor itself might be BRCA deficient or have some other type of deficiency,” Dr. Rocconi explained.

“So we’re trying to tease out specifically what is going on across all the different variations of ovarian cancer patients, and also looking for potential biomarkers for predicting response,” he said. “What we would like to see is a companion test where we’re able to predict which patients can really respond and do best with this technology, and, that way, we know how to stratify patients most appropriately.”

The current trial was sponsored by Gradalis. Dr. Rocconi disclosed relationships with Gradalis, Genentech, Clovis, and Johnson & Johnson.

sworcester@mdedge.com

SOURCE: Rocconi RP et al. SGO 2020, Abstract LBA7.

The autologous tumor cell vaccine gemogenovatucel-T (Vigil Ovarian) is well tolerated as maintenance therapy in stage III-IV ovarian cancer patients and may improve relapse-free survival, particularly in BRCA wild-type disease, according to findings from the ongoing VITAL study.

In patients with and without BRCA1/2 mutations, the median relapse-free survival was longer with gemogenovatucel-T maintenance than with placebo, but the difference did not reach statistical significance (P = .065).

However, among patients with wild-type BRCA, the median relapse-free survival was significantly longer with gemogenovatucel-T (P = .0007).

Rodney P. Rocconi, MD, of the Mitchell Cancer Institute at University of South Alabama, Mobile, reported these results in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancers. The meeting was canceled because of the COVID-19 pandemic. Some data have been updated from the abstract.
 

Study rationale

Gemogenovatucel-T (formerly called FANG) is an autologous tumor cell vaccine transfected with a plasmid encoding granulocyte-macrophage colony–stimulating factor and a novel bifunctional short hairpin interfering RNA targeting furin convertase.

“In the era of personalized, targeted medicine, I think this is about as personalized as you can get, this type of vaccine,” Dr. Rocconi said. “Essentially, we harvest patients’ own cancer cells and create a vaccine that is targeted to the antigens on their cells so that it recognizes only that patient’s cancer.”

The vaccine also helps recruit immune cells to the area and has a very limited off-target effect, Dr. Rocconi added.

He noted that gemogenovatucel-T previously demonstrated promising efficacy and limited side effects in a phase 1 study that included patients with advanced ovarian cancer (Mol Ther. 2012 Mar;20[3]:679-86).

“So we thought that, in ovarian cancer, as a maintenance therapy, it made a lot of sense,” Dr. Rocconi said, noting that the overall prognosis for advanced epithelial ovarian cancer remains limited.
 

Treatment and toxicity

Dr. Rocconi and colleagues reported data on 91 patients in the VITAL study. The patients had achieved a complete response after frontline surgery and chemotherapy, and they were randomized to maintenance with gemogenovatucel-T or placebo.

Patients had a median time from surgery to randomization of 208.5 days in the gemogenovatucel-T group and 200 days in the control group. The patients were treated with 1 x 10⁷ cells/mL of gemogenovatucel-T or placebo intradermally once a month for up to 12 doses.

Gemogenovatucel-T was well tolerated. No added overall toxicity was noted in the gemogenovatucel-T group versus the control group, and no grade 4/5 toxicities were observed, Dr. Rocconi said. Grade 2/3 toxic events were observed in 8% of patients in the gemogenovatucel-T group, compared with 18% in the control group. The most common events were nausea and musculoskeletal pain in the gemogenovatucel-T group, and were bone pain and fatigue in the control group.
 

Relapse-free and overall survival

In the entire cohort, the median relapse-free survival was longer with gemogenovatucel-T maintenance – 12.6 months versus 8.4 months with placebo (hazard ratio, 0.69) – but the difference did not reach statistical significance (P = .065).

However, in the 67 patients with wild-type BRCA, the median relapse-free survival was 19.4 months with gemogenovatucel-T and 14.8 months with placebo, a statistically significant difference (HR, 0.459; P = .0007).

The median overall survival was not reached in the BRCA wild-type patients treated with gemogenovatucel-T, and it was 41.4 months from the time of randomization in those who received placebo (HR, 0.417; P = .02).

No benefit was seen with gemogenovatucel-T in patients with known BRCA1/2 mutations, Dr. Rocconi said.
 

‘Encouraging’ results

The overall improvement in the gemogenovatucel-T group was encouraging, particularly in a maintenance-type trial, Dr. Rocconi said. He noted that prior treatments for maintenance have received approval based on shorter survival gains, and the finding of particular benefit in BRCA wild-type disease could have important implications for a population that usually has lesser benefit from treatments, compared with patients who have BRCA mutations.

“So this result is very unique,” Dr. Rocconi said, explaining that about 85% of ovarian cancer patients have BRCA wild-type disease; with this treatment, patients with wild-type BRCA may achieve similar survival rates as those seen in BRCA-mutant disease.

“I think, in general, immunotherapy has been somewhat disappointing in ovarian cancer, so to have a targeted vaccine work in ovarian cancer, just broadly ... is pretty noteworthy,” he said. “We’re really excited, obviously, about the overall success we’ve seen for all patients, but most importantly in those with BRCA wild type. This is a pretty marked significance in recurrence-free intervals and overall survival, and we’re definitely pleased with that.”
 

Next steps

The findings from this trial have been submitted for publication, and efforts are underway to determine next steps through communication with the Food and Drug Administration, Dr. Rocconi said.

Additionally, other studies are underway to assess gemogenovatucel-T in patients who fall in “the middle ground” – that is, patients who have BRCA wild-type disease but have “some homologous recombination deficiency where the tumor itself might be BRCA deficient or have some other type of deficiency,” Dr. Rocconi explained.

“So we’re trying to tease out specifically what is going on across all the different variations of ovarian cancer patients, and also looking for potential biomarkers for predicting response,” he said. “What we would like to see is a companion test where we’re able to predict which patients can really respond and do best with this technology, and, that way, we know how to stratify patients most appropriately.”

The current trial was sponsored by Gradalis. Dr. Rocconi disclosed relationships with Gradalis, Genentech, Clovis, and Johnson & Johnson.

sworcester@mdedge.com

SOURCE: Rocconi RP et al. SGO 2020, Abstract LBA7.

The autologous tumor cell vaccine gemogenovatucel-T (Vigil Ovarian) is well tolerated as maintenance therapy in stage III-IV ovarian cancer patients and may improve relapse-free survival, particularly in BRCA wild-type disease, according to findings from the ongoing VITAL study.

In patients with and without BRCA1/2 mutations, the median relapse-free survival was longer with gemogenovatucel-T maintenance than with placebo, but the difference did not reach statistical significance (P = .065).

However, among patients with wild-type BRCA, the median relapse-free survival was significantly longer with gemogenovatucel-T (P = .0007).

Rodney P. Rocconi, MD, of the Mitchell Cancer Institute at University of South Alabama, Mobile, reported these results in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancers. The meeting was canceled because of the COVID-19 pandemic. Some data have been updated from the abstract.
 

Study rationale

Gemogenovatucel-T (formerly called FANG) is an autologous tumor cell vaccine transfected with a plasmid encoding granulocyte-macrophage colony–stimulating factor and a novel bifunctional short hairpin interfering RNA targeting furin convertase.

“In the era of personalized, targeted medicine, I think this is about as personalized as you can get, this type of vaccine,” Dr. Rocconi said. “Essentially, we harvest patients’ own cancer cells and create a vaccine that is targeted to the antigens on their cells so that it recognizes only that patient’s cancer.”

The vaccine also helps recruit immune cells to the area and has a very limited off-target effect, Dr. Rocconi added.

He noted that gemogenovatucel-T previously demonstrated promising efficacy and limited side effects in a phase 1 study that included patients with advanced ovarian cancer (Mol Ther. 2012 Mar;20[3]:679-86).

“So we thought that, in ovarian cancer, as a maintenance therapy, it made a lot of sense,” Dr. Rocconi said, noting that the overall prognosis for advanced epithelial ovarian cancer remains limited.
 

Treatment and toxicity

Dr. Rocconi and colleagues reported data on 91 patients in the VITAL study. The patients had achieved a complete response after frontline surgery and chemotherapy, and they were randomized to maintenance with gemogenovatucel-T or placebo.

Patients had a median time from surgery to randomization of 208.5 days in the gemogenovatucel-T group and 200 days in the control group. The patients were treated with 1 x 10⁷ cells/mL of gemogenovatucel-T or placebo intradermally once a month for up to 12 doses.

Gemogenovatucel-T was well tolerated. No added overall toxicity was noted in the gemogenovatucel-T group versus the control group, and no grade 4/5 toxicities were observed, Dr. Rocconi said. Grade 2/3 toxic events were observed in 8% of patients in the gemogenovatucel-T group, compared with 18% in the control group. The most common events were nausea and musculoskeletal pain in the gemogenovatucel-T group, and were bone pain and fatigue in the control group.
 

Relapse-free and overall survival

In the entire cohort, the median relapse-free survival was longer with gemogenovatucel-T maintenance – 12.6 months versus 8.4 months with placebo (hazard ratio, 0.69) – but the difference did not reach statistical significance (P = .065).

However, in the 67 patients with wild-type BRCA, the median relapse-free survival was 19.4 months with gemogenovatucel-T and 14.8 months with placebo, a statistically significant difference (HR, 0.459; P = .0007).

The median overall survival was not reached in the BRCA wild-type patients treated with gemogenovatucel-T, and it was 41.4 months from the time of randomization in those who received placebo (HR, 0.417; P = .02).

No benefit was seen with gemogenovatucel-T in patients with known BRCA1/2 mutations, Dr. Rocconi said.
 

‘Encouraging’ results

The overall improvement in the gemogenovatucel-T group was encouraging, particularly in a maintenance-type trial, Dr. Rocconi said. He noted that prior treatments for maintenance have received approval based on shorter survival gains, and the finding of particular benefit in BRCA wild-type disease could have important implications for a population that usually has lesser benefit from treatments, compared with patients who have BRCA mutations.

“So this result is very unique,” Dr. Rocconi said, explaining that about 85% of ovarian cancer patients have BRCA wild-type disease; with this treatment, patients with wild-type BRCA may achieve similar survival rates as those seen in BRCA-mutant disease.

“I think, in general, immunotherapy has been somewhat disappointing in ovarian cancer, so to have a targeted vaccine work in ovarian cancer, just broadly ... is pretty noteworthy,” he said. “We’re really excited, obviously, about the overall success we’ve seen for all patients, but most importantly in those with BRCA wild type. This is a pretty marked significance in recurrence-free intervals and overall survival, and we’re definitely pleased with that.”
 

Next steps

The findings from this trial have been submitted for publication, and efforts are underway to determine next steps through communication with the Food and Drug Administration, Dr. Rocconi said.

Additionally, other studies are underway to assess gemogenovatucel-T in patients who fall in “the middle ground” – that is, patients who have BRCA wild-type disease but have “some homologous recombination deficiency where the tumor itself might be BRCA deficient or have some other type of deficiency,” Dr. Rocconi explained.

“So we’re trying to tease out specifically what is going on across all the different variations of ovarian cancer patients, and also looking for potential biomarkers for predicting response,” he said. “What we would like to see is a companion test where we’re able to predict which patients can really respond and do best with this technology, and, that way, we know how to stratify patients most appropriately.”

The current trial was sponsored by Gradalis. Dr. Rocconi disclosed relationships with Gradalis, Genentech, Clovis, and Johnson & Johnson.

sworcester@mdedge.com

SOURCE: Rocconi RP et al. SGO 2020, Abstract LBA7.

Gastrointestinal symptoms are more common and severe in patients with Parkinson’s disease than in controls and may relate to an altered microbiome composition and reduced microbial diversity, according to research presented online as part of the 2020 American Academy of Neurology Science Highlights.

Jade E. Kenna, a PhD candidate and research assistant at the Perron Institute of Neurological and Translational Science in Perth, Australia, described findings from a multicenter assessment of 167 patients with Parkinson’s disease and 100 controls from movement disorders clinics in Australia. Participants completed the self-report Gastrointestinal Symptom Rating Scale (GSRS), which rates the frequency and severity of 15 GI symptoms. In addition, stool samples were analyzed using targeted sequencing to characterize gut microbiome composition.

Although Parkinson’s disease is recognized primarily as a motor disorder, GI dysfunction may be one of the first symptoms. “This is hypothesized to result from a change in microbiota towards an inflammatory, dysbiotic composition,” Ms. Kenna said. A limited number of studies have reported an association between altered microbiota composition, GI symptoms, and Parkinson’s disease, but not in Australian cohorts.

Total GSRS score was significantly higher in patients with Parkinson’s disease, compared with controls. Eight of the symptoms – heartburn, acid reflux, nausea or vomiting, borborygmus, increased flatus, decreased passage of stools, feeling of incomplete evacuation, and passing hard stools – were significantly increased in patients with Parkinson’s disease. GSRS symptoms can be categorized as upper, lower, general, hypoactive, or hyperactive, and patients with Parkinson’s disease had significantly increased ratings in the upper, lower, and hypoactive GI symptom domains.

“This is quite a novel finding as not only has this not been assessed in an Australian cohort of individuals before, but the majority of existing literature focuses on the presence of constipation only,” Ms. Kenna said. “The treatment and understanding of nonmotor symptoms of Parkinson’s disease, in particular GI symptoms, remain as one of the top unmet needs reported by patients with Parkinson’s disease themselves. Therefore, a better, more thorough understanding of these symptoms is clearly needed, and research into this area has such value in terms of improving current therapeutic approaches, management strategies, and patient education.”

Microbial analyses found that Firmicutes and Proteobacteria were significantly increased and Verrucomicrobia trended toward an increase in patients with Parkinson’s disease. Fusobacteria was increased in controls. “Proteobacteria and Verrucomicrobia are known to promote inflammation, which can lead to GI symptoms. Furthermore, Faecalibacterium and Ruminococcus, which are reduced in [Parkinson’s disease], can metabolize various substrates to produce [short-chain fatty acids] like butyrate, which are known to aid against intestinal barrier dysfunction and inflammation,” she said.

Individuals with Parkinson’s disease had significantly less microbial diversity. As Parkinson’s disease severity and GI symptom severity increased, microbiome diversity decreased, Ms. Kenna said. “As reduced diversity is associated with increased intestinal inflammation, this indicates that the altered microbiome we saw in [individuals with Parkinson’s disease] may be instigating the increase in incidence and severity of GI symptoms.”

Ms. Kenna reported that she had no disclosures.

jremaly@mdedge.com

SOURCE: Kenna JE. AAN 2020, Abstract S17.006.

Gastrointestinal symptoms are more common and severe in patients with Parkinson’s disease than in controls and may relate to an altered microbiome composition and reduced microbial diversity, according to research presented online as part of the 2020 American Academy of Neurology Science Highlights.

Jade E. Kenna, a PhD candidate and research assistant at the Perron Institute of Neurological and Translational Science in Perth, Australia, described findings from a multicenter assessment of 167 patients with Parkinson’s disease and 100 controls from movement disorders clinics in Australia. Participants completed the self-report Gastrointestinal Symptom Rating Scale (GSRS), which rates the frequency and severity of 15 GI symptoms. In addition, stool samples were analyzed using targeted sequencing to characterize gut microbiome composition.

Although Parkinson’s disease is recognized primarily as a motor disorder, GI dysfunction may be one of the first symptoms. “This is hypothesized to result from a change in microbiota towards an inflammatory, dysbiotic composition,” Ms. Kenna said. A limited number of studies have reported an association between altered microbiota composition, GI symptoms, and Parkinson’s disease, but not in Australian cohorts.

Total GSRS score was significantly higher in patients with Parkinson’s disease, compared with controls. Eight of the symptoms – heartburn, acid reflux, nausea or vomiting, borborygmus, increased flatus, decreased passage of stools, feeling of incomplete evacuation, and passing hard stools – were significantly increased in patients with Parkinson’s disease. GSRS symptoms can be categorized as upper, lower, general, hypoactive, or hyperactive, and patients with Parkinson’s disease had significantly increased ratings in the upper, lower, and hypoactive GI symptom domains.

“This is quite a novel finding as not only has this not been assessed in an Australian cohort of individuals before, but the majority of existing literature focuses on the presence of constipation only,” Ms. Kenna said. “The treatment and understanding of nonmotor symptoms of Parkinson’s disease, in particular GI symptoms, remain as one of the top unmet needs reported by patients with Parkinson’s disease themselves. Therefore, a better, more thorough understanding of these symptoms is clearly needed, and research into this area has such value in terms of improving current therapeutic approaches, management strategies, and patient education.”

Microbial analyses found that Firmicutes and Proteobacteria were significantly increased and Verrucomicrobia trended toward an increase in patients with Parkinson’s disease. Fusobacteria was increased in controls. “Proteobacteria and Verrucomicrobia are known to promote inflammation, which can lead to GI symptoms. Furthermore, Faecalibacterium and Ruminococcus, which are reduced in [Parkinson’s disease], can metabolize various substrates to produce [short-chain fatty acids] like butyrate, which are known to aid against intestinal barrier dysfunction and inflammation,” she said.

Individuals with Parkinson’s disease had significantly less microbial diversity. As Parkinson’s disease severity and GI symptom severity increased, microbiome diversity decreased, Ms. Kenna said. “As reduced diversity is associated with increased intestinal inflammation, this indicates that the altered microbiome we saw in [individuals with Parkinson’s disease] may be instigating the increase in incidence and severity of GI symptoms.”

Ms. Kenna reported that she had no disclosures.

jremaly@mdedge.com

SOURCE: Kenna JE. AAN 2020, Abstract S17.006.

Gastrointestinal symptoms are more common and severe in patients with Parkinson’s disease than in controls and may relate to an altered microbiome composition and reduced microbial diversity, according to research presented online as part of the 2020 American Academy of Neurology Science Highlights.

Jade E. Kenna, a PhD candidate and research assistant at the Perron Institute of Neurological and Translational Science in Perth, Australia, described findings from a multicenter assessment of 167 patients with Parkinson’s disease and 100 controls from movement disorders clinics in Australia. Participants completed the self-report Gastrointestinal Symptom Rating Scale (GSRS), which rates the frequency and severity of 15 GI symptoms. In addition, stool samples were analyzed using targeted sequencing to characterize gut microbiome composition.

Although Parkinson’s disease is recognized primarily as a motor disorder, GI dysfunction may be one of the first symptoms. “This is hypothesized to result from a change in microbiota towards an inflammatory, dysbiotic composition,” Ms. Kenna said. A limited number of studies have reported an association between altered microbiota composition, GI symptoms, and Parkinson’s disease, but not in Australian cohorts.

Total GSRS score was significantly higher in patients with Parkinson’s disease, compared with controls. Eight of the symptoms – heartburn, acid reflux, nausea or vomiting, borborygmus, increased flatus, decreased passage of stools, feeling of incomplete evacuation, and passing hard stools – were significantly increased in patients with Parkinson’s disease. GSRS symptoms can be categorized as upper, lower, general, hypoactive, or hyperactive, and patients with Parkinson’s disease had significantly increased ratings in the upper, lower, and hypoactive GI symptom domains.

“This is quite a novel finding as not only has this not been assessed in an Australian cohort of individuals before, but the majority of existing literature focuses on the presence of constipation only,” Ms. Kenna said. “The treatment and understanding of nonmotor symptoms of Parkinson’s disease, in particular GI symptoms, remain as one of the top unmet needs reported by patients with Parkinson’s disease themselves. Therefore, a better, more thorough understanding of these symptoms is clearly needed, and research into this area has such value in terms of improving current therapeutic approaches, management strategies, and patient education.”

Microbial analyses found that Firmicutes and Proteobacteria were significantly increased and Verrucomicrobia trended toward an increase in patients with Parkinson’s disease. Fusobacteria was increased in controls. “Proteobacteria and Verrucomicrobia are known to promote inflammation, which can lead to GI symptoms. Furthermore, Faecalibacterium and Ruminococcus, which are reduced in [Parkinson’s disease], can metabolize various substrates to produce [short-chain fatty acids] like butyrate, which are known to aid against intestinal barrier dysfunction and inflammation,” she said.

Individuals with Parkinson’s disease had significantly less microbial diversity. As Parkinson’s disease severity and GI symptom severity increased, microbiome diversity decreased, Ms. Kenna said. “As reduced diversity is associated with increased intestinal inflammation, this indicates that the altered microbiome we saw in [individuals with Parkinson’s disease] may be instigating the increase in incidence and severity of GI symptoms.”

Ms. Kenna reported that she had no disclosures.

jremaly@mdedge.com

SOURCE: Kenna JE. AAN 2020, Abstract S17.006.