User login
MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Vaginal artesunate quells CIN 2/3 lesions, clears HPV
In a small study, a self-administered vaginal insert containing the antimalarial agent artesunate resolved cervical intraepithelial neoplasia (CIN) 2/3 lesions in two-thirds of patients and cleared human papillomavirus (HPV) genotypes in nearly half of women whose lesions disappeared.
Among 28 women with biopsy-confirmed CIN 2/3 who used the inserts prior to a planned standard-of-care resection, histologic regression of lesions occurred in 19 patients. In 9 of the 19 women, there was clearance of baseline HPV genotypes.
These results were reported in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The study results were also published in Gynecologic Oncology.
An unexpected treatment
“The implications of having a safe, inexpensive, self-administered, shelf-stable, nonsurgical treatment for HPV intraepithelial disease, not only here in the U.S., but also extending to low-resource settings,” are self-evident, said study author Cornelia L. Trimble, MD, of Johns Hopkins University in Baltimore.
“This could change the entire landscape of care,” Dr. Trimble said in an interview. “Who’d have thunk that a freaking Chinese herbal medicine derived from the bark of a tree could have this effect?”
Artesunate is a derivative of artemisinin, an antimalarial isolated from the plant Artemisia annua, which is used in traditional Chinese medicine. According to the Centers for Disease Control and Prevention, intravenous artesunate is the first-line drug for treatment of severe malaria in the United States.
However, artesunate is neither approved by the Food and Drug Administration nor commercially available in the United States. The CDC provides artesunate to U.S. clinicians on an as-needed basis.
In addition to its antimalarial activity, artesunate has been shown to have a cytotoxic effect on squamous cells transformed by HPV in vitro. Dr. Trimble and colleagues are also testing a topical form of the drug for the treatment of vulvar intraepithelial neoplasia.
Patients, dosing, and efficacy
In the current study, Dr. Trimble and colleagues enrolled adult immunocompetent women with CIN 2/3, visible residual lesions, and detectable HPV. The patients were assigned sequentially to one of four treatment groups: one 5-day cycle of 50-mg inserts or one, two, or three 5-day cycles using 200-mg inserts.
The patients were instructed to place the inserts at bedtime using a vaginal applicator, followed by a tampon, and then remove the inserts in the morning.
In a modified intention-to-treat analysis including all women who received at least one dose of artesunate and who had endpoint data available, 19 of 28 (67.9%) had histologic regression of CIN lesions. Of the 19 patients, 9 (47.4%) had clearance of all HPV genotypes that had been present at baseline.
Asked how the investigators could distinguish between the treatment effect of the inserts and spontaneous clearance of lesions seen as part of the natural history of CIN in some patients, Dr. Trimble pointed to two observations suggesting an immunologic effect from treatment.
Specifically, although there was lesion regression to CIN 1 or less in all treatment groups, the patients who had only a single treatment cycle had a longer time to regression than those who received two or three cycles.
Additionally, among the nine patients who had viral clearance, three had clearance at the same study time point where histologic regression was observed. For the other six patients, the virus did not clear until several weeks following lesion regression.
These two observations suggest the therapeutic effect of artesunate is recognized by the immune system, which may stimulate a localized immune-mediated cytotoxic effect, Dr. Trimble said.
Safety and next steps
The safety analysis showed that side effects were generally mild and well tolerated. There were 161 adverse events among 29 women for whom safety data were available. The most frequently reported adverse events were vaginal itching (n = 13), vaginal pain (n = 12), vaginal discharge (n = 8), spotting (n = 6), uterine cramping (n = 6), vaginal dryness (n = 4), pelvic pain (n = 1), perineal pain (n = 1), and dyspareunia (n = 1).
Grade 2 adverse events included vaginal yeast infection (n = 6), bacterial vaginosis (n = 2), vaginal inflammation (n = 2), urinary tract infection (n = 2), and noninfective cystitis (n = 1). There were no grade 3 or 4 adverse events reported, and three women reported no noticeable side effects.
Dr. Trimble and colleagues are continuing to study immune responses in cervical tissues and are examining the composition and functions of the cervicovaginal metagenome, looking at bacterial, viral, and fungal components. The team has joined with collaborators at the University of Texas MD Anderson Cancer Center in Houston to look for immune markers in longitudinally collected, subject-matched cervical swabs.
Frantz Viral Therapeutics supplied the artesunate vaginal inserts and partial financial support for this study. Dr. Trimble disclosed relationships with a range of companies and organizations outside this work.
SOURCE: Trimble C L et al. SGO 2020, Abstract LBA 1.
In a small study, a self-administered vaginal insert containing the antimalarial agent artesunate resolved cervical intraepithelial neoplasia (CIN) 2/3 lesions in two-thirds of patients and cleared human papillomavirus (HPV) genotypes in nearly half of women whose lesions disappeared.
Among 28 women with biopsy-confirmed CIN 2/3 who used the inserts prior to a planned standard-of-care resection, histologic regression of lesions occurred in 19 patients. In 9 of the 19 women, there was clearance of baseline HPV genotypes.
These results were reported in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The study results were also published in Gynecologic Oncology.
An unexpected treatment
“The implications of having a safe, inexpensive, self-administered, shelf-stable, nonsurgical treatment for HPV intraepithelial disease, not only here in the U.S., but also extending to low-resource settings,” are self-evident, said study author Cornelia L. Trimble, MD, of Johns Hopkins University in Baltimore.
“This could change the entire landscape of care,” Dr. Trimble said in an interview. “Who’d have thunk that a freaking Chinese herbal medicine derived from the bark of a tree could have this effect?”
Artesunate is a derivative of artemisinin, an antimalarial isolated from the plant Artemisia annua, which is used in traditional Chinese medicine. According to the Centers for Disease Control and Prevention, intravenous artesunate is the first-line drug for treatment of severe malaria in the United States.
However, artesunate is neither approved by the Food and Drug Administration nor commercially available in the United States. The CDC provides artesunate to U.S. clinicians on an as-needed basis.
In addition to its antimalarial activity, artesunate has been shown to have a cytotoxic effect on squamous cells transformed by HPV in vitro. Dr. Trimble and colleagues are also testing a topical form of the drug for the treatment of vulvar intraepithelial neoplasia.
Patients, dosing, and efficacy
In the current study, Dr. Trimble and colleagues enrolled adult immunocompetent women with CIN 2/3, visible residual lesions, and detectable HPV. The patients were assigned sequentially to one of four treatment groups: one 5-day cycle of 50-mg inserts or one, two, or three 5-day cycles using 200-mg inserts.
The patients were instructed to place the inserts at bedtime using a vaginal applicator, followed by a tampon, and then remove the inserts in the morning.
In a modified intention-to-treat analysis including all women who received at least one dose of artesunate and who had endpoint data available, 19 of 28 (67.9%) had histologic regression of CIN lesions. Of the 19 patients, 9 (47.4%) had clearance of all HPV genotypes that had been present at baseline.
Asked how the investigators could distinguish between the treatment effect of the inserts and spontaneous clearance of lesions seen as part of the natural history of CIN in some patients, Dr. Trimble pointed to two observations suggesting an immunologic effect from treatment.
Specifically, although there was lesion regression to CIN 1 or less in all treatment groups, the patients who had only a single treatment cycle had a longer time to regression than those who received two or three cycles.
Additionally, among the nine patients who had viral clearance, three had clearance at the same study time point where histologic regression was observed. For the other six patients, the virus did not clear until several weeks following lesion regression.
These two observations suggest the therapeutic effect of artesunate is recognized by the immune system, which may stimulate a localized immune-mediated cytotoxic effect, Dr. Trimble said.
Safety and next steps
The safety analysis showed that side effects were generally mild and well tolerated. There were 161 adverse events among 29 women for whom safety data were available. The most frequently reported adverse events were vaginal itching (n = 13), vaginal pain (n = 12), vaginal discharge (n = 8), spotting (n = 6), uterine cramping (n = 6), vaginal dryness (n = 4), pelvic pain (n = 1), perineal pain (n = 1), and dyspareunia (n = 1).
Grade 2 adverse events included vaginal yeast infection (n = 6), bacterial vaginosis (n = 2), vaginal inflammation (n = 2), urinary tract infection (n = 2), and noninfective cystitis (n = 1). There were no grade 3 or 4 adverse events reported, and three women reported no noticeable side effects.
Dr. Trimble and colleagues are continuing to study immune responses in cervical tissues and are examining the composition and functions of the cervicovaginal metagenome, looking at bacterial, viral, and fungal components. The team has joined with collaborators at the University of Texas MD Anderson Cancer Center in Houston to look for immune markers in longitudinally collected, subject-matched cervical swabs.
Frantz Viral Therapeutics supplied the artesunate vaginal inserts and partial financial support for this study. Dr. Trimble disclosed relationships with a range of companies and organizations outside this work.
SOURCE: Trimble C L et al. SGO 2020, Abstract LBA 1.
In a small study, a self-administered vaginal insert containing the antimalarial agent artesunate resolved cervical intraepithelial neoplasia (CIN) 2/3 lesions in two-thirds of patients and cleared human papillomavirus (HPV) genotypes in nearly half of women whose lesions disappeared.
Among 28 women with biopsy-confirmed CIN 2/3 who used the inserts prior to a planned standard-of-care resection, histologic regression of lesions occurred in 19 patients. In 9 of the 19 women, there was clearance of baseline HPV genotypes.
These results were reported in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The study results were also published in Gynecologic Oncology.
An unexpected treatment
“The implications of having a safe, inexpensive, self-administered, shelf-stable, nonsurgical treatment for HPV intraepithelial disease, not only here in the U.S., but also extending to low-resource settings,” are self-evident, said study author Cornelia L. Trimble, MD, of Johns Hopkins University in Baltimore.
“This could change the entire landscape of care,” Dr. Trimble said in an interview. “Who’d have thunk that a freaking Chinese herbal medicine derived from the bark of a tree could have this effect?”
Artesunate is a derivative of artemisinin, an antimalarial isolated from the plant Artemisia annua, which is used in traditional Chinese medicine. According to the Centers for Disease Control and Prevention, intravenous artesunate is the first-line drug for treatment of severe malaria in the United States.
However, artesunate is neither approved by the Food and Drug Administration nor commercially available in the United States. The CDC provides artesunate to U.S. clinicians on an as-needed basis.
In addition to its antimalarial activity, artesunate has been shown to have a cytotoxic effect on squamous cells transformed by HPV in vitro. Dr. Trimble and colleagues are also testing a topical form of the drug for the treatment of vulvar intraepithelial neoplasia.
Patients, dosing, and efficacy
In the current study, Dr. Trimble and colleagues enrolled adult immunocompetent women with CIN 2/3, visible residual lesions, and detectable HPV. The patients were assigned sequentially to one of four treatment groups: one 5-day cycle of 50-mg inserts or one, two, or three 5-day cycles using 200-mg inserts.
The patients were instructed to place the inserts at bedtime using a vaginal applicator, followed by a tampon, and then remove the inserts in the morning.
In a modified intention-to-treat analysis including all women who received at least one dose of artesunate and who had endpoint data available, 19 of 28 (67.9%) had histologic regression of CIN lesions. Of the 19 patients, 9 (47.4%) had clearance of all HPV genotypes that had been present at baseline.
Asked how the investigators could distinguish between the treatment effect of the inserts and spontaneous clearance of lesions seen as part of the natural history of CIN in some patients, Dr. Trimble pointed to two observations suggesting an immunologic effect from treatment.
Specifically, although there was lesion regression to CIN 1 or less in all treatment groups, the patients who had only a single treatment cycle had a longer time to regression than those who received two or three cycles.
Additionally, among the nine patients who had viral clearance, three had clearance at the same study time point where histologic regression was observed. For the other six patients, the virus did not clear until several weeks following lesion regression.
These two observations suggest the therapeutic effect of artesunate is recognized by the immune system, which may stimulate a localized immune-mediated cytotoxic effect, Dr. Trimble said.
Safety and next steps
The safety analysis showed that side effects were generally mild and well tolerated. There were 161 adverse events among 29 women for whom safety data were available. The most frequently reported adverse events were vaginal itching (n = 13), vaginal pain (n = 12), vaginal discharge (n = 8), spotting (n = 6), uterine cramping (n = 6), vaginal dryness (n = 4), pelvic pain (n = 1), perineal pain (n = 1), and dyspareunia (n = 1).
Grade 2 adverse events included vaginal yeast infection (n = 6), bacterial vaginosis (n = 2), vaginal inflammation (n = 2), urinary tract infection (n = 2), and noninfective cystitis (n = 1). There were no grade 3 or 4 adverse events reported, and three women reported no noticeable side effects.
Dr. Trimble and colleagues are continuing to study immune responses in cervical tissues and are examining the composition and functions of the cervicovaginal metagenome, looking at bacterial, viral, and fungal components. The team has joined with collaborators at the University of Texas MD Anderson Cancer Center in Houston to look for immune markers in longitudinally collected, subject-matched cervical swabs.
Frantz Viral Therapeutics supplied the artesunate vaginal inserts and partial financial support for this study. Dr. Trimble disclosed relationships with a range of companies and organizations outside this work.
SOURCE: Trimble C L et al. SGO 2020, Abstract LBA 1.
FROM SGO 2020
VICTORIA: Vericiguat seen as novel success in tough-to-treat, high-risk heart failure
Not too many years ago, clinicians who treat patients with heart failure, especially those at high risk for decompensation, lamented what seemed a dearth of new drug therapy options.
Now, with the toolbox brimming with new guideline-supported alternatives, .
Importantly, it entered an especially high-risk population with heart failure and reduced ejection fraction (HFrEF); everyone in the trial had experienced a prior, usually quite recent, heart failure exacerbation.
In such patients, the addition of vericiguat (Merck/Bayer) to standard drug and device therapies was followed by a moderately but significantly reduced relative risk for the trial’s primary clinical endpoint over about 11 months.
Recipients benefited with a 10% drop in adjusted risk (P = .019) for cardiovascular (CV) death or first heart failure hospitalization compared to a placebo control group.
But researchers leading the 5050-patient Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), as well as unaffiliated experts who have studied the trial, say that in this case, risk reduction in absolute numbers is a more telling outcome.
“Remember who we’re talking about here in terms of the patients who have this degree of morbidity and mortality,” VICTORIA study chair Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada, told theheart.org | Medscape Cardiology, pointing to the “incredible placebo-group event rate and relatively modest follow-up of 10.8 months.”
The control group’s primary-endpoint event rate was 37.8 per 100 patient-years, 4.2 points higher than the rate for patients who received vericiguat. “And from there you get a number needed to treat of 24 to prevent one event, which is low,” Armstrong said.
“Think about the hundreds of thousands of people with this disease and what that means at the public health level.” About one in four patients with heart failure experience such exacerbations each year, he said.
Armstrong is lead author on the 42-country trial’s publication today in the New England Journal of Medicine, timed to coincide with his online presentation for the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). The annual session was conducted virtually this year following the traditional live meeting’s cancelation due to the COVID-19 pandemic.
The VICTORIA presentation and publication flesh out the cursory top-line primary results that Merck unveiled in November 2019, which had not included the magnitude of the vericiguat relative benefit for the primary endpoint.
The trial represents “another win” for the treatment of heart failure, Clyde W. Yancy, MD, Northwestern University, Chicago, Illinois, said as an invited discussant following Armstrong’s presentation.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
Symptomatic hypotension occurred in less than 10% and syncope in 4% or less of both groups; neither difference between the two groups was significant. Anemia developed more often in patients receiving vericiguat (7.6%) than in the control group (5.7%).
“We think that on balance, vericiguat is a useful alternative option for patients. But certainly the only thing we can say at this point is it works in the high-risk population that we studied,” Armstrong said. “Whether it works in lower-risk populations and how it compares is speculation, of course.”
The drug’s cost, whatever it might be if approved, is another factor affecting how it would be used, noted several observers.
“We don’t know what the cost-effectiveness will be. It should be reasonable because the benefit was on hospitalization. That’s a costly outcome,” Yancy said.
McMurray was also hopeful. “If the treatment is well tolerated and reasonably priced, it may still be a valuable asset for at least a subset of patients.”
VICTORIA was supported by Merck Sharp & Dohme Corp and Bayer AG. Armstrong discloses receiving research grants from Merck, Bayer AG, Sanofi-Aventis, Boehringer Ingelheim, and CSL Ltd and consulting fees from Merck, Bayer AG, AstraZeneca, and Novartis. Y ancy has previously disclosed no relevant financial relationships. Stevenson has previously disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical. McMurray has previously disclosed nonfinancial support or other support from AstraZeneca, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, AbbVie, DalCor, Pfizer, Merck, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Vifor-Fresenius.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Presented March 28, 2020. Session 402-08.
N Engl J Med. Published online March 28, 2020. Full text; Circulation. Published online March 28, 2020. Full text.
This article first appeared on Medscape.com.
Not too many years ago, clinicians who treat patients with heart failure, especially those at high risk for decompensation, lamented what seemed a dearth of new drug therapy options.
Now, with the toolbox brimming with new guideline-supported alternatives, .
Importantly, it entered an especially high-risk population with heart failure and reduced ejection fraction (HFrEF); everyone in the trial had experienced a prior, usually quite recent, heart failure exacerbation.
In such patients, the addition of vericiguat (Merck/Bayer) to standard drug and device therapies was followed by a moderately but significantly reduced relative risk for the trial’s primary clinical endpoint over about 11 months.
Recipients benefited with a 10% drop in adjusted risk (P = .019) for cardiovascular (CV) death or first heart failure hospitalization compared to a placebo control group.
But researchers leading the 5050-patient Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), as well as unaffiliated experts who have studied the trial, say that in this case, risk reduction in absolute numbers is a more telling outcome.
“Remember who we’re talking about here in terms of the patients who have this degree of morbidity and mortality,” VICTORIA study chair Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada, told theheart.org | Medscape Cardiology, pointing to the “incredible placebo-group event rate and relatively modest follow-up of 10.8 months.”
The control group’s primary-endpoint event rate was 37.8 per 100 patient-years, 4.2 points higher than the rate for patients who received vericiguat. “And from there you get a number needed to treat of 24 to prevent one event, which is low,” Armstrong said.
“Think about the hundreds of thousands of people with this disease and what that means at the public health level.” About one in four patients with heart failure experience such exacerbations each year, he said.
Armstrong is lead author on the 42-country trial’s publication today in the New England Journal of Medicine, timed to coincide with his online presentation for the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). The annual session was conducted virtually this year following the traditional live meeting’s cancelation due to the COVID-19 pandemic.
The VICTORIA presentation and publication flesh out the cursory top-line primary results that Merck unveiled in November 2019, which had not included the magnitude of the vericiguat relative benefit for the primary endpoint.
The trial represents “another win” for the treatment of heart failure, Clyde W. Yancy, MD, Northwestern University, Chicago, Illinois, said as an invited discussant following Armstrong’s presentation.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
Symptomatic hypotension occurred in less than 10% and syncope in 4% or less of both groups; neither difference between the two groups was significant. Anemia developed more often in patients receiving vericiguat (7.6%) than in the control group (5.7%).
“We think that on balance, vericiguat is a useful alternative option for patients. But certainly the only thing we can say at this point is it works in the high-risk population that we studied,” Armstrong said. “Whether it works in lower-risk populations and how it compares is speculation, of course.”
The drug’s cost, whatever it might be if approved, is another factor affecting how it would be used, noted several observers.
“We don’t know what the cost-effectiveness will be. It should be reasonable because the benefit was on hospitalization. That’s a costly outcome,” Yancy said.
McMurray was also hopeful. “If the treatment is well tolerated and reasonably priced, it may still be a valuable asset for at least a subset of patients.”
VICTORIA was supported by Merck Sharp & Dohme Corp and Bayer AG. Armstrong discloses receiving research grants from Merck, Bayer AG, Sanofi-Aventis, Boehringer Ingelheim, and CSL Ltd and consulting fees from Merck, Bayer AG, AstraZeneca, and Novartis. Y ancy has previously disclosed no relevant financial relationships. Stevenson has previously disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical. McMurray has previously disclosed nonfinancial support or other support from AstraZeneca, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, AbbVie, DalCor, Pfizer, Merck, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Vifor-Fresenius.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Presented March 28, 2020. Session 402-08.
N Engl J Med. Published online March 28, 2020. Full text; Circulation. Published online March 28, 2020. Full text.
This article first appeared on Medscape.com.
Not too many years ago, clinicians who treat patients with heart failure, especially those at high risk for decompensation, lamented what seemed a dearth of new drug therapy options.
Now, with the toolbox brimming with new guideline-supported alternatives, .
Importantly, it entered an especially high-risk population with heart failure and reduced ejection fraction (HFrEF); everyone in the trial had experienced a prior, usually quite recent, heart failure exacerbation.
In such patients, the addition of vericiguat (Merck/Bayer) to standard drug and device therapies was followed by a moderately but significantly reduced relative risk for the trial’s primary clinical endpoint over about 11 months.
Recipients benefited with a 10% drop in adjusted risk (P = .019) for cardiovascular (CV) death or first heart failure hospitalization compared to a placebo control group.
But researchers leading the 5050-patient Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), as well as unaffiliated experts who have studied the trial, say that in this case, risk reduction in absolute numbers is a more telling outcome.
“Remember who we’re talking about here in terms of the patients who have this degree of morbidity and mortality,” VICTORIA study chair Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada, told theheart.org | Medscape Cardiology, pointing to the “incredible placebo-group event rate and relatively modest follow-up of 10.8 months.”
The control group’s primary-endpoint event rate was 37.8 per 100 patient-years, 4.2 points higher than the rate for patients who received vericiguat. “And from there you get a number needed to treat of 24 to prevent one event, which is low,” Armstrong said.
“Think about the hundreds of thousands of people with this disease and what that means at the public health level.” About one in four patients with heart failure experience such exacerbations each year, he said.
Armstrong is lead author on the 42-country trial’s publication today in the New England Journal of Medicine, timed to coincide with his online presentation for the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). The annual session was conducted virtually this year following the traditional live meeting’s cancelation due to the COVID-19 pandemic.
The VICTORIA presentation and publication flesh out the cursory top-line primary results that Merck unveiled in November 2019, which had not included the magnitude of the vericiguat relative benefit for the primary endpoint.
The trial represents “another win” for the treatment of heart failure, Clyde W. Yancy, MD, Northwestern University, Chicago, Illinois, said as an invited discussant following Armstrong’s presentation.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
Symptomatic hypotension occurred in less than 10% and syncope in 4% or less of both groups; neither difference between the two groups was significant. Anemia developed more often in patients receiving vericiguat (7.6%) than in the control group (5.7%).
“We think that on balance, vericiguat is a useful alternative option for patients. But certainly the only thing we can say at this point is it works in the high-risk population that we studied,” Armstrong said. “Whether it works in lower-risk populations and how it compares is speculation, of course.”
The drug’s cost, whatever it might be if approved, is another factor affecting how it would be used, noted several observers.
“We don’t know what the cost-effectiveness will be. It should be reasonable because the benefit was on hospitalization. That’s a costly outcome,” Yancy said.
McMurray was also hopeful. “If the treatment is well tolerated and reasonably priced, it may still be a valuable asset for at least a subset of patients.”
VICTORIA was supported by Merck Sharp & Dohme Corp and Bayer AG. Armstrong discloses receiving research grants from Merck, Bayer AG, Sanofi-Aventis, Boehringer Ingelheim, and CSL Ltd and consulting fees from Merck, Bayer AG, AstraZeneca, and Novartis. Y ancy has previously disclosed no relevant financial relationships. Stevenson has previously disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical. McMurray has previously disclosed nonfinancial support or other support from AstraZeneca, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, AbbVie, DalCor, Pfizer, Merck, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Vifor-Fresenius.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Presented March 28, 2020. Session 402-08.
N Engl J Med. Published online March 28, 2020. Full text; Circulation. Published online March 28, 2020. Full text.
This article first appeared on Medscape.com.
TAILOR-PCI: Clopidogrel genotyping trial narrowly misses endpoint
The largest trial to date investigating the clinical utility of using genetic testing to detect clopidogrel loss-of-function genotype to guide antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) missed its primary endpoint of a 50% reduction in cardiovascular events at 1 year.
However, the TAILOR-PCI trial did show a 34% reduction in such events at 1 year, as well as a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.
In addition, a post hoc analysis found a significant 79% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy compared with those who did not.
The study was presented March 28 during the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.
“Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not,” concluded Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.
Pereira said the post hoc analysis of the first 3 months of treatment was particularly interesting. “This period immediately after PCI is when patients are at the highest risk for adverse events. We now know that antiplatelet drug therapy is critical during the first 3 months after PCI. Our findings suggest that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period,” he noted.
However, he added, “Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”
Asked during an ACC virtual press conference how these results may influence clinical practice, Pereira said he hopes it changes practice toward genotyping.
“We set a very high standard in trying to achieve a 50% reduction in events, but we did see a 34% reduction. I think the probability of the results being true is very high,” he said. “I hope people pay attention to that. I’m not sure what the guidelines will do, but I believe if clopidogrel genetic information is made available to the physician, not changing therapy in a patient who has the loss-of-function gene will now be very difficult.”
Discussant of the trial, Roxana Mehran, MD, Mount Sinai Hospital, New York City, said she thought the results were good enough clinically to justify using genotyping to guide therapy.
“The trial showed an absolute 1.8% reduction and a relative 34% reduction in cardiovascular events, which did not quite meet the P value for significance, and they are supported by a significant reduction in multiple events, and a large difference at 3 months, although these are not primary analyses. So, for me this trial has shown that tailoring antiplatelet therapy by genetic testing is beneficial,” she said.
Another outside commentator, Patrick O’Gara, MD, Brigham and Women’s Hospital, Boston, Massachusetts, described TAILOR-PCI as a “terrific study.”
“Together with the study presented last year showing genotype-guided clopidogrel treatment was noninferior to ticagrelor/prasugrel in STEMI [non-ST-segment elevation myocardial infarction] patients, it chips away at the biologic appropriateness of targeting therapies based on genetic risk,” he said.
“I would hate people to focus on the fact the primary endpoint was missed by one hundredth of a percentage point but hope they would rather consider the bigger picture of making this genotype test more available and accessible to inform clinical decision making,” O’Gara added. “It just makes too much sense to ignore this potential.”
The TAILOR-PCI trial enrolled 5302 patients from 40 centers in the United States, Canada, Mexico, and South Korea who had undergone PCI with stenting. They were randomly assigned to genetic testing for the clopidogrel loss-of-function variant or a group that received standard treatment (clopidogrel) without genetic testing.
In the genetic testing group, 35% of patients were found to have the clopidogrel loss-of-function variant and were therefore prescribed ticagrelor, whereas those without the loss-of-function variant received clopidogrel.
After 1 year, the primary endpoint, a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia, occurred in 35 patients (4%) of the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group (adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43 - 1.02; P = .56).
A prespecified analysis of total events (rather than just analysis of first event per patient) showed a 40% reduction in the genotyped group (HR, 0.60; 95% CI, 0.41 - 0.89; P = .011).
“Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy,” Pereira said.
There was no difference in the safety endpoint of TIMI major bleeding or minor bleeding between the two groups: 1.9% in the genetically guided group vs 1.6% in the conventional treatment group.
The results did not differ between various subgroups in the trial, including race or ethnicity. Although Asian patients have a higher occurrence of the clopidogrel loss-of-function gene, the event risk reductions were similar in Asian and white patients in the study.
Pereira said the study may have been underpowered because of recent improvements in care. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, but during the trial, greater use of drug-coated stents and other treatments significantly reduced the expected rate of adverse events and made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, he explained.
As part of the discussion, Mehran pointed out that more than 80% of the patients in the trial had acute coronary syndrome (ACS) and yet were being sent home on clopidogrel, which she said she found “daunting.”
“This begs the question of whether they were lower-risk patients and not really the hot unstable ACS patients with large thrombus burden where we see higher event rates,” Mehran commented. She also noted the results must be considered in the new era of platelet monotherapy, where aspirin is being withdrawn, and asked whether clopidogrel monotherapy would be considered safe without aspirin on board.
The researchers are planning a cost-effectiveness analysis of genetically guided therapy based on these data, and they are also continuing to follow patients over the longer term.
The TAILOR-PCI study was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience Inc supplied the genetic tests used. Pereira reports no relevant disclosures.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 20-LB-20309-ACC. Presented March 28, 2020.
This article first appeared on Medscape.com.
The largest trial to date investigating the clinical utility of using genetic testing to detect clopidogrel loss-of-function genotype to guide antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) missed its primary endpoint of a 50% reduction in cardiovascular events at 1 year.
However, the TAILOR-PCI trial did show a 34% reduction in such events at 1 year, as well as a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.
In addition, a post hoc analysis found a significant 79% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy compared with those who did not.
The study was presented March 28 during the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.
“Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not,” concluded Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.
Pereira said the post hoc analysis of the first 3 months of treatment was particularly interesting. “This period immediately after PCI is when patients are at the highest risk for adverse events. We now know that antiplatelet drug therapy is critical during the first 3 months after PCI. Our findings suggest that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period,” he noted.
However, he added, “Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”
Asked during an ACC virtual press conference how these results may influence clinical practice, Pereira said he hopes it changes practice toward genotyping.
“We set a very high standard in trying to achieve a 50% reduction in events, but we did see a 34% reduction. I think the probability of the results being true is very high,” he said. “I hope people pay attention to that. I’m not sure what the guidelines will do, but I believe if clopidogrel genetic information is made available to the physician, not changing therapy in a patient who has the loss-of-function gene will now be very difficult.”
Discussant of the trial, Roxana Mehran, MD, Mount Sinai Hospital, New York City, said she thought the results were good enough clinically to justify using genotyping to guide therapy.
“The trial showed an absolute 1.8% reduction and a relative 34% reduction in cardiovascular events, which did not quite meet the P value for significance, and they are supported by a significant reduction in multiple events, and a large difference at 3 months, although these are not primary analyses. So, for me this trial has shown that tailoring antiplatelet therapy by genetic testing is beneficial,” she said.
Another outside commentator, Patrick O’Gara, MD, Brigham and Women’s Hospital, Boston, Massachusetts, described TAILOR-PCI as a “terrific study.”
“Together with the study presented last year showing genotype-guided clopidogrel treatment was noninferior to ticagrelor/prasugrel in STEMI [non-ST-segment elevation myocardial infarction] patients, it chips away at the biologic appropriateness of targeting therapies based on genetic risk,” he said.
“I would hate people to focus on the fact the primary endpoint was missed by one hundredth of a percentage point but hope they would rather consider the bigger picture of making this genotype test more available and accessible to inform clinical decision making,” O’Gara added. “It just makes too much sense to ignore this potential.”
The TAILOR-PCI trial enrolled 5302 patients from 40 centers in the United States, Canada, Mexico, and South Korea who had undergone PCI with stenting. They were randomly assigned to genetic testing for the clopidogrel loss-of-function variant or a group that received standard treatment (clopidogrel) without genetic testing.
In the genetic testing group, 35% of patients were found to have the clopidogrel loss-of-function variant and were therefore prescribed ticagrelor, whereas those without the loss-of-function variant received clopidogrel.
After 1 year, the primary endpoint, a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia, occurred in 35 patients (4%) of the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group (adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43 - 1.02; P = .56).
A prespecified analysis of total events (rather than just analysis of first event per patient) showed a 40% reduction in the genotyped group (HR, 0.60; 95% CI, 0.41 - 0.89; P = .011).
“Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy,” Pereira said.
There was no difference in the safety endpoint of TIMI major bleeding or minor bleeding between the two groups: 1.9% in the genetically guided group vs 1.6% in the conventional treatment group.
The results did not differ between various subgroups in the trial, including race or ethnicity. Although Asian patients have a higher occurrence of the clopidogrel loss-of-function gene, the event risk reductions were similar in Asian and white patients in the study.
Pereira said the study may have been underpowered because of recent improvements in care. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, but during the trial, greater use of drug-coated stents and other treatments significantly reduced the expected rate of adverse events and made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, he explained.
As part of the discussion, Mehran pointed out that more than 80% of the patients in the trial had acute coronary syndrome (ACS) and yet were being sent home on clopidogrel, which she said she found “daunting.”
“This begs the question of whether they were lower-risk patients and not really the hot unstable ACS patients with large thrombus burden where we see higher event rates,” Mehran commented. She also noted the results must be considered in the new era of platelet monotherapy, where aspirin is being withdrawn, and asked whether clopidogrel monotherapy would be considered safe without aspirin on board.
The researchers are planning a cost-effectiveness analysis of genetically guided therapy based on these data, and they are also continuing to follow patients over the longer term.
The TAILOR-PCI study was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience Inc supplied the genetic tests used. Pereira reports no relevant disclosures.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 20-LB-20309-ACC. Presented March 28, 2020.
This article first appeared on Medscape.com.
The largest trial to date investigating the clinical utility of using genetic testing to detect clopidogrel loss-of-function genotype to guide antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) missed its primary endpoint of a 50% reduction in cardiovascular events at 1 year.
However, the TAILOR-PCI trial did show a 34% reduction in such events at 1 year, as well as a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.
In addition, a post hoc analysis found a significant 79% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy compared with those who did not.
The study was presented March 28 during the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.
“Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not,” concluded Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.
Pereira said the post hoc analysis of the first 3 months of treatment was particularly interesting. “This period immediately after PCI is when patients are at the highest risk for adverse events. We now know that antiplatelet drug therapy is critical during the first 3 months after PCI. Our findings suggest that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period,” he noted.
However, he added, “Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”
Asked during an ACC virtual press conference how these results may influence clinical practice, Pereira said he hopes it changes practice toward genotyping.
“We set a very high standard in trying to achieve a 50% reduction in events, but we did see a 34% reduction. I think the probability of the results being true is very high,” he said. “I hope people pay attention to that. I’m not sure what the guidelines will do, but I believe if clopidogrel genetic information is made available to the physician, not changing therapy in a patient who has the loss-of-function gene will now be very difficult.”
Discussant of the trial, Roxana Mehran, MD, Mount Sinai Hospital, New York City, said she thought the results were good enough clinically to justify using genotyping to guide therapy.
“The trial showed an absolute 1.8% reduction and a relative 34% reduction in cardiovascular events, which did not quite meet the P value for significance, and they are supported by a significant reduction in multiple events, and a large difference at 3 months, although these are not primary analyses. So, for me this trial has shown that tailoring antiplatelet therapy by genetic testing is beneficial,” she said.
Another outside commentator, Patrick O’Gara, MD, Brigham and Women’s Hospital, Boston, Massachusetts, described TAILOR-PCI as a “terrific study.”
“Together with the study presented last year showing genotype-guided clopidogrel treatment was noninferior to ticagrelor/prasugrel in STEMI [non-ST-segment elevation myocardial infarction] patients, it chips away at the biologic appropriateness of targeting therapies based on genetic risk,” he said.
“I would hate people to focus on the fact the primary endpoint was missed by one hundredth of a percentage point but hope they would rather consider the bigger picture of making this genotype test more available and accessible to inform clinical decision making,” O’Gara added. “It just makes too much sense to ignore this potential.”
The TAILOR-PCI trial enrolled 5302 patients from 40 centers in the United States, Canada, Mexico, and South Korea who had undergone PCI with stenting. They were randomly assigned to genetic testing for the clopidogrel loss-of-function variant or a group that received standard treatment (clopidogrel) without genetic testing.
In the genetic testing group, 35% of patients were found to have the clopidogrel loss-of-function variant and were therefore prescribed ticagrelor, whereas those without the loss-of-function variant received clopidogrel.
After 1 year, the primary endpoint, a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia, occurred in 35 patients (4%) of the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group (adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43 - 1.02; P = .56).
A prespecified analysis of total events (rather than just analysis of first event per patient) showed a 40% reduction in the genotyped group (HR, 0.60; 95% CI, 0.41 - 0.89; P = .011).
“Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy,” Pereira said.
There was no difference in the safety endpoint of TIMI major bleeding or minor bleeding between the two groups: 1.9% in the genetically guided group vs 1.6% in the conventional treatment group.
The results did not differ between various subgroups in the trial, including race or ethnicity. Although Asian patients have a higher occurrence of the clopidogrel loss-of-function gene, the event risk reductions were similar in Asian and white patients in the study.
Pereira said the study may have been underpowered because of recent improvements in care. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, but during the trial, greater use of drug-coated stents and other treatments significantly reduced the expected rate of adverse events and made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, he explained.
As part of the discussion, Mehran pointed out that more than 80% of the patients in the trial had acute coronary syndrome (ACS) and yet were being sent home on clopidogrel, which she said she found “daunting.”
“This begs the question of whether they were lower-risk patients and not really the hot unstable ACS patients with large thrombus burden where we see higher event rates,” Mehran commented. She also noted the results must be considered in the new era of platelet monotherapy, where aspirin is being withdrawn, and asked whether clopidogrel monotherapy would be considered safe without aspirin on board.
The researchers are planning a cost-effectiveness analysis of genetically guided therapy based on these data, and they are also continuing to follow patients over the longer term.
The TAILOR-PCI study was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience Inc supplied the genetic tests used. Pereira reports no relevant disclosures.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 20-LB-20309-ACC. Presented March 28, 2020.
This article first appeared on Medscape.com.
More than one in three cardiologists burned out, many ready to bolt
Even before the COVID-19 pandemic, , a new survey shows.
“It is important to recognize the personal and professional repercussions of physician burnout,” lead author Laxmi Mehta, MD, director of preventive cardiology and women’s cardiovascular health at Ohio State University, Columbus, said during an online session of the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
The new ACC 2019 Well Being Survey was sent to 19,348 ACC members in the fall of 2019 and sought to take a deeper dive into the issue of burnout after the ACC’s most recent Professional Life Survey revealed that one in four U.S. cardiologists were burned out in 2015.
While the number of cardiologists who reported feeling stressed fell from 49.5% in 2015 to 43.9% in 2019, the number of cardiologists who reported being burned out increased by 32% from 26.8% to 35.4%, Mehta said.
Among those currently feeling burned out, 23.9% reported having one or more symptoms of burnout, 9.9% had chronic burnout and work frustrations, and 1.6% were “completely burned out” and at the point where they may need to seek help.
Burned-out cardiologists were more likely than those who felt stressed or no burnout to say they may have made a major medical error in the past 3 months (58.3% vs 33.1% and 8.6%; P ≤ .001).
The Usual Suspects
As previously observed, burnout was highest among mid-career cardiologists with 8 to 21 years in practice vs early-career and late-career cardiologists (45.3% vs 35.4% and 31.5%; P ≤ .001) and in women vs men (45.3% vs 33.5%; P ≤ .001). Of the 2025 ACC members who responded, 362 were women.
Several initiatives are underway by the ACC to increase the diversity of cardiology as a specialty, but attention is also needed for mid-career cardiologists, who may not see the “light at the end of the tunnel,” as they take on more clinical demands and more administrative roles, Mehta observed.
Not surprising, clocking 60 or more hours per week increased the risk for burnout, compared with working 40 to 59 hours per week or fewer than 40 hours per week (41.5% vs 29.5% and 17.9%; P ≤ .001).
Burned-out cardiologists were also more likely than those who felt stressed or no burnout to report working in a hectic work environment (59.5% vs 32.3% and 14.6%; P ≤ .001) and to have plans to leave their current practice setting (58.1% vs 27.9% and 14.0%; P ≤ .001).
Factors that played a significant role in those plans were the desire to spend more time with family, on-call time, excessive work or relative value unit (RVU) targets, electronic health records, and the pressure to maintain high patient satisfaction scores, Mehta noted.
“Is any of this relatable to decreasing numbers of cardiologists in the U.S., or is there work to try and relate actual work force availability to burnout?” asked session moderator B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute in Charlotte, North Carolina, and a member of ACC’s Board of Trustees, following the presentation.
“It’s hard to decipher all of those exact details, but we do know that the cardiology work force tends to be older, so the mid-careers are going to be pulling on a lot more weight in the next few years, so that is a concern,” Mehta replied.
A big factor, however, is the excessive work hours put in by all cardiologists, especially the increasing amount of time spent with electronic medical records and administrative tasks, which is “taking away the fun we had in cardiology,” she added.
Limitations of the survey include the potential for bias; burnout was self-reported and may vary over time; and the 14% response rate was less than ideal, although the results are consistent with other national surveys, Mehta said.
In the recent Medscape Cardiologist Lifestyle, Happiness & Burnout Report 2020, 29% of respondents reported feeling burnout, 2% depressed, and 15% both burned out and depressed.
The Elephant in the Room
The new findings are “certainly a call to action, but it’s hard to avoid the elephant in the room, which is COVID-19,” said panelist Sandra Lewis, MD, Legacy Good Samaritan Hospital & Medical Center, Portland, Oregon.
“The implications of burnout are really front-and-center with our colleagues, who are working long hours, have hectic work environments, lack of control, and, more than that, a lack of safety of the work situations that we have worked so hard to achieve, as we run out of protective gear, we don’t have masks, as we see our colleagues falling victim to this.”
During her presentation, Mehta highlighted the ACC Clinician Well Being Portal and its COVID-19 Hub, but also several self-care strategies to employ, such as relinquishing control during these uncharted waters, revisiting personal strengths and abilities leveraged in other times of uncertainty, and giving yourself a “brain break” by challenging yourself to chat with a colleague for 30 minutes on topics unrelated to COVID-19 and other workplace stressors.
Wilson said the global pandemic only heightens concerns about burnout among cardiologists, which he likened to a “runaway train.”
“These are not great signals, I think they’re shocking, quite frankly,” Wilson told theheart.org | Medscape Cardiology.
“ACC is setting up a task force from the board of trustees to get to work right away and see about ways we can turn this around as quickly as possible and be a voice for the clinicians,” he said. “It’s not only cardiologists, it’s everybody on our cardiovascular care team, including nurses, physician assistants, nurse practitioners, and even pharmacists. Everybody’s burning out.”
The authors and Wilson report no relevant conflicts of interest.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 403.08. Presented March 28, 2020.
This article first appeared on Medscape.com.
Even before the COVID-19 pandemic, , a new survey shows.
“It is important to recognize the personal and professional repercussions of physician burnout,” lead author Laxmi Mehta, MD, director of preventive cardiology and women’s cardiovascular health at Ohio State University, Columbus, said during an online session of the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
The new ACC 2019 Well Being Survey was sent to 19,348 ACC members in the fall of 2019 and sought to take a deeper dive into the issue of burnout after the ACC’s most recent Professional Life Survey revealed that one in four U.S. cardiologists were burned out in 2015.
While the number of cardiologists who reported feeling stressed fell from 49.5% in 2015 to 43.9% in 2019, the number of cardiologists who reported being burned out increased by 32% from 26.8% to 35.4%, Mehta said.
Among those currently feeling burned out, 23.9% reported having one or more symptoms of burnout, 9.9% had chronic burnout and work frustrations, and 1.6% were “completely burned out” and at the point where they may need to seek help.
Burned-out cardiologists were more likely than those who felt stressed or no burnout to say they may have made a major medical error in the past 3 months (58.3% vs 33.1% and 8.6%; P ≤ .001).
The Usual Suspects
As previously observed, burnout was highest among mid-career cardiologists with 8 to 21 years in practice vs early-career and late-career cardiologists (45.3% vs 35.4% and 31.5%; P ≤ .001) and in women vs men (45.3% vs 33.5%; P ≤ .001). Of the 2025 ACC members who responded, 362 were women.
Several initiatives are underway by the ACC to increase the diversity of cardiology as a specialty, but attention is also needed for mid-career cardiologists, who may not see the “light at the end of the tunnel,” as they take on more clinical demands and more administrative roles, Mehta observed.
Not surprising, clocking 60 or more hours per week increased the risk for burnout, compared with working 40 to 59 hours per week or fewer than 40 hours per week (41.5% vs 29.5% and 17.9%; P ≤ .001).
Burned-out cardiologists were also more likely than those who felt stressed or no burnout to report working in a hectic work environment (59.5% vs 32.3% and 14.6%; P ≤ .001) and to have plans to leave their current practice setting (58.1% vs 27.9% and 14.0%; P ≤ .001).
Factors that played a significant role in those plans were the desire to spend more time with family, on-call time, excessive work or relative value unit (RVU) targets, electronic health records, and the pressure to maintain high patient satisfaction scores, Mehta noted.
“Is any of this relatable to decreasing numbers of cardiologists in the U.S., or is there work to try and relate actual work force availability to burnout?” asked session moderator B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute in Charlotte, North Carolina, and a member of ACC’s Board of Trustees, following the presentation.
“It’s hard to decipher all of those exact details, but we do know that the cardiology work force tends to be older, so the mid-careers are going to be pulling on a lot more weight in the next few years, so that is a concern,” Mehta replied.
A big factor, however, is the excessive work hours put in by all cardiologists, especially the increasing amount of time spent with electronic medical records and administrative tasks, which is “taking away the fun we had in cardiology,” she added.
Limitations of the survey include the potential for bias; burnout was self-reported and may vary over time; and the 14% response rate was less than ideal, although the results are consistent with other national surveys, Mehta said.
In the recent Medscape Cardiologist Lifestyle, Happiness & Burnout Report 2020, 29% of respondents reported feeling burnout, 2% depressed, and 15% both burned out and depressed.
The Elephant in the Room
The new findings are “certainly a call to action, but it’s hard to avoid the elephant in the room, which is COVID-19,” said panelist Sandra Lewis, MD, Legacy Good Samaritan Hospital & Medical Center, Portland, Oregon.
“The implications of burnout are really front-and-center with our colleagues, who are working long hours, have hectic work environments, lack of control, and, more than that, a lack of safety of the work situations that we have worked so hard to achieve, as we run out of protective gear, we don’t have masks, as we see our colleagues falling victim to this.”
During her presentation, Mehta highlighted the ACC Clinician Well Being Portal and its COVID-19 Hub, but also several self-care strategies to employ, such as relinquishing control during these uncharted waters, revisiting personal strengths and abilities leveraged in other times of uncertainty, and giving yourself a “brain break” by challenging yourself to chat with a colleague for 30 minutes on topics unrelated to COVID-19 and other workplace stressors.
Wilson said the global pandemic only heightens concerns about burnout among cardiologists, which he likened to a “runaway train.”
“These are not great signals, I think they’re shocking, quite frankly,” Wilson told theheart.org | Medscape Cardiology.
“ACC is setting up a task force from the board of trustees to get to work right away and see about ways we can turn this around as quickly as possible and be a voice for the clinicians,” he said. “It’s not only cardiologists, it’s everybody on our cardiovascular care team, including nurses, physician assistants, nurse practitioners, and even pharmacists. Everybody’s burning out.”
The authors and Wilson report no relevant conflicts of interest.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 403.08. Presented March 28, 2020.
This article first appeared on Medscape.com.
Even before the COVID-19 pandemic, , a new survey shows.
“It is important to recognize the personal and professional repercussions of physician burnout,” lead author Laxmi Mehta, MD, director of preventive cardiology and women’s cardiovascular health at Ohio State University, Columbus, said during an online session of the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
The new ACC 2019 Well Being Survey was sent to 19,348 ACC members in the fall of 2019 and sought to take a deeper dive into the issue of burnout after the ACC’s most recent Professional Life Survey revealed that one in four U.S. cardiologists were burned out in 2015.
While the number of cardiologists who reported feeling stressed fell from 49.5% in 2015 to 43.9% in 2019, the number of cardiologists who reported being burned out increased by 32% from 26.8% to 35.4%, Mehta said.
Among those currently feeling burned out, 23.9% reported having one or more symptoms of burnout, 9.9% had chronic burnout and work frustrations, and 1.6% were “completely burned out” and at the point where they may need to seek help.
Burned-out cardiologists were more likely than those who felt stressed or no burnout to say they may have made a major medical error in the past 3 months (58.3% vs 33.1% and 8.6%; P ≤ .001).
The Usual Suspects
As previously observed, burnout was highest among mid-career cardiologists with 8 to 21 years in practice vs early-career and late-career cardiologists (45.3% vs 35.4% and 31.5%; P ≤ .001) and in women vs men (45.3% vs 33.5%; P ≤ .001). Of the 2025 ACC members who responded, 362 were women.
Several initiatives are underway by the ACC to increase the diversity of cardiology as a specialty, but attention is also needed for mid-career cardiologists, who may not see the “light at the end of the tunnel,” as they take on more clinical demands and more administrative roles, Mehta observed.
Not surprising, clocking 60 or more hours per week increased the risk for burnout, compared with working 40 to 59 hours per week or fewer than 40 hours per week (41.5% vs 29.5% and 17.9%; P ≤ .001).
Burned-out cardiologists were also more likely than those who felt stressed or no burnout to report working in a hectic work environment (59.5% vs 32.3% and 14.6%; P ≤ .001) and to have plans to leave their current practice setting (58.1% vs 27.9% and 14.0%; P ≤ .001).
Factors that played a significant role in those plans were the desire to spend more time with family, on-call time, excessive work or relative value unit (RVU) targets, electronic health records, and the pressure to maintain high patient satisfaction scores, Mehta noted.
“Is any of this relatable to decreasing numbers of cardiologists in the U.S., or is there work to try and relate actual work force availability to burnout?” asked session moderator B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute in Charlotte, North Carolina, and a member of ACC’s Board of Trustees, following the presentation.
“It’s hard to decipher all of those exact details, but we do know that the cardiology work force tends to be older, so the mid-careers are going to be pulling on a lot more weight in the next few years, so that is a concern,” Mehta replied.
A big factor, however, is the excessive work hours put in by all cardiologists, especially the increasing amount of time spent with electronic medical records and administrative tasks, which is “taking away the fun we had in cardiology,” she added.
Limitations of the survey include the potential for bias; burnout was self-reported and may vary over time; and the 14% response rate was less than ideal, although the results are consistent with other national surveys, Mehta said.
In the recent Medscape Cardiologist Lifestyle, Happiness & Burnout Report 2020, 29% of respondents reported feeling burnout, 2% depressed, and 15% both burned out and depressed.
The Elephant in the Room
The new findings are “certainly a call to action, but it’s hard to avoid the elephant in the room, which is COVID-19,” said panelist Sandra Lewis, MD, Legacy Good Samaritan Hospital & Medical Center, Portland, Oregon.
“The implications of burnout are really front-and-center with our colleagues, who are working long hours, have hectic work environments, lack of control, and, more than that, a lack of safety of the work situations that we have worked so hard to achieve, as we run out of protective gear, we don’t have masks, as we see our colleagues falling victim to this.”
During her presentation, Mehta highlighted the ACC Clinician Well Being Portal and its COVID-19 Hub, but also several self-care strategies to employ, such as relinquishing control during these uncharted waters, revisiting personal strengths and abilities leveraged in other times of uncertainty, and giving yourself a “brain break” by challenging yourself to chat with a colleague for 30 minutes on topics unrelated to COVID-19 and other workplace stressors.
Wilson said the global pandemic only heightens concerns about burnout among cardiologists, which he likened to a “runaway train.”
“These are not great signals, I think they’re shocking, quite frankly,” Wilson told theheart.org | Medscape Cardiology.
“ACC is setting up a task force from the board of trustees to get to work right away and see about ways we can turn this around as quickly as possible and be a voice for the clinicians,” he said. “It’s not only cardiologists, it’s everybody on our cardiovascular care team, including nurses, physician assistants, nurse practitioners, and even pharmacists. Everybody’s burning out.”
The authors and Wilson report no relevant conflicts of interest.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 403.08. Presented March 28, 2020.
This article first appeared on Medscape.com.
Primordial cardiovascular prevention draws closer
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, 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.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, 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.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, 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.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
REPORTING FROM ACC 20
Rivaroxaban plus aspirin safely benefits PAD patients after limb revascularization
A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.
The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 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.
The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.
“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”
“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.
Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.
VOYAGER PAD trial
The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).
Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.
“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.
VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.
A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.
The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 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.
The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.
“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”
“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.
Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.
VOYAGER PAD trial
The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).
Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.
“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.
VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.
A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.
The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 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.
The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.
“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”
“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.
Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.
VOYAGER PAD trial
The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).
Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.
“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.
VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.
REPORTING FROM ACC 20
Key clinical point: Combined treatment with rivaroxaban plus aspirin safely reduced a composite measure of adverse ischemic events in PAD patients following lower-limb revascularization.
Major finding: The primary event outcome occurred in 17.3% of patients on rivaroxaban plus aspirin, and in 19.9% on aspirin alone.
Study details: VOYAGER PAD, a multicenter, international randomized trial with 6,564 patients.
Disclosures: VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
Source: Bonaca MP. ACC 20, Abstract 402-10.
Before the COVID-19 surge hits your facility, take steps to boost capacity
, according to a physician leader and a health workforce expert.
Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.
Stephen Parodi, MD, agreed that effective communication is job one in the health care workplace during the crisis. “I can’t stress enough ... that communications are paramount and you can’t overcommunicate,” said Dr. Parodi, executive vice president of external affairs, communications, and brand at the Permanente Federation and associate executive director of the Permanente Medical Group, Vallejo, Calif.
“We’re in a situation of confusion and improvisation right now,” regarding protection of health care workers, said Dr. Pittman. The potential exists for “a downward spiral where you have the lack of training, the shortages in terms of protective gear, weakening of guidelines, and confusion regarding guidelines at federal level, creating a potential cascade” that may result in “moral distress and fatigue. ... That’s not occurring now, but that’s the danger” unless the personal protective equipment (PPE) situation is adequately addressed very soon, she said.
Dr. Pittman also pointed out the concerns that many of the 18 million U.S. health care workers have for their families should they themselves fall ill or transmit coronavirus to family members. “The danger exists of a mass exodus. People don’t have to show up at work, and they won’t show up at work if they don’t feel supported and safe.”
Dr. Parodi said that the Permanente organization is on a better footing than many workplaces. “We actually had an early experience because of the work that we did to support the Diamond Princess cruise ship evacuees from Yokahama in February.” That ship was quarantined upon arrival in Yokahama on Feb. 3 because a passenger had a confirmed test for SARS-CoV-2 infection, and a quarter of the 428 Americans on board subsequently tested positive. Most of them were evacuated to California or Texas. “That actually gave us the experience for providing care within the hospital setting – and also for containment strategies,” he said.
“We quickly understood that we needed to move to a mitigation strategy,” said Dr. Parodi. Use of PPE has been “tailored for how the virus is spread.” In the absence of the risk of aerosol transmission from certain procedures, health care workers use gowns, gloves, surgical masks, and goggles.
Because of anticipated “supply chain shortfalls,” Dr. Parodi said that his organization implemented Centers for Disease Control and Prevention guidelines for reuse and extended use of N95 respirators early on. “Even if you’re not in a locale that’s been hit, you need to be on wartime footing for preserving PPE.”
Telehealth, said Dr. Parodi, has been implemented “in a huge way” throughout the Permanente system. “We have reduced primary care visits by 90% in the past week, and also subspecialty visits by 50%. … A large amount of the workforce can work from home. We turned off elective surgeries more than a week ago to reduce the number of patients who are requiring intensive care.” Making these changes means the organization is more prepared now for a surge they expect in the coming weeks.
Dr. Pittman voiced an opinion widely shared by those who are implementing large-scale telehealth efforts “We’re going to learn a lot. Many of the traditional doctor-patient visits can be done by telemedicine in the future.”
Knowledge about local trends in infection rates is key to preparedness. “We’ve ramped up testing, to understand what’s happening in the community,” said Dr. Parodi, noting that test turnaround time is currently running 8-24 hours. Tightening up this window can free up resources when an admitted patient’s test is negative.
Still, some national projections forecast a need for hospital beds at two to three times current capacity – or even more, said Dr. Parodi.
He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.
To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.
Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.
Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.
Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”
The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.
All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”
Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.
, according to a physician leader and a health workforce expert.
Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.
Stephen Parodi, MD, agreed that effective communication is job one in the health care workplace during the crisis. “I can’t stress enough ... that communications are paramount and you can’t overcommunicate,” said Dr. Parodi, executive vice president of external affairs, communications, and brand at the Permanente Federation and associate executive director of the Permanente Medical Group, Vallejo, Calif.
“We’re in a situation of confusion and improvisation right now,” regarding protection of health care workers, said Dr. Pittman. The potential exists for “a downward spiral where you have the lack of training, the shortages in terms of protective gear, weakening of guidelines, and confusion regarding guidelines at federal level, creating a potential cascade” that may result in “moral distress and fatigue. ... That’s not occurring now, but that’s the danger” unless the personal protective equipment (PPE) situation is adequately addressed very soon, she said.
Dr. Pittman also pointed out the concerns that many of the 18 million U.S. health care workers have for their families should they themselves fall ill or transmit coronavirus to family members. “The danger exists of a mass exodus. People don’t have to show up at work, and they won’t show up at work if they don’t feel supported and safe.”
Dr. Parodi said that the Permanente organization is on a better footing than many workplaces. “We actually had an early experience because of the work that we did to support the Diamond Princess cruise ship evacuees from Yokahama in February.” That ship was quarantined upon arrival in Yokahama on Feb. 3 because a passenger had a confirmed test for SARS-CoV-2 infection, and a quarter of the 428 Americans on board subsequently tested positive. Most of them were evacuated to California or Texas. “That actually gave us the experience for providing care within the hospital setting – and also for containment strategies,” he said.
“We quickly understood that we needed to move to a mitigation strategy,” said Dr. Parodi. Use of PPE has been “tailored for how the virus is spread.” In the absence of the risk of aerosol transmission from certain procedures, health care workers use gowns, gloves, surgical masks, and goggles.
Because of anticipated “supply chain shortfalls,” Dr. Parodi said that his organization implemented Centers for Disease Control and Prevention guidelines for reuse and extended use of N95 respirators early on. “Even if you’re not in a locale that’s been hit, you need to be on wartime footing for preserving PPE.”
Telehealth, said Dr. Parodi, has been implemented “in a huge way” throughout the Permanente system. “We have reduced primary care visits by 90% in the past week, and also subspecialty visits by 50%. … A large amount of the workforce can work from home. We turned off elective surgeries more than a week ago to reduce the number of patients who are requiring intensive care.” Making these changes means the organization is more prepared now for a surge they expect in the coming weeks.
Dr. Pittman voiced an opinion widely shared by those who are implementing large-scale telehealth efforts “We’re going to learn a lot. Many of the traditional doctor-patient visits can be done by telemedicine in the future.”
Knowledge about local trends in infection rates is key to preparedness. “We’ve ramped up testing, to understand what’s happening in the community,” said Dr. Parodi, noting that test turnaround time is currently running 8-24 hours. Tightening up this window can free up resources when an admitted patient’s test is negative.
Still, some national projections forecast a need for hospital beds at two to three times current capacity – or even more, said Dr. Parodi.
He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.
To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.
Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.
Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.
Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”
The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.
All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”
Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.
, according to a physician leader and a health workforce expert.
Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.
Stephen Parodi, MD, agreed that effective communication is job one in the health care workplace during the crisis. “I can’t stress enough ... that communications are paramount and you can’t overcommunicate,” said Dr. Parodi, executive vice president of external affairs, communications, and brand at the Permanente Federation and associate executive director of the Permanente Medical Group, Vallejo, Calif.
“We’re in a situation of confusion and improvisation right now,” regarding protection of health care workers, said Dr. Pittman. The potential exists for “a downward spiral where you have the lack of training, the shortages in terms of protective gear, weakening of guidelines, and confusion regarding guidelines at federal level, creating a potential cascade” that may result in “moral distress and fatigue. ... That’s not occurring now, but that’s the danger” unless the personal protective equipment (PPE) situation is adequately addressed very soon, she said.
Dr. Pittman also pointed out the concerns that many of the 18 million U.S. health care workers have for their families should they themselves fall ill or transmit coronavirus to family members. “The danger exists of a mass exodus. People don’t have to show up at work, and they won’t show up at work if they don’t feel supported and safe.”
Dr. Parodi said that the Permanente organization is on a better footing than many workplaces. “We actually had an early experience because of the work that we did to support the Diamond Princess cruise ship evacuees from Yokahama in February.” That ship was quarantined upon arrival in Yokahama on Feb. 3 because a passenger had a confirmed test for SARS-CoV-2 infection, and a quarter of the 428 Americans on board subsequently tested positive. Most of them were evacuated to California or Texas. “That actually gave us the experience for providing care within the hospital setting – and also for containment strategies,” he said.
“We quickly understood that we needed to move to a mitigation strategy,” said Dr. Parodi. Use of PPE has been “tailored for how the virus is spread.” In the absence of the risk of aerosol transmission from certain procedures, health care workers use gowns, gloves, surgical masks, and goggles.
Because of anticipated “supply chain shortfalls,” Dr. Parodi said that his organization implemented Centers for Disease Control and Prevention guidelines for reuse and extended use of N95 respirators early on. “Even if you’re not in a locale that’s been hit, you need to be on wartime footing for preserving PPE.”
Telehealth, said Dr. Parodi, has been implemented “in a huge way” throughout the Permanente system. “We have reduced primary care visits by 90% in the past week, and also subspecialty visits by 50%. … A large amount of the workforce can work from home. We turned off elective surgeries more than a week ago to reduce the number of patients who are requiring intensive care.” Making these changes means the organization is more prepared now for a surge they expect in the coming weeks.
Dr. Pittman voiced an opinion widely shared by those who are implementing large-scale telehealth efforts “We’re going to learn a lot. Many of the traditional doctor-patient visits can be done by telemedicine in the future.”
Knowledge about local trends in infection rates is key to preparedness. “We’ve ramped up testing, to understand what’s happening in the community,” said Dr. Parodi, noting that test turnaround time is currently running 8-24 hours. Tightening up this window can free up resources when an admitted patient’s test is negative.
Still, some national projections forecast a need for hospital beds at two to three times current capacity – or even more, said Dr. Parodi.
He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.
To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.
Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.
Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.
Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”
The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.
All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”
Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.
REPORTING FROM AN ALLIANCE FOR HEALTH POLICY WEBINAR
Stage I mycosis fungoides is the general dermatologist’s bailiwick
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
EULAR cancels June congress, will hold virtual meeting instead
The European League Against Rheumatism has canceled its annual congress scheduled for June 3-6, 2020, in Frankfurt, Germany, and will instead hold a virtual meeting around the same time frame, according to a message from the organization’s president, Iain McInnes, MD, PhD.
“As a scientific medical society, it is our duty to ensure that our medical and health professional participants are available at the forefront of patient care. We are also concerned that bringing our RMD [rheumatic and musculoskeletal disease] patient delegates into a large meeting venue would be extremely unwise at this time,” Dr. McInnes wrote.
While the details of the virtual congress experience have yet to be worked out, Dr. McInnes said that its offerings “will be accessible on demand over a timeframe of several months,” and they “will also publish abstracts/posters online and provide registered delegates with the 1-year access to our journal, the Annals of Rheumatic Diseases.”
The EULAR president also asked for patience as the details of the virtual congress are determined. “We ask you to be patient for a little while longer to give us the time to develop clear answers to all your questions. Our volunteers and staff in the EULAR Office are currently working hard to develop the best possible solutions for this new scenario.”
The European League Against Rheumatism has canceled its annual congress scheduled for June 3-6, 2020, in Frankfurt, Germany, and will instead hold a virtual meeting around the same time frame, according to a message from the organization’s president, Iain McInnes, MD, PhD.
“As a scientific medical society, it is our duty to ensure that our medical and health professional participants are available at the forefront of patient care. We are also concerned that bringing our RMD [rheumatic and musculoskeletal disease] patient delegates into a large meeting venue would be extremely unwise at this time,” Dr. McInnes wrote.
While the details of the virtual congress experience have yet to be worked out, Dr. McInnes said that its offerings “will be accessible on demand over a timeframe of several months,” and they “will also publish abstracts/posters online and provide registered delegates with the 1-year access to our journal, the Annals of Rheumatic Diseases.”
The EULAR president also asked for patience as the details of the virtual congress are determined. “We ask you to be patient for a little while longer to give us the time to develop clear answers to all your questions. Our volunteers and staff in the EULAR Office are currently working hard to develop the best possible solutions for this new scenario.”
The European League Against Rheumatism has canceled its annual congress scheduled for June 3-6, 2020, in Frankfurt, Germany, and will instead hold a virtual meeting around the same time frame, according to a message from the organization’s president, Iain McInnes, MD, PhD.
“As a scientific medical society, it is our duty to ensure that our medical and health professional participants are available at the forefront of patient care. We are also concerned that bringing our RMD [rheumatic and musculoskeletal disease] patient delegates into a large meeting venue would be extremely unwise at this time,” Dr. McInnes wrote.
While the details of the virtual congress experience have yet to be worked out, Dr. McInnes said that its offerings “will be accessible on demand over a timeframe of several months,” and they “will also publish abstracts/posters online and provide registered delegates with the 1-year access to our journal, the Annals of Rheumatic Diseases.”
The EULAR president also asked for patience as the details of the virtual congress are determined. “We ask you to be patient for a little while longer to give us the time to develop clear answers to all your questions. Our volunteers and staff in the EULAR Office are currently working hard to develop the best possible solutions for this new scenario.”
Study challenges role of birth canal exposure in newborn microbiome establishment
During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.
This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.
“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.
According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.
“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.
Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.
The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).
Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.
Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.
The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.
“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”
Dr. Yassour said that these findings may have an immediate effect on clinical practice.
“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”
Dr. Yassour disclosed no conflicts of interest.
SOURCE: Yassour M et al. GMFH 2020.
During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.
This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.
“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.
According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.
“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.
Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.
The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).
Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.
Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.
The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.
“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”
Dr. Yassour said that these findings may have an immediate effect on clinical practice.
“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”
Dr. Yassour disclosed no conflicts of interest.
SOURCE: Yassour M et al. GMFH 2020.
During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.
This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.
“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.
According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.
“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.
Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.
The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).
Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.
Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.
The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.
“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”
Dr. Yassour said that these findings may have an immediate effect on clinical practice.
“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”
Dr. Yassour disclosed no conflicts of interest.
SOURCE: Yassour M et al. GMFH 2020.
FROM GMFH 2020