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Inactivated quadrivalent influenza vaccine safe, effective in 6- to 35-month-olds
MADRID – An intramuscular inactivated quadrivalent influenza vaccine reduced the risk of laboratory-confirmed influenza by up to 69% in previously unvaccinated children aged 6-35 months in a large randomized trial, Stephanie Pepin, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
The quadrivalent influenza vaccine (QIV) is licensed by the Food and Drug Administration as Fluzone Quadrivalent for use in patients as young as 6 months of age. It contains two A- and two B-lineage influenza strains in order to address the common problem of mismatches between circulating influenza B and the single B-lineage strain included in trivalent vaccines.
The incidence of any laboratory confirmed strain of influenza illness during the period from 14 days post-vaccination to the end of flu season was 4.72% in the QIV group, compared with 9.84% in controls who received placebo, which translated to 52% efficacy. The incidence of influenza from vaccine-similar strains as determined by the Sanger sequencing method was 1.01% in children randomized to QIV, compared with 3.28% with placebo, for a 69% efficacy rate.
The QIV had a safety profile in this young population that was similar to the older licensed trivalent vaccine. The most frequently reported adverse reactions to the QIV were injection site pain, irritability, loss of appetite, abnormal crying, and malaise, each reported in 19%-25% of children after the first injection and in 14%-18% after the second. These were typically mild grade 1 or 2 reactions, which arose in the first 3 days after vaccination and resolved spontaneously 1-3 days later.
The trial was sponsored by Sanofi Pasteur and presented by a company employee.
MADRID – An intramuscular inactivated quadrivalent influenza vaccine reduced the risk of laboratory-confirmed influenza by up to 69% in previously unvaccinated children aged 6-35 months in a large randomized trial, Stephanie Pepin, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
The quadrivalent influenza vaccine (QIV) is licensed by the Food and Drug Administration as Fluzone Quadrivalent for use in patients as young as 6 months of age. It contains two A- and two B-lineage influenza strains in order to address the common problem of mismatches between circulating influenza B and the single B-lineage strain included in trivalent vaccines.
The incidence of any laboratory confirmed strain of influenza illness during the period from 14 days post-vaccination to the end of flu season was 4.72% in the QIV group, compared with 9.84% in controls who received placebo, which translated to 52% efficacy. The incidence of influenza from vaccine-similar strains as determined by the Sanger sequencing method was 1.01% in children randomized to QIV, compared with 3.28% with placebo, for a 69% efficacy rate.
The QIV had a safety profile in this young population that was similar to the older licensed trivalent vaccine. The most frequently reported adverse reactions to the QIV were injection site pain, irritability, loss of appetite, abnormal crying, and malaise, each reported in 19%-25% of children after the first injection and in 14%-18% after the second. These were typically mild grade 1 or 2 reactions, which arose in the first 3 days after vaccination and resolved spontaneously 1-3 days later.
The trial was sponsored by Sanofi Pasteur and presented by a company employee.
MADRID – An intramuscular inactivated quadrivalent influenza vaccine reduced the risk of laboratory-confirmed influenza by up to 69% in previously unvaccinated children aged 6-35 months in a large randomized trial, Stephanie Pepin, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
The quadrivalent influenza vaccine (QIV) is licensed by the Food and Drug Administration as Fluzone Quadrivalent for use in patients as young as 6 months of age. It contains two A- and two B-lineage influenza strains in order to address the common problem of mismatches between circulating influenza B and the single B-lineage strain included in trivalent vaccines.
The incidence of any laboratory confirmed strain of influenza illness during the period from 14 days post-vaccination to the end of flu season was 4.72% in the QIV group, compared with 9.84% in controls who received placebo, which translated to 52% efficacy. The incidence of influenza from vaccine-similar strains as determined by the Sanger sequencing method was 1.01% in children randomized to QIV, compared with 3.28% with placebo, for a 69% efficacy rate.
The QIV had a safety profile in this young population that was similar to the older licensed trivalent vaccine. The most frequently reported adverse reactions to the QIV were injection site pain, irritability, loss of appetite, abnormal crying, and malaise, each reported in 19%-25% of children after the first injection and in 14%-18% after the second. These were typically mild grade 1 or 2 reactions, which arose in the first 3 days after vaccination and resolved spontaneously 1-3 days later.
The trial was sponsored by Sanofi Pasteur and presented by a company employee.
AT ESPID 2017
Key clinical point:
Major finding: The intramuscular inactivated influenza vaccine, Fluzone Quadrivalent, reduced the risk of laboratory-confirmed influenza by up to 69% in 6- to 35-month-olds.
Data source: This randomized, multinational, placebo-controlled trial included 5,806 healthy 6- to 35-month-old children.
Disclosures: The study was sponsored by Sanofi Pasteur and presented by a company employee.
Pertussis resurgence is real, but possible solutions exist
MADRID – The explanation for the ongoing resurgence in pertussis in adolescents and adults in the United States and other developed countries lies largely in the waning effectiveness of current acellular pertussis vaccines as early as 2-3 years post boosters, according to Stanley A. Plotkin, MD, chair of the steering committee for the Global Pertussis Initiative.
“The problem seems to lie in the lack of persistence of immunity after vaccination using the acellular pertussis vaccines. To say that this is not controversial would clearly be wrong, but that is my view,” he declared at the annual meeting of the European Society for Paediatric Infectious Diseases.
It’s a view supported by persuasive evidence, added Dr. Plotkin, emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia.
In the United States, investigators at Northern California Kaiser Permanente have shown that the effectiveness of acellular pertussis in the Tdap vaccine wanes rapidly in adolescents. Indeed, it plunged from 69% effectiveness in the first year after vaccination to less than 9% by year 4 (Pediatrics. 2016 Mar;137[3]:e20153326).
In contrast, whole-cell pertussis vaccines provide roughly 6-10 years of protection against infection, and native infection provides persistent protection against reinfection for 7-20 years, Dr. Plotkin noted.
He was senior coauthor of a recent study that addresses why acellular pertussis vaccine immunity wanes so quickly. He and his coinvestigators demonstrated that while whole-cell pertussis vaccines promote vigorous Th1 and Th17 responses, which discourage pharyngeal colonization, acellular pertussis vaccines orient the immune system toward a less salutary Th1/Th2 response (Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029454).
In addition, other investigators have shown that repeated booster doses of acellular pertussis vaccine generate higher levels of antigen-specific IgG4, which doesn’t bind complement and results in impaired phagocytosis and a suboptimal inflammatory response. In contrast, priming of the immune system via administration of a whole-cell pertussis vaccine at birth followed by acellular pertussis boosters results in improved phagocytosis and complement-mediated microbial killing via preferential induction of IgG1(Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029553).
Possible solutions to the pertussis problem
Infants don’t need a new vaccine; that’s not where the vaccine failures are occurring. “Again, I stress that the problem so far has not been in infants, it has been in adolescents and adults,” he said.
A new vaccine is a daunting prospect. Given the huge investment vaccine manufacturers made in the 1990s to bring the current acellular vaccines to the market, they are hardly eager to launch development programs for new pertussis vaccines. They have other vaccine development priorities.
Moreover, the regulatory challenges are huge unless the Food and Drug Administration and other licensing authorities are willing to forgo the large, long, and expensive clinical trials that have traditionally been required. In lieu of such efficacy studies, they would need to consider studies demonstrating better immunogenicity based upon antibody titers, or animal studies.
“The possibility of a human challenge study in adults is an idea I like; I’m not sure about the FDA,” the pediatrician said.
Until a new or improved vaccine becomes available, the most important strategy to control the resurgence of pertussis is acellular vaccination of pregnant women in their third trimester to provide passive protection to the newborn via transplacental antibody. That practice is already recommended in the United States and many other countries. And while it reduces the risk of pertussis in early infancy – the most serious form of the disease – that strategy won’t have any real impact on the adult burden of disease, which Dr. Plotkin estimated at more than 600,000 cases annually.
Cocooning – a strategy of vaccinating all of a newborn’s family contacts – has been promoted in guidelines but has proved difficult to implement. “I think cocooning strategies by and large have been a failure,” he declared.
More frequent boosters of current acellular pertussis vaccines would presumably increase effectiveness, but that would be costly and tough to put in place on a public health scale.
A return to using conventional whole-cell pertussis vaccines would be a tough sell to the public and is probably flat out unacceptable. Developing a less reactogenic whole-cell vaccine might be a work-around, but it hasn’t been done yet.
The easiest way to improve acellular pertussis vaccine for adolescents and adults is to improve the pertussis toxin antigen component. Increasing the dose of pertussis toxin could generate more and longer-lasting antibodies to it. An even more exciting possibility is based upon evidence more than a decade old that genetic inactivation of pertussis toxin results in antibody levels far higher and presumably more bactericidal than the formalin-inactivated pertussis toxin included in current vaccines, according to Dr. Plotkin.
Adding stronger adjuvants to a Tdap vaccine for adolescents is another appealing strategy. There are plenty to choose from, including some that would presumably have an easier pathway to regulatory approval because they are already contained in licensed vaccines. This beefed-up adjuvant strategy, like the notion of changing the antigens in acellular pertussis vaccines to those from currently circulating strains, is feasible albeit more difficult than simply improving the pertussis toxin component of existing vaccines, he said.
The Global Pertussis Initiative is sponsored by Sanofi Pasteur. Dr. Plotkin reported serving as a consultant to that vaccine manufacturer and numerous others but declared he had no financial conflicts regarding his presentation.
MADRID – The explanation for the ongoing resurgence in pertussis in adolescents and adults in the United States and other developed countries lies largely in the waning effectiveness of current acellular pertussis vaccines as early as 2-3 years post boosters, according to Stanley A. Plotkin, MD, chair of the steering committee for the Global Pertussis Initiative.
“The problem seems to lie in the lack of persistence of immunity after vaccination using the acellular pertussis vaccines. To say that this is not controversial would clearly be wrong, but that is my view,” he declared at the annual meeting of the European Society for Paediatric Infectious Diseases.
It’s a view supported by persuasive evidence, added Dr. Plotkin, emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia.
In the United States, investigators at Northern California Kaiser Permanente have shown that the effectiveness of acellular pertussis in the Tdap vaccine wanes rapidly in adolescents. Indeed, it plunged from 69% effectiveness in the first year after vaccination to less than 9% by year 4 (Pediatrics. 2016 Mar;137[3]:e20153326).
In contrast, whole-cell pertussis vaccines provide roughly 6-10 years of protection against infection, and native infection provides persistent protection against reinfection for 7-20 years, Dr. Plotkin noted.
He was senior coauthor of a recent study that addresses why acellular pertussis vaccine immunity wanes so quickly. He and his coinvestigators demonstrated that while whole-cell pertussis vaccines promote vigorous Th1 and Th17 responses, which discourage pharyngeal colonization, acellular pertussis vaccines orient the immune system toward a less salutary Th1/Th2 response (Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029454).
In addition, other investigators have shown that repeated booster doses of acellular pertussis vaccine generate higher levels of antigen-specific IgG4, which doesn’t bind complement and results in impaired phagocytosis and a suboptimal inflammatory response. In contrast, priming of the immune system via administration of a whole-cell pertussis vaccine at birth followed by acellular pertussis boosters results in improved phagocytosis and complement-mediated microbial killing via preferential induction of IgG1(Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029553).
Possible solutions to the pertussis problem
Infants don’t need a new vaccine; that’s not where the vaccine failures are occurring. “Again, I stress that the problem so far has not been in infants, it has been in adolescents and adults,” he said.
A new vaccine is a daunting prospect. Given the huge investment vaccine manufacturers made in the 1990s to bring the current acellular vaccines to the market, they are hardly eager to launch development programs for new pertussis vaccines. They have other vaccine development priorities.
Moreover, the regulatory challenges are huge unless the Food and Drug Administration and other licensing authorities are willing to forgo the large, long, and expensive clinical trials that have traditionally been required. In lieu of such efficacy studies, they would need to consider studies demonstrating better immunogenicity based upon antibody titers, or animal studies.
“The possibility of a human challenge study in adults is an idea I like; I’m not sure about the FDA,” the pediatrician said.
Until a new or improved vaccine becomes available, the most important strategy to control the resurgence of pertussis is acellular vaccination of pregnant women in their third trimester to provide passive protection to the newborn via transplacental antibody. That practice is already recommended in the United States and many other countries. And while it reduces the risk of pertussis in early infancy – the most serious form of the disease – that strategy won’t have any real impact on the adult burden of disease, which Dr. Plotkin estimated at more than 600,000 cases annually.
Cocooning – a strategy of vaccinating all of a newborn’s family contacts – has been promoted in guidelines but has proved difficult to implement. “I think cocooning strategies by and large have been a failure,” he declared.
More frequent boosters of current acellular pertussis vaccines would presumably increase effectiveness, but that would be costly and tough to put in place on a public health scale.
A return to using conventional whole-cell pertussis vaccines would be a tough sell to the public and is probably flat out unacceptable. Developing a less reactogenic whole-cell vaccine might be a work-around, but it hasn’t been done yet.
The easiest way to improve acellular pertussis vaccine for adolescents and adults is to improve the pertussis toxin antigen component. Increasing the dose of pertussis toxin could generate more and longer-lasting antibodies to it. An even more exciting possibility is based upon evidence more than a decade old that genetic inactivation of pertussis toxin results in antibody levels far higher and presumably more bactericidal than the formalin-inactivated pertussis toxin included in current vaccines, according to Dr. Plotkin.
Adding stronger adjuvants to a Tdap vaccine for adolescents is another appealing strategy. There are plenty to choose from, including some that would presumably have an easier pathway to regulatory approval because they are already contained in licensed vaccines. This beefed-up adjuvant strategy, like the notion of changing the antigens in acellular pertussis vaccines to those from currently circulating strains, is feasible albeit more difficult than simply improving the pertussis toxin component of existing vaccines, he said.
The Global Pertussis Initiative is sponsored by Sanofi Pasteur. Dr. Plotkin reported serving as a consultant to that vaccine manufacturer and numerous others but declared he had no financial conflicts regarding his presentation.
MADRID – The explanation for the ongoing resurgence in pertussis in adolescents and adults in the United States and other developed countries lies largely in the waning effectiveness of current acellular pertussis vaccines as early as 2-3 years post boosters, according to Stanley A. Plotkin, MD, chair of the steering committee for the Global Pertussis Initiative.
“The problem seems to lie in the lack of persistence of immunity after vaccination using the acellular pertussis vaccines. To say that this is not controversial would clearly be wrong, but that is my view,” he declared at the annual meeting of the European Society for Paediatric Infectious Diseases.
It’s a view supported by persuasive evidence, added Dr. Plotkin, emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia.
In the United States, investigators at Northern California Kaiser Permanente have shown that the effectiveness of acellular pertussis in the Tdap vaccine wanes rapidly in adolescents. Indeed, it plunged from 69% effectiveness in the first year after vaccination to less than 9% by year 4 (Pediatrics. 2016 Mar;137[3]:e20153326).
In contrast, whole-cell pertussis vaccines provide roughly 6-10 years of protection against infection, and native infection provides persistent protection against reinfection for 7-20 years, Dr. Plotkin noted.
He was senior coauthor of a recent study that addresses why acellular pertussis vaccine immunity wanes so quickly. He and his coinvestigators demonstrated that while whole-cell pertussis vaccines promote vigorous Th1 and Th17 responses, which discourage pharyngeal colonization, acellular pertussis vaccines orient the immune system toward a less salutary Th1/Th2 response (Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029454).
In addition, other investigators have shown that repeated booster doses of acellular pertussis vaccine generate higher levels of antigen-specific IgG4, which doesn’t bind complement and results in impaired phagocytosis and a suboptimal inflammatory response. In contrast, priming of the immune system via administration of a whole-cell pertussis vaccine at birth followed by acellular pertussis boosters results in improved phagocytosis and complement-mediated microbial killing via preferential induction of IgG1(Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029553).
Possible solutions to the pertussis problem
Infants don’t need a new vaccine; that’s not where the vaccine failures are occurring. “Again, I stress that the problem so far has not been in infants, it has been in adolescents and adults,” he said.
A new vaccine is a daunting prospect. Given the huge investment vaccine manufacturers made in the 1990s to bring the current acellular vaccines to the market, they are hardly eager to launch development programs for new pertussis vaccines. They have other vaccine development priorities.
Moreover, the regulatory challenges are huge unless the Food and Drug Administration and other licensing authorities are willing to forgo the large, long, and expensive clinical trials that have traditionally been required. In lieu of such efficacy studies, they would need to consider studies demonstrating better immunogenicity based upon antibody titers, or animal studies.
“The possibility of a human challenge study in adults is an idea I like; I’m not sure about the FDA,” the pediatrician said.
Until a new or improved vaccine becomes available, the most important strategy to control the resurgence of pertussis is acellular vaccination of pregnant women in their third trimester to provide passive protection to the newborn via transplacental antibody. That practice is already recommended in the United States and many other countries. And while it reduces the risk of pertussis in early infancy – the most serious form of the disease – that strategy won’t have any real impact on the adult burden of disease, which Dr. Plotkin estimated at more than 600,000 cases annually.
Cocooning – a strategy of vaccinating all of a newborn’s family contacts – has been promoted in guidelines but has proved difficult to implement. “I think cocooning strategies by and large have been a failure,” he declared.
More frequent boosters of current acellular pertussis vaccines would presumably increase effectiveness, but that would be costly and tough to put in place on a public health scale.
A return to using conventional whole-cell pertussis vaccines would be a tough sell to the public and is probably flat out unacceptable. Developing a less reactogenic whole-cell vaccine might be a work-around, but it hasn’t been done yet.
The easiest way to improve acellular pertussis vaccine for adolescents and adults is to improve the pertussis toxin antigen component. Increasing the dose of pertussis toxin could generate more and longer-lasting antibodies to it. An even more exciting possibility is based upon evidence more than a decade old that genetic inactivation of pertussis toxin results in antibody levels far higher and presumably more bactericidal than the formalin-inactivated pertussis toxin included in current vaccines, according to Dr. Plotkin.
Adding stronger adjuvants to a Tdap vaccine for adolescents is another appealing strategy. There are plenty to choose from, including some that would presumably have an easier pathway to regulatory approval because they are already contained in licensed vaccines. This beefed-up adjuvant strategy, like the notion of changing the antigens in acellular pertussis vaccines to those from currently circulating strains, is feasible albeit more difficult than simply improving the pertussis toxin component of existing vaccines, he said.
The Global Pertussis Initiative is sponsored by Sanofi Pasteur. Dr. Plotkin reported serving as a consultant to that vaccine manufacturer and numerous others but declared he had no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM ESPID 2017
New findings from first all-female TAVR registry
Paris – A history of pregnancy did not protect against adverse outcomes at 1 year in the Women’s International Transcatheter Aortic Valve Implantation Registry (WIN-TAVI), even though it did within the first 30 days, Alaide Chieffo, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
One year ago, at EuroPCR 2016, she reported that in WIN-TAVI, a history of pregnancy – albeit typically more than half a century previously – was independently associated with a 43% reduction in the Valve Academic Research Consortium-2 (VARC-2) 30-day composite endpoint, including death, stroke, major vascular complications, life-threatening bleeding, stage 2 or 3 acute kidney injury, coronary artery obstruction, or repeat transcatheter aortic valve replacement (TAVR) done because of valve-related dysfunction. Those early findings, first reported in this publication, were later published (JACC Cardiovasc Interv. 2016 Aug 8;9[15]:1589-600).
At 1 year of follow-up, however, the rate of the VARC-2 composite endpoint was no longer significantly different in women with or without a history of pregnancy. Nor was a history of pregnancy associated with a significantly reduced risk of the secondary endpoint of death or stroke: The 27% reduction in risk of this secondary endpoint in women with a history of pregnancy, compared with that of nulliparous women, didn’t achieve statistical significance in multivariate analysis, according to Dr. Chieffo of the San Raffaele Scientific Institute in Milan.
She speculated that pregnancy earlier in life provided strong protection against poor 30-day outcomes and a similar trend – albeit not statistically significant – at 1 year because women without children may have less family support.
“They are old women, left alone, without the family taking care of them. This is socially important, I think, because we are investing quite a lot of money in a procedure, and then maybe we’re adding adverse events because these patients are not properly taken care of when they are out of the hospital,” the interventional cardiologist said.
Neither of the other two female-specific characteristics evaluated in WIN-TAVI – having a history of osteoporosis or age at menopause – turned out to be related to the risk of bad outcomes at 1 year, she added.
WIN-TAVI is the first all-female registry of patients undergoing TAVR for severe aortic stenosis. The prospective, observational registry includes 1,019 women treated at 19 highly experienced European and North American TAVR centers. They averaged 82.5 years of age with a mean Society of Thoracic Surgeons score of 8.3%, putting them at intermediate or high surgical risk. A percutaneous transfemoral approach was used in 91% of cases. TAVR was performed under conscious sedation in 28% of the women and under local anesthesia in another 37%. Of the women in the registry, 42% received a newer-generation device.
In addition to the lack of significant impact of prior pregnancy on 1-year outcomes, another noteworthy finding at 1 year of follow-up was that preprocedural atrial fibrillation was independently associated with a 58% increase in the risk of death or stroke (P = .02). Prior percutaneous coronary intervention and EuroSCORE (European System for Cardiac Operative Risk Evaluation) were the only other independent predictors.
This observation suggests the need for a women-only randomized trial of TAVR versus surgical aortic valve replacement in women with intermediate surgical risk, Dr. Chieffo suggested. It will be important to learn whether the ability to surgically ablate preoperative atrial fibrillation in women during surgical valve replacement results in a lower 1-year risk of death or stroke than is achieved with TAVR.
Overall, the 1-year clinical outcomes seen in WIN-TAVI are “very good,” she noted. The VARC-2 composite endpoint occurred in 16.5% of women, all-cause mortality in 12.5%, cardiovascular mortality in 10.8%, and stroke in 2.2%. Only 3.2% of women were hospitalized for heart failure or valve-related symptoms. A new pacemaker was implanted in 12.7% of participants. At baseline 74% of women were New York Heart Association functional class III or IV; at 1 year, only 8.1% were. Moderate paravalvular aortic regurgitation was present in 6% of patients at 6 months and in 9.7% at 1 year
The WIN-TAVI registry is entirely self-funded. Dr. Chieffo reported having no financial conflicts regarding her presentation.
Paris – A history of pregnancy did not protect against adverse outcomes at 1 year in the Women’s International Transcatheter Aortic Valve Implantation Registry (WIN-TAVI), even though it did within the first 30 days, Alaide Chieffo, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
One year ago, at EuroPCR 2016, she reported that in WIN-TAVI, a history of pregnancy – albeit typically more than half a century previously – was independently associated with a 43% reduction in the Valve Academic Research Consortium-2 (VARC-2) 30-day composite endpoint, including death, stroke, major vascular complications, life-threatening bleeding, stage 2 or 3 acute kidney injury, coronary artery obstruction, or repeat transcatheter aortic valve replacement (TAVR) done because of valve-related dysfunction. Those early findings, first reported in this publication, were later published (JACC Cardiovasc Interv. 2016 Aug 8;9[15]:1589-600).
At 1 year of follow-up, however, the rate of the VARC-2 composite endpoint was no longer significantly different in women with or without a history of pregnancy. Nor was a history of pregnancy associated with a significantly reduced risk of the secondary endpoint of death or stroke: The 27% reduction in risk of this secondary endpoint in women with a history of pregnancy, compared with that of nulliparous women, didn’t achieve statistical significance in multivariate analysis, according to Dr. Chieffo of the San Raffaele Scientific Institute in Milan.
She speculated that pregnancy earlier in life provided strong protection against poor 30-day outcomes and a similar trend – albeit not statistically significant – at 1 year because women without children may have less family support.
“They are old women, left alone, without the family taking care of them. This is socially important, I think, because we are investing quite a lot of money in a procedure, and then maybe we’re adding adverse events because these patients are not properly taken care of when they are out of the hospital,” the interventional cardiologist said.
Neither of the other two female-specific characteristics evaluated in WIN-TAVI – having a history of osteoporosis or age at menopause – turned out to be related to the risk of bad outcomes at 1 year, she added.
WIN-TAVI is the first all-female registry of patients undergoing TAVR for severe aortic stenosis. The prospective, observational registry includes 1,019 women treated at 19 highly experienced European and North American TAVR centers. They averaged 82.5 years of age with a mean Society of Thoracic Surgeons score of 8.3%, putting them at intermediate or high surgical risk. A percutaneous transfemoral approach was used in 91% of cases. TAVR was performed under conscious sedation in 28% of the women and under local anesthesia in another 37%. Of the women in the registry, 42% received a newer-generation device.
In addition to the lack of significant impact of prior pregnancy on 1-year outcomes, another noteworthy finding at 1 year of follow-up was that preprocedural atrial fibrillation was independently associated with a 58% increase in the risk of death or stroke (P = .02). Prior percutaneous coronary intervention and EuroSCORE (European System for Cardiac Operative Risk Evaluation) were the only other independent predictors.
This observation suggests the need for a women-only randomized trial of TAVR versus surgical aortic valve replacement in women with intermediate surgical risk, Dr. Chieffo suggested. It will be important to learn whether the ability to surgically ablate preoperative atrial fibrillation in women during surgical valve replacement results in a lower 1-year risk of death or stroke than is achieved with TAVR.
Overall, the 1-year clinical outcomes seen in WIN-TAVI are “very good,” she noted. The VARC-2 composite endpoint occurred in 16.5% of women, all-cause mortality in 12.5%, cardiovascular mortality in 10.8%, and stroke in 2.2%. Only 3.2% of women were hospitalized for heart failure or valve-related symptoms. A new pacemaker was implanted in 12.7% of participants. At baseline 74% of women were New York Heart Association functional class III or IV; at 1 year, only 8.1% were. Moderate paravalvular aortic regurgitation was present in 6% of patients at 6 months and in 9.7% at 1 year
The WIN-TAVI registry is entirely self-funded. Dr. Chieffo reported having no financial conflicts regarding her presentation.
Paris – A history of pregnancy did not protect against adverse outcomes at 1 year in the Women’s International Transcatheter Aortic Valve Implantation Registry (WIN-TAVI), even though it did within the first 30 days, Alaide Chieffo, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
One year ago, at EuroPCR 2016, she reported that in WIN-TAVI, a history of pregnancy – albeit typically more than half a century previously – was independently associated with a 43% reduction in the Valve Academic Research Consortium-2 (VARC-2) 30-day composite endpoint, including death, stroke, major vascular complications, life-threatening bleeding, stage 2 or 3 acute kidney injury, coronary artery obstruction, or repeat transcatheter aortic valve replacement (TAVR) done because of valve-related dysfunction. Those early findings, first reported in this publication, were later published (JACC Cardiovasc Interv. 2016 Aug 8;9[15]:1589-600).
At 1 year of follow-up, however, the rate of the VARC-2 composite endpoint was no longer significantly different in women with or without a history of pregnancy. Nor was a history of pregnancy associated with a significantly reduced risk of the secondary endpoint of death or stroke: The 27% reduction in risk of this secondary endpoint in women with a history of pregnancy, compared with that of nulliparous women, didn’t achieve statistical significance in multivariate analysis, according to Dr. Chieffo of the San Raffaele Scientific Institute in Milan.
She speculated that pregnancy earlier in life provided strong protection against poor 30-day outcomes and a similar trend – albeit not statistically significant – at 1 year because women without children may have less family support.
“They are old women, left alone, without the family taking care of them. This is socially important, I think, because we are investing quite a lot of money in a procedure, and then maybe we’re adding adverse events because these patients are not properly taken care of when they are out of the hospital,” the interventional cardiologist said.
Neither of the other two female-specific characteristics evaluated in WIN-TAVI – having a history of osteoporosis or age at menopause – turned out to be related to the risk of bad outcomes at 1 year, she added.
WIN-TAVI is the first all-female registry of patients undergoing TAVR for severe aortic stenosis. The prospective, observational registry includes 1,019 women treated at 19 highly experienced European and North American TAVR centers. They averaged 82.5 years of age with a mean Society of Thoracic Surgeons score of 8.3%, putting them at intermediate or high surgical risk. A percutaneous transfemoral approach was used in 91% of cases. TAVR was performed under conscious sedation in 28% of the women and under local anesthesia in another 37%. Of the women in the registry, 42% received a newer-generation device.
In addition to the lack of significant impact of prior pregnancy on 1-year outcomes, another noteworthy finding at 1 year of follow-up was that preprocedural atrial fibrillation was independently associated with a 58% increase in the risk of death or stroke (P = .02). Prior percutaneous coronary intervention and EuroSCORE (European System for Cardiac Operative Risk Evaluation) were the only other independent predictors.
This observation suggests the need for a women-only randomized trial of TAVR versus surgical aortic valve replacement in women with intermediate surgical risk, Dr. Chieffo suggested. It will be important to learn whether the ability to surgically ablate preoperative atrial fibrillation in women during surgical valve replacement results in a lower 1-year risk of death or stroke than is achieved with TAVR.
Overall, the 1-year clinical outcomes seen in WIN-TAVI are “very good,” she noted. The VARC-2 composite endpoint occurred in 16.5% of women, all-cause mortality in 12.5%, cardiovascular mortality in 10.8%, and stroke in 2.2%. Only 3.2% of women were hospitalized for heart failure or valve-related symptoms. A new pacemaker was implanted in 12.7% of participants. At baseline 74% of women were New York Heart Association functional class III or IV; at 1 year, only 8.1% were. Moderate paravalvular aortic regurgitation was present in 6% of patients at 6 months and in 9.7% at 1 year
The WIN-TAVI registry is entirely self-funded. Dr. Chieffo reported having no financial conflicts regarding her presentation.
AT EuroPCR
Key clinical point:
Major finding: Prior pregnancy didn’t protect women against death or stroke at 1 year post TAVR.
Data source: WIN-TAVI, a prospective, multicenter, observational registry includes 1,019 women who underwent TAVR.
Disclosures: WIN-TAVI is entirely self-funded. The presenter reported having no financial conflicts.
Folic acid fortification prevents millions of cases of anemia
DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.
“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.
Extrapolating from the nationally representative survey to the full U.S. population, Dr. Mills estimated that translates to roughly 10 million cases of folate-deficiency anemia prevented per year as a result of the mandatory fortification of grain introduced in 1998. That represents an enormous financial savings in avoided costs of diagnosis and treatment of this disorder.
The Food Fortification Initiative reports that 86 countries have embraced mandatory food fortification of wheat, maize, and/or rice. More than two dozen reports from around the world describe 40%-60% reductions in neural tube defect rates as a consequence. However, some of the world’s most populous nations are not on board. These include China, India, Russia, and the entire European Union.
Among the arguments raised by opponents of mandatory food fortification is the notion that it exposes the entire population to folic acid while benefiting only a small group of individuals who are spared having a neural tube defect. But the findings regarding prevention of folate-deficiency anemia demonstrate that argument is incorrect, Dr. Mills said.
Increased risks of asthma, cancer, and twinning as a consequence of mandatory food fortification have been proposed but are not supported by evidence. The only well-established adverse event is masking of vitamin B12 deficiency by correction of the anemia. But most reported cases have occurred after exposure to folic acid in milligram per day amounts, whereas the average U.S. exposure in women of childbearing age is just 163 mcg per day, less than half the recommended daily intake for that group. Also, no increase in cases of newly diagnosed vitamin B12 deficiency without anemia occurred in the U.S. after mandatory fortification was introduced, according to Dr. Mills.
Audience member Godfrey P. Oakley Jr., MD, noted that there is randomized trial evidence to indicate that folic acid supplementation has another important benefit: primary prevention of stroke in hypertensive adults. He cited the randomized, double-blind China Stroke Primary Prevention Trial, in which almost 21,000 hypertensive Chinese adults without a history of myocardial infarction or stroke were randomized to a single-pill combination of 10 mg of enalapril and 0.8 mg of folic acid daily or to a tablet containing 10 mg of enalapril alone.
During a median 4.5 years of follow-up, the enalapril/folic acid group had a 24% reduction in the risk of ischemic stroke and a 20% reduction in the composite of cardiovascular death, MI, and stroke (JAMA. 2015 Apr 7;313[13]:1325-35).
This is a potential game-changing finding which cries out for a confirmatory trial, he said. “There’s a lot going for that paper. I don’t know of a research agenda item that’s more important than trying to find out the relationship between folic acid fortification and stroke. I wish somebody would put some money into it,” said Dr. Oakley, research professor of epidemiology at Emory University in Atlanta.
Dr. Mills responded that he has reservations about the quality of the Chinese study, particularly in light of a Chinese government analysis that concluded that 80% of Chinese clinical trials were fraudulent (BMJ. 2016 Oct 5;355:i5396).
“That makes me want to see more data from a source I have a little bit more confidence in,” he added.
Another possible benefit of folic acid supplementation worthy of investigation is its theoretic potential for cancer prevention. “Folic acid provides one-carbon atoms for DNA repair,” Dr. Mills noted.
Dr. Mills reported having no relevant financial disclosures.
DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.
“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.
Extrapolating from the nationally representative survey to the full U.S. population, Dr. Mills estimated that translates to roughly 10 million cases of folate-deficiency anemia prevented per year as a result of the mandatory fortification of grain introduced in 1998. That represents an enormous financial savings in avoided costs of diagnosis and treatment of this disorder.
The Food Fortification Initiative reports that 86 countries have embraced mandatory food fortification of wheat, maize, and/or rice. More than two dozen reports from around the world describe 40%-60% reductions in neural tube defect rates as a consequence. However, some of the world’s most populous nations are not on board. These include China, India, Russia, and the entire European Union.
Among the arguments raised by opponents of mandatory food fortification is the notion that it exposes the entire population to folic acid while benefiting only a small group of individuals who are spared having a neural tube defect. But the findings regarding prevention of folate-deficiency anemia demonstrate that argument is incorrect, Dr. Mills said.
Increased risks of asthma, cancer, and twinning as a consequence of mandatory food fortification have been proposed but are not supported by evidence. The only well-established adverse event is masking of vitamin B12 deficiency by correction of the anemia. But most reported cases have occurred after exposure to folic acid in milligram per day amounts, whereas the average U.S. exposure in women of childbearing age is just 163 mcg per day, less than half the recommended daily intake for that group. Also, no increase in cases of newly diagnosed vitamin B12 deficiency without anemia occurred in the U.S. after mandatory fortification was introduced, according to Dr. Mills.
Audience member Godfrey P. Oakley Jr., MD, noted that there is randomized trial evidence to indicate that folic acid supplementation has another important benefit: primary prevention of stroke in hypertensive adults. He cited the randomized, double-blind China Stroke Primary Prevention Trial, in which almost 21,000 hypertensive Chinese adults without a history of myocardial infarction or stroke were randomized to a single-pill combination of 10 mg of enalapril and 0.8 mg of folic acid daily or to a tablet containing 10 mg of enalapril alone.
During a median 4.5 years of follow-up, the enalapril/folic acid group had a 24% reduction in the risk of ischemic stroke and a 20% reduction in the composite of cardiovascular death, MI, and stroke (JAMA. 2015 Apr 7;313[13]:1325-35).
This is a potential game-changing finding which cries out for a confirmatory trial, he said. “There’s a lot going for that paper. I don’t know of a research agenda item that’s more important than trying to find out the relationship between folic acid fortification and stroke. I wish somebody would put some money into it,” said Dr. Oakley, research professor of epidemiology at Emory University in Atlanta.
Dr. Mills responded that he has reservations about the quality of the Chinese study, particularly in light of a Chinese government analysis that concluded that 80% of Chinese clinical trials were fraudulent (BMJ. 2016 Oct 5;355:i5396).
“That makes me want to see more data from a source I have a little bit more confidence in,” he added.
Another possible benefit of folic acid supplementation worthy of investigation is its theoretic potential for cancer prevention. “Folic acid provides one-carbon atoms for DNA repair,” Dr. Mills noted.
Dr. Mills reported having no relevant financial disclosures.
DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.
“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.
Extrapolating from the nationally representative survey to the full U.S. population, Dr. Mills estimated that translates to roughly 10 million cases of folate-deficiency anemia prevented per year as a result of the mandatory fortification of grain introduced in 1998. That represents an enormous financial savings in avoided costs of diagnosis and treatment of this disorder.
The Food Fortification Initiative reports that 86 countries have embraced mandatory food fortification of wheat, maize, and/or rice. More than two dozen reports from around the world describe 40%-60% reductions in neural tube defect rates as a consequence. However, some of the world’s most populous nations are not on board. These include China, India, Russia, and the entire European Union.
Among the arguments raised by opponents of mandatory food fortification is the notion that it exposes the entire population to folic acid while benefiting only a small group of individuals who are spared having a neural tube defect. But the findings regarding prevention of folate-deficiency anemia demonstrate that argument is incorrect, Dr. Mills said.
Increased risks of asthma, cancer, and twinning as a consequence of mandatory food fortification have been proposed but are not supported by evidence. The only well-established adverse event is masking of vitamin B12 deficiency by correction of the anemia. But most reported cases have occurred after exposure to folic acid in milligram per day amounts, whereas the average U.S. exposure in women of childbearing age is just 163 mcg per day, less than half the recommended daily intake for that group. Also, no increase in cases of newly diagnosed vitamin B12 deficiency without anemia occurred in the U.S. after mandatory fortification was introduced, according to Dr. Mills.
Audience member Godfrey P. Oakley Jr., MD, noted that there is randomized trial evidence to indicate that folic acid supplementation has another important benefit: primary prevention of stroke in hypertensive adults. He cited the randomized, double-blind China Stroke Primary Prevention Trial, in which almost 21,000 hypertensive Chinese adults without a history of myocardial infarction or stroke were randomized to a single-pill combination of 10 mg of enalapril and 0.8 mg of folic acid daily or to a tablet containing 10 mg of enalapril alone.
During a median 4.5 years of follow-up, the enalapril/folic acid group had a 24% reduction in the risk of ischemic stroke and a 20% reduction in the composite of cardiovascular death, MI, and stroke (JAMA. 2015 Apr 7;313[13]:1325-35).
This is a potential game-changing finding which cries out for a confirmatory trial, he said. “There’s a lot going for that paper. I don’t know of a research agenda item that’s more important than trying to find out the relationship between folic acid fortification and stroke. I wish somebody would put some money into it,” said Dr. Oakley, research professor of epidemiology at Emory University in Atlanta.
Dr. Mills responded that he has reservations about the quality of the Chinese study, particularly in light of a Chinese government analysis that concluded that 80% of Chinese clinical trials were fraudulent (BMJ. 2016 Oct 5;355:i5396).
“That makes me want to see more data from a source I have a little bit more confidence in,” he added.
Another possible benefit of folic acid supplementation worthy of investigation is its theoretic potential for cancer prevention. “Folic acid provides one-carbon atoms for DNA repair,” Dr. Mills noted.
Dr. Mills reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Preop atrial fib in CABG patients spells trouble
COLORADO SPRINGS – Preoperative atrial fibrillation is present in more than 10% of patients undergoing isolated coronary artery bypass graft (CABG) surgery, and if not subjected to concomitant surgical ablation it’s associated with increased perioperative and long-term major morbidity and mortality, S. Chris Malaisrie, MD, reported at the annual meeting of the Western Thoracic Surgical Association.
The increased early and late risks posed by preoperative atrial fibrillation (AF) that go unaddressed remain significant even after adjusting for the numerous comorbid conditions more prevalent in CABG patients with preoperative AF than in those without the arrhythmia, added Dr. Malaisrie, a cardiac surgeon at Northwestern University in Chicago.
The unadjusted operative mortality rate was 1.8% in the no-AF group and 4.0% in patients with preoperative AF. Unadjusted in-hospital rates of permanent stroke, prolonged ventilation, reoperation, and new renal failure were also significantly higher in the preoperative AF group.
Not surprisingly, the preoperative AF group was older. They also had significantly higher baseline rates of numerous comorbid conditions, including diabetes, peripheral vascular disease, renal failure, and prior stroke, as well as a lower mean left ventricular ejection fraction. However, after adjustment for the many comorbidities in multivariate regression analysis, the risks of all in-hospital adverse outcomes remained significantly higher in the preoperative AF group. For example, their adjusted risk of operative mortality was 1.5-fold greater than in the no-AF patients.
In the long-term follow-up analysis, the unadjusted risk of mortality in the first 5 years after CABG was 2.5-fold greater in the preoperative AF group. Their 5-year risk of stroke or systemic embolization was 1.5-fold greater, too. Upon adjustment for potentially confounding comorbid conditions, preoperative AF was associated with a 1.5-fold increased 5-year risk of mortality and a 1.2-fold increase in stroke or systemic embolism.
In an effort to identify a particularly high-risk group of CABG patients with preoperative AF, Dr. Malaisrie and his coinvestigators stratified the group’s long-term stroke and mortality risks by their CHA2DS2-VASc score at the time of surgery. The results were revealing: the unadjusted 5-year risk of stroke or systemic embolization was 7.9% in those with a CHA2DS2-VASc score of 1-3, 12.2% with a score of 4-6, and 15.4% with a score of 7-9. The 5-year survival rate was 74.8% with a score of 1-3, 56.5% with a score of 4-6, and 41.2% with a score of 7-9.
“That’s really a striking finding,” Dr. Malaisrie observed. “When you consider a patient who’s, say, 72-75 years old, who is undergoing isolated CABG with preoperative atrial fibrillation and who has a high CHA2DS2-VASc score of 7-9, 5-year survival is only 41%, with a 15% risk of stroke or systemic embolization.”
Discussant William T. Caine, MD, found the study results unsettling.
“I was surprised to see that in this day and age, fully two-thirds of the patients who had preoperative atrial fibrillation had no attempt at any ablation procedure to treat their atrial fibrillation,” declared Dr. Caine of Intermountain Medical Center in Salt Lake City.
In reply, Dr. Malaisrie noted that other, smaller studies have also found that only about 30% of CABG patients with preoperative AF undergo surgical AF ablation through a maze procedure or some other method.
“Probably most of us in this room would go ahead and perform surgical ablation, but the STS database represents all isolated CABG procedures done throughout the United States,” Dr. Malaisrie said. “I think this dataset should help convince the other 70% of surgeons out there that there is a high cost for preoperative AF – in particular, in patients with very high CHA2DS2-VASc scores. If you can identify a group of patients at increased risk for stroke and mortality, you’d certainly want to bend their survival curve.”
The maze procedure has been convincingly shown to be very safe, with no associated increased risk of perioperative morbidity and mortality. The downside is cost. But while it’s true that adding surgical ablation to an isolated CABG procedure boosts OR time and procedural costs, a successful ablation is likely to pay dividends through reduced downstream rates of major morbidity and mortality.
“I look forward to the second part of our analysis, where we’ll look at the comparative data for the patients who did in fact have surgical ablation. That dataset is pending from the Duke Clinical Research Institute,” according to Dr. Malaisrie.
He cited as study limitations the inability to complete linkage to the Medicare database in about 37% of CABG patients in the STS database, or more than 200,000 people. Also, the Medicare database is an administrative dataset reliant upon medical record coding. The mortality data are probably quite accurate, but the stroke and systemic embolization rates cited in this analysis likely underestimate the true rates.
He reported serving as a consultant to Edwards Lifesciences, Abbott Vascular, and Baxter, and serving on speakers’ bureaus for Bolton and Abiomed. However, the STS analysis was funded exclusively by philanthropy.
COLORADO SPRINGS – Preoperative atrial fibrillation is present in more than 10% of patients undergoing isolated coronary artery bypass graft (CABG) surgery, and if not subjected to concomitant surgical ablation it’s associated with increased perioperative and long-term major morbidity and mortality, S. Chris Malaisrie, MD, reported at the annual meeting of the Western Thoracic Surgical Association.
The increased early and late risks posed by preoperative atrial fibrillation (AF) that go unaddressed remain significant even after adjusting for the numerous comorbid conditions more prevalent in CABG patients with preoperative AF than in those without the arrhythmia, added Dr. Malaisrie, a cardiac surgeon at Northwestern University in Chicago.
The unadjusted operative mortality rate was 1.8% in the no-AF group and 4.0% in patients with preoperative AF. Unadjusted in-hospital rates of permanent stroke, prolonged ventilation, reoperation, and new renal failure were also significantly higher in the preoperative AF group.
Not surprisingly, the preoperative AF group was older. They also had significantly higher baseline rates of numerous comorbid conditions, including diabetes, peripheral vascular disease, renal failure, and prior stroke, as well as a lower mean left ventricular ejection fraction. However, after adjustment for the many comorbidities in multivariate regression analysis, the risks of all in-hospital adverse outcomes remained significantly higher in the preoperative AF group. For example, their adjusted risk of operative mortality was 1.5-fold greater than in the no-AF patients.
In the long-term follow-up analysis, the unadjusted risk of mortality in the first 5 years after CABG was 2.5-fold greater in the preoperative AF group. Their 5-year risk of stroke or systemic embolization was 1.5-fold greater, too. Upon adjustment for potentially confounding comorbid conditions, preoperative AF was associated with a 1.5-fold increased 5-year risk of mortality and a 1.2-fold increase in stroke or systemic embolism.
In an effort to identify a particularly high-risk group of CABG patients with preoperative AF, Dr. Malaisrie and his coinvestigators stratified the group’s long-term stroke and mortality risks by their CHA2DS2-VASc score at the time of surgery. The results were revealing: the unadjusted 5-year risk of stroke or systemic embolization was 7.9% in those with a CHA2DS2-VASc score of 1-3, 12.2% with a score of 4-6, and 15.4% with a score of 7-9. The 5-year survival rate was 74.8% with a score of 1-3, 56.5% with a score of 4-6, and 41.2% with a score of 7-9.
“That’s really a striking finding,” Dr. Malaisrie observed. “When you consider a patient who’s, say, 72-75 years old, who is undergoing isolated CABG with preoperative atrial fibrillation and who has a high CHA2DS2-VASc score of 7-9, 5-year survival is only 41%, with a 15% risk of stroke or systemic embolization.”
Discussant William T. Caine, MD, found the study results unsettling.
“I was surprised to see that in this day and age, fully two-thirds of the patients who had preoperative atrial fibrillation had no attempt at any ablation procedure to treat their atrial fibrillation,” declared Dr. Caine of Intermountain Medical Center in Salt Lake City.
In reply, Dr. Malaisrie noted that other, smaller studies have also found that only about 30% of CABG patients with preoperative AF undergo surgical AF ablation through a maze procedure or some other method.
“Probably most of us in this room would go ahead and perform surgical ablation, but the STS database represents all isolated CABG procedures done throughout the United States,” Dr. Malaisrie said. “I think this dataset should help convince the other 70% of surgeons out there that there is a high cost for preoperative AF – in particular, in patients with very high CHA2DS2-VASc scores. If you can identify a group of patients at increased risk for stroke and mortality, you’d certainly want to bend their survival curve.”
The maze procedure has been convincingly shown to be very safe, with no associated increased risk of perioperative morbidity and mortality. The downside is cost. But while it’s true that adding surgical ablation to an isolated CABG procedure boosts OR time and procedural costs, a successful ablation is likely to pay dividends through reduced downstream rates of major morbidity and mortality.
“I look forward to the second part of our analysis, where we’ll look at the comparative data for the patients who did in fact have surgical ablation. That dataset is pending from the Duke Clinical Research Institute,” according to Dr. Malaisrie.
He cited as study limitations the inability to complete linkage to the Medicare database in about 37% of CABG patients in the STS database, or more than 200,000 people. Also, the Medicare database is an administrative dataset reliant upon medical record coding. The mortality data are probably quite accurate, but the stroke and systemic embolization rates cited in this analysis likely underestimate the true rates.
He reported serving as a consultant to Edwards Lifesciences, Abbott Vascular, and Baxter, and serving on speakers’ bureaus for Bolton and Abiomed. However, the STS analysis was funded exclusively by philanthropy.
COLORADO SPRINGS – Preoperative atrial fibrillation is present in more than 10% of patients undergoing isolated coronary artery bypass graft (CABG) surgery, and if not subjected to concomitant surgical ablation it’s associated with increased perioperative and long-term major morbidity and mortality, S. Chris Malaisrie, MD, reported at the annual meeting of the Western Thoracic Surgical Association.
The increased early and late risks posed by preoperative atrial fibrillation (AF) that go unaddressed remain significant even after adjusting for the numerous comorbid conditions more prevalent in CABG patients with preoperative AF than in those without the arrhythmia, added Dr. Malaisrie, a cardiac surgeon at Northwestern University in Chicago.
The unadjusted operative mortality rate was 1.8% in the no-AF group and 4.0% in patients with preoperative AF. Unadjusted in-hospital rates of permanent stroke, prolonged ventilation, reoperation, and new renal failure were also significantly higher in the preoperative AF group.
Not surprisingly, the preoperative AF group was older. They also had significantly higher baseline rates of numerous comorbid conditions, including diabetes, peripheral vascular disease, renal failure, and prior stroke, as well as a lower mean left ventricular ejection fraction. However, after adjustment for the many comorbidities in multivariate regression analysis, the risks of all in-hospital adverse outcomes remained significantly higher in the preoperative AF group. For example, their adjusted risk of operative mortality was 1.5-fold greater than in the no-AF patients.
In the long-term follow-up analysis, the unadjusted risk of mortality in the first 5 years after CABG was 2.5-fold greater in the preoperative AF group. Their 5-year risk of stroke or systemic embolization was 1.5-fold greater, too. Upon adjustment for potentially confounding comorbid conditions, preoperative AF was associated with a 1.5-fold increased 5-year risk of mortality and a 1.2-fold increase in stroke or systemic embolism.
In an effort to identify a particularly high-risk group of CABG patients with preoperative AF, Dr. Malaisrie and his coinvestigators stratified the group’s long-term stroke and mortality risks by their CHA2DS2-VASc score at the time of surgery. The results were revealing: the unadjusted 5-year risk of stroke or systemic embolization was 7.9% in those with a CHA2DS2-VASc score of 1-3, 12.2% with a score of 4-6, and 15.4% with a score of 7-9. The 5-year survival rate was 74.8% with a score of 1-3, 56.5% with a score of 4-6, and 41.2% with a score of 7-9.
“That’s really a striking finding,” Dr. Malaisrie observed. “When you consider a patient who’s, say, 72-75 years old, who is undergoing isolated CABG with preoperative atrial fibrillation and who has a high CHA2DS2-VASc score of 7-9, 5-year survival is only 41%, with a 15% risk of stroke or systemic embolization.”
Discussant William T. Caine, MD, found the study results unsettling.
“I was surprised to see that in this day and age, fully two-thirds of the patients who had preoperative atrial fibrillation had no attempt at any ablation procedure to treat their atrial fibrillation,” declared Dr. Caine of Intermountain Medical Center in Salt Lake City.
In reply, Dr. Malaisrie noted that other, smaller studies have also found that only about 30% of CABG patients with preoperative AF undergo surgical AF ablation through a maze procedure or some other method.
“Probably most of us in this room would go ahead and perform surgical ablation, but the STS database represents all isolated CABG procedures done throughout the United States,” Dr. Malaisrie said. “I think this dataset should help convince the other 70% of surgeons out there that there is a high cost for preoperative AF – in particular, in patients with very high CHA2DS2-VASc scores. If you can identify a group of patients at increased risk for stroke and mortality, you’d certainly want to bend their survival curve.”
The maze procedure has been convincingly shown to be very safe, with no associated increased risk of perioperative morbidity and mortality. The downside is cost. But while it’s true that adding surgical ablation to an isolated CABG procedure boosts OR time and procedural costs, a successful ablation is likely to pay dividends through reduced downstream rates of major morbidity and mortality.
“I look forward to the second part of our analysis, where we’ll look at the comparative data for the patients who did in fact have surgical ablation. That dataset is pending from the Duke Clinical Research Institute,” according to Dr. Malaisrie.
He cited as study limitations the inability to complete linkage to the Medicare database in about 37% of CABG patients in the STS database, or more than 200,000 people. Also, the Medicare database is an administrative dataset reliant upon medical record coding. The mortality data are probably quite accurate, but the stroke and systemic embolization rates cited in this analysis likely underestimate the true rates.
He reported serving as a consultant to Edwards Lifesciences, Abbott Vascular, and Baxter, and serving on speakers’ bureaus for Bolton and Abiomed. However, the STS analysis was funded exclusively by philanthropy.
AT THE WTSA ANNUAL MEETING
Key clinical point:
Major finding: Preoperative AF in patients undergoing isolated CABG was tied to an adjusted 45% greater 5-year mortality and 25% increase in stroke and systemic embolization risk, compared with CABG patients without the preoperative arrhythmia.
Data source: This retrospective study compared perioperative and long-term morbidity and mortality in nearly 350,000 patients in the Society of Thoracic Surgeons database who underwent isolated CABG, including more than 24,000 who had preoperative atrial fibrillation that wasn’t addressed surgically.
Disclosures: The study presenter reported serving as a consultant to Edwards Lifesciences, Abbott Vascular, and Baxter, and serving on speakers’ bureaus for Bolton and Abiomed. However, the STS analysis was funded exclusively by philanthropy.
Oral antibiotics successfully treat community-acquired pneumonia with empyema
MADRID – Outpatient oral antibiotics were more successful than outpatient parenteral antibiotic therapy at treating children with community-acquired pneumonia complicated by empyema, in a study presented at the annual meeting of the European Society for Paediatric Infectious Diseases.
Thirty-five percent of the patients were culture positive, a typically low rate that makes treatment of this disease particularly challenging, Lauren Kushner, a medical student at the University of California, Irvine, and one of the study’s authors, said at the meeting.
The treatment success rates, which were defined as improvement with no change in treatment, were 93% for the patients taking oral antibiotics and 58% in the patients on outpatient parenteral antibiotic therapy.
This retrospective observational study included 149 patients under age 18 years hospitalized for community-acquired pneumonia complicated by empyema, at Children’s Hospital of Orange County, Calif. Only 12 of the patients were treated with parenteral antibiotic therapy and none of the study participants had comorbid chronic medical conditions. As in other studies, Streptococcus pneumoniae was the most commonly identified pathogen.
Laboratory markers of inflammation are useful in guiding oral antibiotic therapy for children with CAP complicated by empyema, reported Ms. Kushner.
“A rapid drop in C-reactive protein [CRP] in combination with a decrease in white blood cell count [WBC] can be used acutely in the hospitalization phase to tell you the patient is improving on the selected antibiotic and also to help dictate when the patient might be able to go home, whereas improvement in the erythrocyte sedimentation rate [ESR] does not happen until much later in the course of treatment but can be used to tell you when a patient has been adequately treated,” said Ms. Kushner.
One hundred thirty-seven patients were discharged on oral antibiotic therapy, as is strongly recommended in Infectious Diseases Society of America guidelines for postdischarge treatment of complicated pneumonia, even though there are no randomized clinical trials demonstrating it to be superior or even noninferior to outpatient parenteral antibiotics. An aminopenicillin was the most frequently prescribed type of oral antibiotic, while ceftriaxone was the top choice for outpatient parenteral therapy.
The average total duration of antibiotic therapy, inpatient plus outpatient, was similar in the two groups: 30.4 days in the oral antibiotic group and 33.2 days in children on outpatient IV therapy.
The transition to oral therapy occurred a median of 6 days after admission. At that point, CRP levels had dropped sharply by a mean of 204 mg/L from a baseline of more than 250 mg/L at admission. In the same time frame, mean WBC dropped by 6,400 cells/mcL from close to 20,000/mcL at admission. Thus, sharp declines in these two inflammatory markers while a patient is still in the hospital provide reassurance that antibiotic therapy is on the right track. Their rate of decline slowed considerably after the switch to oral therapy: for example, mean CRP decreased by only another 44 mg/L from switch to discharge, and by a further 19 mg/L from discharge to end of treatment.
In contrast, the mean ESR remained elevated at a level approaching 100 mm/hour with little fluctuation from admission through discharge. Weekly monitoring of ESR post discharge showed that this inflammatory marker improved only late in the course of oral therapy. A drop to less than 30 mm/hour indicates the infection has resolved, Ms. Kushner said.
She noted that in contrast to her study findings, a recent multicenter, 2,123-patient study by the Pediatric Research in Inpatient Settings Network found that treatment failure rates didn’t differ significantly between the two treatment strategies (Pediatrics. 2016 Dec;138[6]. pii: e20161692). Similarly, a retrospective study of 391 children with empyema admitted to Primary Children’s Hospital in Salt Lake City found closely similar rates of treatment failure and other complications regardless of whether the patients were placed on outpatient oral or parenteral antibiotic therapy (Hosp Pediatr. 2015 Dec;5[12]:605-12).
Ms. Kushner reported having no financial conflicts of interest regarding the study.
MADRID – Outpatient oral antibiotics were more successful than outpatient parenteral antibiotic therapy at treating children with community-acquired pneumonia complicated by empyema, in a study presented at the annual meeting of the European Society for Paediatric Infectious Diseases.
Thirty-five percent of the patients were culture positive, a typically low rate that makes treatment of this disease particularly challenging, Lauren Kushner, a medical student at the University of California, Irvine, and one of the study’s authors, said at the meeting.
The treatment success rates, which were defined as improvement with no change in treatment, were 93% for the patients taking oral antibiotics and 58% in the patients on outpatient parenteral antibiotic therapy.
This retrospective observational study included 149 patients under age 18 years hospitalized for community-acquired pneumonia complicated by empyema, at Children’s Hospital of Orange County, Calif. Only 12 of the patients were treated with parenteral antibiotic therapy and none of the study participants had comorbid chronic medical conditions. As in other studies, Streptococcus pneumoniae was the most commonly identified pathogen.
Laboratory markers of inflammation are useful in guiding oral antibiotic therapy for children with CAP complicated by empyema, reported Ms. Kushner.
“A rapid drop in C-reactive protein [CRP] in combination with a decrease in white blood cell count [WBC] can be used acutely in the hospitalization phase to tell you the patient is improving on the selected antibiotic and also to help dictate when the patient might be able to go home, whereas improvement in the erythrocyte sedimentation rate [ESR] does not happen until much later in the course of treatment but can be used to tell you when a patient has been adequately treated,” said Ms. Kushner.
One hundred thirty-seven patients were discharged on oral antibiotic therapy, as is strongly recommended in Infectious Diseases Society of America guidelines for postdischarge treatment of complicated pneumonia, even though there are no randomized clinical trials demonstrating it to be superior or even noninferior to outpatient parenteral antibiotics. An aminopenicillin was the most frequently prescribed type of oral antibiotic, while ceftriaxone was the top choice for outpatient parenteral therapy.
The average total duration of antibiotic therapy, inpatient plus outpatient, was similar in the two groups: 30.4 days in the oral antibiotic group and 33.2 days in children on outpatient IV therapy.
The transition to oral therapy occurred a median of 6 days after admission. At that point, CRP levels had dropped sharply by a mean of 204 mg/L from a baseline of more than 250 mg/L at admission. In the same time frame, mean WBC dropped by 6,400 cells/mcL from close to 20,000/mcL at admission. Thus, sharp declines in these two inflammatory markers while a patient is still in the hospital provide reassurance that antibiotic therapy is on the right track. Their rate of decline slowed considerably after the switch to oral therapy: for example, mean CRP decreased by only another 44 mg/L from switch to discharge, and by a further 19 mg/L from discharge to end of treatment.
In contrast, the mean ESR remained elevated at a level approaching 100 mm/hour with little fluctuation from admission through discharge. Weekly monitoring of ESR post discharge showed that this inflammatory marker improved only late in the course of oral therapy. A drop to less than 30 mm/hour indicates the infection has resolved, Ms. Kushner said.
She noted that in contrast to her study findings, a recent multicenter, 2,123-patient study by the Pediatric Research in Inpatient Settings Network found that treatment failure rates didn’t differ significantly between the two treatment strategies (Pediatrics. 2016 Dec;138[6]. pii: e20161692). Similarly, a retrospective study of 391 children with empyema admitted to Primary Children’s Hospital in Salt Lake City found closely similar rates of treatment failure and other complications regardless of whether the patients were placed on outpatient oral or parenteral antibiotic therapy (Hosp Pediatr. 2015 Dec;5[12]:605-12).
Ms. Kushner reported having no financial conflicts of interest regarding the study.
MADRID – Outpatient oral antibiotics were more successful than outpatient parenteral antibiotic therapy at treating children with community-acquired pneumonia complicated by empyema, in a study presented at the annual meeting of the European Society for Paediatric Infectious Diseases.
Thirty-five percent of the patients were culture positive, a typically low rate that makes treatment of this disease particularly challenging, Lauren Kushner, a medical student at the University of California, Irvine, and one of the study’s authors, said at the meeting.
The treatment success rates, which were defined as improvement with no change in treatment, were 93% for the patients taking oral antibiotics and 58% in the patients on outpatient parenteral antibiotic therapy.
This retrospective observational study included 149 patients under age 18 years hospitalized for community-acquired pneumonia complicated by empyema, at Children’s Hospital of Orange County, Calif. Only 12 of the patients were treated with parenteral antibiotic therapy and none of the study participants had comorbid chronic medical conditions. As in other studies, Streptococcus pneumoniae was the most commonly identified pathogen.
Laboratory markers of inflammation are useful in guiding oral antibiotic therapy for children with CAP complicated by empyema, reported Ms. Kushner.
“A rapid drop in C-reactive protein [CRP] in combination with a decrease in white blood cell count [WBC] can be used acutely in the hospitalization phase to tell you the patient is improving on the selected antibiotic and also to help dictate when the patient might be able to go home, whereas improvement in the erythrocyte sedimentation rate [ESR] does not happen until much later in the course of treatment but can be used to tell you when a patient has been adequately treated,” said Ms. Kushner.
One hundred thirty-seven patients were discharged on oral antibiotic therapy, as is strongly recommended in Infectious Diseases Society of America guidelines for postdischarge treatment of complicated pneumonia, even though there are no randomized clinical trials demonstrating it to be superior or even noninferior to outpatient parenteral antibiotics. An aminopenicillin was the most frequently prescribed type of oral antibiotic, while ceftriaxone was the top choice for outpatient parenteral therapy.
The average total duration of antibiotic therapy, inpatient plus outpatient, was similar in the two groups: 30.4 days in the oral antibiotic group and 33.2 days in children on outpatient IV therapy.
The transition to oral therapy occurred a median of 6 days after admission. At that point, CRP levels had dropped sharply by a mean of 204 mg/L from a baseline of more than 250 mg/L at admission. In the same time frame, mean WBC dropped by 6,400 cells/mcL from close to 20,000/mcL at admission. Thus, sharp declines in these two inflammatory markers while a patient is still in the hospital provide reassurance that antibiotic therapy is on the right track. Their rate of decline slowed considerably after the switch to oral therapy: for example, mean CRP decreased by only another 44 mg/L from switch to discharge, and by a further 19 mg/L from discharge to end of treatment.
In contrast, the mean ESR remained elevated at a level approaching 100 mm/hour with little fluctuation from admission through discharge. Weekly monitoring of ESR post discharge showed that this inflammatory marker improved only late in the course of oral therapy. A drop to less than 30 mm/hour indicates the infection has resolved, Ms. Kushner said.
She noted that in contrast to her study findings, a recent multicenter, 2,123-patient study by the Pediatric Research in Inpatient Settings Network found that treatment failure rates didn’t differ significantly between the two treatment strategies (Pediatrics. 2016 Dec;138[6]. pii: e20161692). Similarly, a retrospective study of 391 children with empyema admitted to Primary Children’s Hospital in Salt Lake City found closely similar rates of treatment failure and other complications regardless of whether the patients were placed on outpatient oral or parenteral antibiotic therapy (Hosp Pediatr. 2015 Dec;5[12]:605-12).
Ms. Kushner reported having no financial conflicts of interest regarding the study.
AT ESPID 2017
Key clinical point:
Major finding: The treatment success rate with outpatient oral antibiotic therapy for pediatric community-acquired pneumonia with empyema was 93% in a retrospective study, significantly better than the 58% rate in a much smaller group of patients discharged with outpatient parenteral antibiotic therapy.
Data source: This retrospective single-center study included 149 patients under age 18 years hospitalized for community-acquired pneumonia complicated by empyema and later sent home on either oral or parenteral antibiotic therapy.
Disclosures: The study presenter reported having no financial conflicts of interest.
How to counsel women about marijuana in pregnancy
DENVER – , Torri D. Metz, MD, observed at the annual meeting of the Teratology Society.
This is of particular concern because the increasing legalization of recreational marijuana across the United States means growing use, possibly including use by pregnant women. National surveys indicate a high percentage of pregnant women believe there is slight or no harm in using marijuana once or twice per week, said Dr. Metz, an ob.gyn. at the University of Colorado, Denver, who is researching the effects of marijuana in pregnancy.
Here’s how she likes to handle that situation: She starts out by freely admitting that that’s true. The available evidence is limited, mixed, and often flawed.
“I say, ‘I can’t give you data that says absolutely it’s not safe, but I also absolutely cannot give you data saying it is safe.’ I would favor saying, ‘I can’t tell you it’s safe. And if there’s any possible risk, let’s talk about things we know are safe we can use as alternatives for whatever you’re using cannabis for,’ ” she explained.
A Colorado survey of more than 1,700 mothers in the WIC (Women, Infants, and Children) nutrition program shed light on the reasons women use marijuana while pregnant or breastfeeding. Sixty-three percent of current users cited as a perceived benefit that it helped with depression, anxiety, and/or stress. Sixty percent reported it helped with pain. Nearly half used marijuana for nausea and vomiting. Just 39% did so for recreation.
Dr. Metz’s anecdotal experience has been that many health care providers are flubbing the opportunity to counsel women about marijuana use in pregnancy. This impression was bolstered by a recent study by investigators at the University of Pittsburgh who audio-recorded 468 first prenatal visits.
In total, 19% of patients disclosed marijuana use to 47 health care providers. In nearly half of those encounters, the providers didn’t respond to the disclosure at all. And when they did respond, it typically wasn’t by providing thoughtful, informed counseling on the risks or outcomes of using marijuana in pregnancy. Instead, the response was most often punitive: for example, a warning that evidence of use at delivery would result in a call to child protective services (Obstet Gynecol. 2016 Apr;127[4]:681-7).
Because of Colorado’s lengthy experience with legalized marijuana, the state Department of Public Health and Environment has endeavored to create resources of value for health care providers and patients (www.colorado.gov/cdphe/marijuana-clinical-guidelines). The website contains a fact sheet for patients regarding marijuana in pregnancy and breastfeeding. For physicians, there is plain-language guidance on how to talk effectively about marijuana with patients, including suggested responses to selected commonly voiced misconceptions.
The website also includes the results of a 2014 marijuana-in-pregnancy literature review by a state advisory committee composed of Colorado specialists in pediatrics, ob.gyn., family medicine, public health, and addiction medicine.
The committee determined that there is moderate evidence that the use of marijuana in pregnancy is associated with increased risk of reduced fetal growth, lower IQ scores in young children, adverse effects on a child’s cognitive function and academic ability, and an increase in attention problems. There was deemed to be limited evidence of an association with stillbirth and isolated ventricular septal defects. There is also “mixed” evidence for associations with preterm delivery, reduced birth weight, and selected congenital anomalies.
Since that 2014 review, a new signal of potential harm stemming from maternal marijuana use in pregnancy has appeared: a possible increased risk of neonatal ICU admission. In one retrospective study including 361 marijuana users and 6,107 nonusers, the users had a 1.54-fold increased risk for neonatal ICU admission in an analysis adjusted for maternal demographics and tobacco use (J Perinatol. 2015 Dec;35[12]:991-5).
Moreover, investigators at the University of Arizona in Tucson performed a meta-analysis of 24 studies and concluded that infants exposed to cannabis in utero were at 2.02-fold increased likelihood of neonatal ICU admission, a 1.77-fold increased risk of low birth weight, and 1.36-fold increased odds of anemia (BMJ Open. 2016 Apr 5;6[4]:e0009986. doi: 10.1136/bmjopen-2015-009986).
“That obviously would have a big public health impact,” Dr. Metz said.
In marked contrast, however, just a few months later investigators at Washington University in St. Louis reported finding no significantly increased risk of neonatal ICU admission or any other adverse neonatal outcome after adjustment for tobacco use and other potential confounders in a meta-analysis of 31 studies (Obstet Gynecol. 2016 Oct;128[4]:713-23).
These contradictory meta-analyses underscore a key point about the existing literature on the safety of marijuana use in pregnancy: It provides few, if any, definitive answers. The studies conducted in the 1980s and 1990s are of limited generalizability because concentrations of tetrahydrocannabinol were so small, compared with today’s products. Ascertainment of exposure to marijuana in pregnancy is unreliable in the absence of confirmatory biologic sampling. Self-reported use is unreliable and is typically an underestimate. Adjustment for confounders associated with adverse neonatal outcomes is challenging.
“Biologic sampling is critical,” Dr. Metz said. “We actually don’t know who’s using, and we lack information on the timing and quantity of exposure.
“Part of the problem is the data are so mixed that you can really find whatever you want in the literature to support your bias,” she added.
Still, in light of the signals of possible harm, she urged her colleagues to advise patients not to use marijuana in pregnancy. Patients need to understand that there are no known benefits of marijuana use in pregnancy, there are possible risks, and there is no known safe amount of cannabis in pregnancy.
Dr. Metz reported having no financial conflicts related to her presentation.
DENVER – , Torri D. Metz, MD, observed at the annual meeting of the Teratology Society.
This is of particular concern because the increasing legalization of recreational marijuana across the United States means growing use, possibly including use by pregnant women. National surveys indicate a high percentage of pregnant women believe there is slight or no harm in using marijuana once or twice per week, said Dr. Metz, an ob.gyn. at the University of Colorado, Denver, who is researching the effects of marijuana in pregnancy.
Here’s how she likes to handle that situation: She starts out by freely admitting that that’s true. The available evidence is limited, mixed, and often flawed.
“I say, ‘I can’t give you data that says absolutely it’s not safe, but I also absolutely cannot give you data saying it is safe.’ I would favor saying, ‘I can’t tell you it’s safe. And if there’s any possible risk, let’s talk about things we know are safe we can use as alternatives for whatever you’re using cannabis for,’ ” she explained.
A Colorado survey of more than 1,700 mothers in the WIC (Women, Infants, and Children) nutrition program shed light on the reasons women use marijuana while pregnant or breastfeeding. Sixty-three percent of current users cited as a perceived benefit that it helped with depression, anxiety, and/or stress. Sixty percent reported it helped with pain. Nearly half used marijuana for nausea and vomiting. Just 39% did so for recreation.
Dr. Metz’s anecdotal experience has been that many health care providers are flubbing the opportunity to counsel women about marijuana use in pregnancy. This impression was bolstered by a recent study by investigators at the University of Pittsburgh who audio-recorded 468 first prenatal visits.
In total, 19% of patients disclosed marijuana use to 47 health care providers. In nearly half of those encounters, the providers didn’t respond to the disclosure at all. And when they did respond, it typically wasn’t by providing thoughtful, informed counseling on the risks or outcomes of using marijuana in pregnancy. Instead, the response was most often punitive: for example, a warning that evidence of use at delivery would result in a call to child protective services (Obstet Gynecol. 2016 Apr;127[4]:681-7).
Because of Colorado’s lengthy experience with legalized marijuana, the state Department of Public Health and Environment has endeavored to create resources of value for health care providers and patients (www.colorado.gov/cdphe/marijuana-clinical-guidelines). The website contains a fact sheet for patients regarding marijuana in pregnancy and breastfeeding. For physicians, there is plain-language guidance on how to talk effectively about marijuana with patients, including suggested responses to selected commonly voiced misconceptions.
The website also includes the results of a 2014 marijuana-in-pregnancy literature review by a state advisory committee composed of Colorado specialists in pediatrics, ob.gyn., family medicine, public health, and addiction medicine.
The committee determined that there is moderate evidence that the use of marijuana in pregnancy is associated with increased risk of reduced fetal growth, lower IQ scores in young children, adverse effects on a child’s cognitive function and academic ability, and an increase in attention problems. There was deemed to be limited evidence of an association with stillbirth and isolated ventricular septal defects. There is also “mixed” evidence for associations with preterm delivery, reduced birth weight, and selected congenital anomalies.
Since that 2014 review, a new signal of potential harm stemming from maternal marijuana use in pregnancy has appeared: a possible increased risk of neonatal ICU admission. In one retrospective study including 361 marijuana users and 6,107 nonusers, the users had a 1.54-fold increased risk for neonatal ICU admission in an analysis adjusted for maternal demographics and tobacco use (J Perinatol. 2015 Dec;35[12]:991-5).
Moreover, investigators at the University of Arizona in Tucson performed a meta-analysis of 24 studies and concluded that infants exposed to cannabis in utero were at 2.02-fold increased likelihood of neonatal ICU admission, a 1.77-fold increased risk of low birth weight, and 1.36-fold increased odds of anemia (BMJ Open. 2016 Apr 5;6[4]:e0009986. doi: 10.1136/bmjopen-2015-009986).
“That obviously would have a big public health impact,” Dr. Metz said.
In marked contrast, however, just a few months later investigators at Washington University in St. Louis reported finding no significantly increased risk of neonatal ICU admission or any other adverse neonatal outcome after adjustment for tobacco use and other potential confounders in a meta-analysis of 31 studies (Obstet Gynecol. 2016 Oct;128[4]:713-23).
These contradictory meta-analyses underscore a key point about the existing literature on the safety of marijuana use in pregnancy: It provides few, if any, definitive answers. The studies conducted in the 1980s and 1990s are of limited generalizability because concentrations of tetrahydrocannabinol were so small, compared with today’s products. Ascertainment of exposure to marijuana in pregnancy is unreliable in the absence of confirmatory biologic sampling. Self-reported use is unreliable and is typically an underestimate. Adjustment for confounders associated with adverse neonatal outcomes is challenging.
“Biologic sampling is critical,” Dr. Metz said. “We actually don’t know who’s using, and we lack information on the timing and quantity of exposure.
“Part of the problem is the data are so mixed that you can really find whatever you want in the literature to support your bias,” she added.
Still, in light of the signals of possible harm, she urged her colleagues to advise patients not to use marijuana in pregnancy. Patients need to understand that there are no known benefits of marijuana use in pregnancy, there are possible risks, and there is no known safe amount of cannabis in pregnancy.
Dr. Metz reported having no financial conflicts related to her presentation.
DENVER – , Torri D. Metz, MD, observed at the annual meeting of the Teratology Society.
This is of particular concern because the increasing legalization of recreational marijuana across the United States means growing use, possibly including use by pregnant women. National surveys indicate a high percentage of pregnant women believe there is slight or no harm in using marijuana once or twice per week, said Dr. Metz, an ob.gyn. at the University of Colorado, Denver, who is researching the effects of marijuana in pregnancy.
Here’s how she likes to handle that situation: She starts out by freely admitting that that’s true. The available evidence is limited, mixed, and often flawed.
“I say, ‘I can’t give you data that says absolutely it’s not safe, but I also absolutely cannot give you data saying it is safe.’ I would favor saying, ‘I can’t tell you it’s safe. And if there’s any possible risk, let’s talk about things we know are safe we can use as alternatives for whatever you’re using cannabis for,’ ” she explained.
A Colorado survey of more than 1,700 mothers in the WIC (Women, Infants, and Children) nutrition program shed light on the reasons women use marijuana while pregnant or breastfeeding. Sixty-three percent of current users cited as a perceived benefit that it helped with depression, anxiety, and/or stress. Sixty percent reported it helped with pain. Nearly half used marijuana for nausea and vomiting. Just 39% did so for recreation.
Dr. Metz’s anecdotal experience has been that many health care providers are flubbing the opportunity to counsel women about marijuana use in pregnancy. This impression was bolstered by a recent study by investigators at the University of Pittsburgh who audio-recorded 468 first prenatal visits.
In total, 19% of patients disclosed marijuana use to 47 health care providers. In nearly half of those encounters, the providers didn’t respond to the disclosure at all. And when they did respond, it typically wasn’t by providing thoughtful, informed counseling on the risks or outcomes of using marijuana in pregnancy. Instead, the response was most often punitive: for example, a warning that evidence of use at delivery would result in a call to child protective services (Obstet Gynecol. 2016 Apr;127[4]:681-7).
Because of Colorado’s lengthy experience with legalized marijuana, the state Department of Public Health and Environment has endeavored to create resources of value for health care providers and patients (www.colorado.gov/cdphe/marijuana-clinical-guidelines). The website contains a fact sheet for patients regarding marijuana in pregnancy and breastfeeding. For physicians, there is plain-language guidance on how to talk effectively about marijuana with patients, including suggested responses to selected commonly voiced misconceptions.
The website also includes the results of a 2014 marijuana-in-pregnancy literature review by a state advisory committee composed of Colorado specialists in pediatrics, ob.gyn., family medicine, public health, and addiction medicine.
The committee determined that there is moderate evidence that the use of marijuana in pregnancy is associated with increased risk of reduced fetal growth, lower IQ scores in young children, adverse effects on a child’s cognitive function and academic ability, and an increase in attention problems. There was deemed to be limited evidence of an association with stillbirth and isolated ventricular septal defects. There is also “mixed” evidence for associations with preterm delivery, reduced birth weight, and selected congenital anomalies.
Since that 2014 review, a new signal of potential harm stemming from maternal marijuana use in pregnancy has appeared: a possible increased risk of neonatal ICU admission. In one retrospective study including 361 marijuana users and 6,107 nonusers, the users had a 1.54-fold increased risk for neonatal ICU admission in an analysis adjusted for maternal demographics and tobacco use (J Perinatol. 2015 Dec;35[12]:991-5).
Moreover, investigators at the University of Arizona in Tucson performed a meta-analysis of 24 studies and concluded that infants exposed to cannabis in utero were at 2.02-fold increased likelihood of neonatal ICU admission, a 1.77-fold increased risk of low birth weight, and 1.36-fold increased odds of anemia (BMJ Open. 2016 Apr 5;6[4]:e0009986. doi: 10.1136/bmjopen-2015-009986).
“That obviously would have a big public health impact,” Dr. Metz said.
In marked contrast, however, just a few months later investigators at Washington University in St. Louis reported finding no significantly increased risk of neonatal ICU admission or any other adverse neonatal outcome after adjustment for tobacco use and other potential confounders in a meta-analysis of 31 studies (Obstet Gynecol. 2016 Oct;128[4]:713-23).
These contradictory meta-analyses underscore a key point about the existing literature on the safety of marijuana use in pregnancy: It provides few, if any, definitive answers. The studies conducted in the 1980s and 1990s are of limited generalizability because concentrations of tetrahydrocannabinol were so small, compared with today’s products. Ascertainment of exposure to marijuana in pregnancy is unreliable in the absence of confirmatory biologic sampling. Self-reported use is unreliable and is typically an underestimate. Adjustment for confounders associated with adverse neonatal outcomes is challenging.
“Biologic sampling is critical,” Dr. Metz said. “We actually don’t know who’s using, and we lack information on the timing and quantity of exposure.
“Part of the problem is the data are so mixed that you can really find whatever you want in the literature to support your bias,” she added.
Still, in light of the signals of possible harm, she urged her colleagues to advise patients not to use marijuana in pregnancy. Patients need to understand that there are no known benefits of marijuana use in pregnancy, there are possible risks, and there is no known safe amount of cannabis in pregnancy.
Dr. Metz reported having no financial conflicts related to her presentation.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
How to rule out secondary causes of osteoporosis
ESTES PARK, COLO. – Everyone diagnosed with osteoporosis deserves a laboratory assessment to rule out unsuspected secondary causes, according to Sterling West, MD. And he’s got a doozy of a workup he recommends to primary care physicians as “incredibly cost effective.”
“With this workup you’ll identify 98% of abnormalities at a mean cost of $366 per diagnosis. That’s incredibly cost effective. You’re going to get a lot of information with actually not very much outlay at all,” he said at a conference on internal medicine sponsored by the University of Colorado.
The tests he advocates that primary care physicians order in all their patients with osteoporosis include a complete blood count, a complete metabolic panel, a 24-hour urine calcium/sodium/creatinine, a serum 25-hydroxyvitamin D level, and a serum phosphorus. In addition, men with osteoporosis should have their serum testosterone measured. A thyroid-stimulating hormone level should be obtained in patients who are taking thyroxine or if they look clinically hyperthyroid.
A measurement of parathyroid hormone is warranted as part of the screen in patients with an abnormal serum calcium. If the parathyroid hormone is normal, hyperparathyroidism can be ruled out.
Ordering a serum protein electrophoresis to check for multiple myeloma is appropriate in osteoporotic patients over age 50 years with an abnormal complete blood count.
This basic laboratory workup will identify patients with the relatively common secondary causes of low bone mineral density which account for 98% of all cases. These causes include vitamin D deficiency, malabsorption, hypogonadism, hypercalciuria, and myeloma.
“Leave the other 2% to me,” the rheumatologist suggested.
Special laboratory tests Dr. Sterling recommended that are best left to bone disease specialists include bone turnover markers, a serum tryptase/urine N-methylhistamine to screen for systemic mastocytosis, antitransglutaminase antibodies for celiac disease, a 24-hour urinary free cortisol and/or overnight dexamethasone suppression test to identify patients with Cushing syndrome, and bone biopsy.
Who should be referred to a bone specialist for a more extensive workup?
“If somebody is losing bone or fracturing and they’re on appropriate therapy and you believe they’re taking their medication, that’s for sure somebody that we should see. Also, a premenopausal woman with a high Z score who has had a fracture that’s atypical. And patients with stage 4 or 5 chronic kidney disease; those are some of the toughest cases and are best referred to a bone expert,” Dr. Sterling said.
On the other hand, if an osteoporotic patient simply can’t tolerate guideline-recommended initial therapy with an oral bisphosphonate such as alendronate (Fosamax) or risedronate (Actonel), there’s no need to bring in a specialist. Simply switch the patient to denosumab (Prolia), a monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, administered by subcutaneous injection once every 6 months. The cost is about $2,200 per year, but the drug is covered by Medicare Part B. Clinical trials have demonstrated that denosumab boosts bone mineral density by 6%-9%, with an absolute 5% reduction in fractures and a 40%-68% relative risk reduction, he noted.
Dr. West reported having no financial conflicts of interest regarding his presentation.
ESTES PARK, COLO. – Everyone diagnosed with osteoporosis deserves a laboratory assessment to rule out unsuspected secondary causes, according to Sterling West, MD. And he’s got a doozy of a workup he recommends to primary care physicians as “incredibly cost effective.”
“With this workup you’ll identify 98% of abnormalities at a mean cost of $366 per diagnosis. That’s incredibly cost effective. You’re going to get a lot of information with actually not very much outlay at all,” he said at a conference on internal medicine sponsored by the University of Colorado.
The tests he advocates that primary care physicians order in all their patients with osteoporosis include a complete blood count, a complete metabolic panel, a 24-hour urine calcium/sodium/creatinine, a serum 25-hydroxyvitamin D level, and a serum phosphorus. In addition, men with osteoporosis should have their serum testosterone measured. A thyroid-stimulating hormone level should be obtained in patients who are taking thyroxine or if they look clinically hyperthyroid.
A measurement of parathyroid hormone is warranted as part of the screen in patients with an abnormal serum calcium. If the parathyroid hormone is normal, hyperparathyroidism can be ruled out.
Ordering a serum protein electrophoresis to check for multiple myeloma is appropriate in osteoporotic patients over age 50 years with an abnormal complete blood count.
This basic laboratory workup will identify patients with the relatively common secondary causes of low bone mineral density which account for 98% of all cases. These causes include vitamin D deficiency, malabsorption, hypogonadism, hypercalciuria, and myeloma.
“Leave the other 2% to me,” the rheumatologist suggested.
Special laboratory tests Dr. Sterling recommended that are best left to bone disease specialists include bone turnover markers, a serum tryptase/urine N-methylhistamine to screen for systemic mastocytosis, antitransglutaminase antibodies for celiac disease, a 24-hour urinary free cortisol and/or overnight dexamethasone suppression test to identify patients with Cushing syndrome, and bone biopsy.
Who should be referred to a bone specialist for a more extensive workup?
“If somebody is losing bone or fracturing and they’re on appropriate therapy and you believe they’re taking their medication, that’s for sure somebody that we should see. Also, a premenopausal woman with a high Z score who has had a fracture that’s atypical. And patients with stage 4 or 5 chronic kidney disease; those are some of the toughest cases and are best referred to a bone expert,” Dr. Sterling said.
On the other hand, if an osteoporotic patient simply can’t tolerate guideline-recommended initial therapy with an oral bisphosphonate such as alendronate (Fosamax) or risedronate (Actonel), there’s no need to bring in a specialist. Simply switch the patient to denosumab (Prolia), a monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, administered by subcutaneous injection once every 6 months. The cost is about $2,200 per year, but the drug is covered by Medicare Part B. Clinical trials have demonstrated that denosumab boosts bone mineral density by 6%-9%, with an absolute 5% reduction in fractures and a 40%-68% relative risk reduction, he noted.
Dr. West reported having no financial conflicts of interest regarding his presentation.
ESTES PARK, COLO. – Everyone diagnosed with osteoporosis deserves a laboratory assessment to rule out unsuspected secondary causes, according to Sterling West, MD. And he’s got a doozy of a workup he recommends to primary care physicians as “incredibly cost effective.”
“With this workup you’ll identify 98% of abnormalities at a mean cost of $366 per diagnosis. That’s incredibly cost effective. You’re going to get a lot of information with actually not very much outlay at all,” he said at a conference on internal medicine sponsored by the University of Colorado.
The tests he advocates that primary care physicians order in all their patients with osteoporosis include a complete blood count, a complete metabolic panel, a 24-hour urine calcium/sodium/creatinine, a serum 25-hydroxyvitamin D level, and a serum phosphorus. In addition, men with osteoporosis should have their serum testosterone measured. A thyroid-stimulating hormone level should be obtained in patients who are taking thyroxine or if they look clinically hyperthyroid.
A measurement of parathyroid hormone is warranted as part of the screen in patients with an abnormal serum calcium. If the parathyroid hormone is normal, hyperparathyroidism can be ruled out.
Ordering a serum protein electrophoresis to check for multiple myeloma is appropriate in osteoporotic patients over age 50 years with an abnormal complete blood count.
This basic laboratory workup will identify patients with the relatively common secondary causes of low bone mineral density which account for 98% of all cases. These causes include vitamin D deficiency, malabsorption, hypogonadism, hypercalciuria, and myeloma.
“Leave the other 2% to me,” the rheumatologist suggested.
Special laboratory tests Dr. Sterling recommended that are best left to bone disease specialists include bone turnover markers, a serum tryptase/urine N-methylhistamine to screen for systemic mastocytosis, antitransglutaminase antibodies for celiac disease, a 24-hour urinary free cortisol and/or overnight dexamethasone suppression test to identify patients with Cushing syndrome, and bone biopsy.
Who should be referred to a bone specialist for a more extensive workup?
“If somebody is losing bone or fracturing and they’re on appropriate therapy and you believe they’re taking their medication, that’s for sure somebody that we should see. Also, a premenopausal woman with a high Z score who has had a fracture that’s atypical. And patients with stage 4 or 5 chronic kidney disease; those are some of the toughest cases and are best referred to a bone expert,” Dr. Sterling said.
On the other hand, if an osteoporotic patient simply can’t tolerate guideline-recommended initial therapy with an oral bisphosphonate such as alendronate (Fosamax) or risedronate (Actonel), there’s no need to bring in a specialist. Simply switch the patient to denosumab (Prolia), a monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, administered by subcutaneous injection once every 6 months. The cost is about $2,200 per year, but the drug is covered by Medicare Part B. Clinical trials have demonstrated that denosumab boosts bone mineral density by 6%-9%, with an absolute 5% reduction in fractures and a 40%-68% relative risk reduction, he noted.
Dr. West reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE ANNUAL INTERNAL MEDICINE PROGRAM
First trial of TAVR vs. SAVR in low-risk patients
PARIS – Five-year hemodynamic results of the first randomized trial of transcatheter versus surgical aortic valve replacement in low-surgical-risk patients with severe aortic stenosis showed continued superior valve performance in the TAVR group, Lars Sondergaard, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
“The durability results are very encouraging. We can’t see that the TAVR patients are doing worse. So I think this is setting the scene to try to move forward in patients at low risk and also in younger patients,” declared Dr. Sondergaard, professor of cardiology at the University of Copenhagen.
He presented an update from the Nordic Aortic Valve Intervention (NOTION) trial, a prospective, multicenter, randomized, all-comers clinical trial in which 280 patients with symptomatic severe aortic stenosis at low surgical risk were assigned to surgical aortic valve replacement (SAVR) or to TAVR with the self-expanding CoreValve. Their mean age was 79 years, with an average Society of Thoracic Surgeons projected risk of mortality score of 3%. Eighty-two percent of participants had an STS score below 4%. Roughly 40% of TAVR patients got the first-generation CoreValve in the 26-mm size, 40% received the 29-mm version, and the rest got the 31-mm CoreValve.
Among patients in the lowest-surgical-risk and youngest subgroup – those aged 70-75 with a Society of Thoracic Surgeons risk score below 4% – the composite primary endpoint rate at 4 years was 15.6% with TAVR compared with 27.2% with SAVR. However, only 62 NOTION participants fell into this category, so the between-group difference, while sizable, didn’t achieve statistical significance, according to Dr. Sondergaard.
There was a trade-off between the two valve replacement strategies with regard to procedural complications. The rate of new-onset atrial fibrillation was far higher in the SAVR group: 59.4% at 1 year and 60.2% at 4 years of follow-up, compared with 21.2% and 24.5% at 1 and 4 years, respectively, in the TAVR group.
On the other hand, 38% of the TAVR patients got a new pacemaker within the first year of follow-up, compared with only 2.4% in the SAVR group. At 4 years, 43.7% of the TAVR group had a pacemaker, versus 9% of the SAVR group.
Turning to the hemodynamic data, the cardiologist noted that the effective orifice area in the TAVR group went from 0.71 cm2 at baseline to 1.66 at 1 year and remained steady thereafter at 1.67 cm2 through 5 years. The TAVR group’s mean gradient improved from 45.4 mm Hg at baseline to 8.6 mm Hg at 1 year and 7.9 mm Hg at 5 years. These outcomes were significantly better than in the SAVR group, where the effective orifice area went from 0.74 cm2 at baseline to 1.32 at 1 year and 1.24 cm2 at 5 years, while the mean gradient fell from 44.9 mm Hg to 12.5 at 1 year and 13.6 mm Hg at 5 years.
Moderate hemodynamic structural valve deterioration was significantly more common in the SAVR group: 20.7% at 5 years, compared with 2.9% in the TAVR patients. The opposite was true with regard to moderate paravalvular leak, which occurred in 20.9% of the TAVI group but only 1.5% of SAVR patients.
Late complications were rare following either procedure. There were no cases of valve thrombosis through 5 years. The incidence of endocarditis at 5 years was 4.3% in the TAVR patients and similar at 5.9% in the SAVR group.
Discussant Samer Mansour, MD, of the University of Montreal, remarked that the rate of new pacemaker implantation following TAVR seemed extraordinarily high.
“This was early days,” Dr. Sondergaard explained. “We had a lower threshold for putting in a pacemaker and we put the valves in a little deeper.”
About half of new pacemaker recipients didn’t use the device after the first year, he added. Also, neither getting a new pacemaker nor moderate paravalvular leak was associated with increased mortality in the TAVR group.
Dr. Mansour observed that subtle but real differences in mortality probably wouldn’t show up in a 280-patient trial. Dr. Sondergaard concurred.
“We designed the NOTION trial in 2008-2009. Knowing what we know now, we should have had a larger study, but at that time TAVR volume wasn’t that big and it wasn’t realistic as a Nordic trial to include 1,000 patients. This was the best we could do,” he said.
Follow-up in the NOTION study will continue out to 10 years.
The study is funded by Medtronic. Dr. Sondergaard reported serving as a consultant to and receiving research grant support from the company.
PARIS – Five-year hemodynamic results of the first randomized trial of transcatheter versus surgical aortic valve replacement in low-surgical-risk patients with severe aortic stenosis showed continued superior valve performance in the TAVR group, Lars Sondergaard, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
“The durability results are very encouraging. We can’t see that the TAVR patients are doing worse. So I think this is setting the scene to try to move forward in patients at low risk and also in younger patients,” declared Dr. Sondergaard, professor of cardiology at the University of Copenhagen.
He presented an update from the Nordic Aortic Valve Intervention (NOTION) trial, a prospective, multicenter, randomized, all-comers clinical trial in which 280 patients with symptomatic severe aortic stenosis at low surgical risk were assigned to surgical aortic valve replacement (SAVR) or to TAVR with the self-expanding CoreValve. Their mean age was 79 years, with an average Society of Thoracic Surgeons projected risk of mortality score of 3%. Eighty-two percent of participants had an STS score below 4%. Roughly 40% of TAVR patients got the first-generation CoreValve in the 26-mm size, 40% received the 29-mm version, and the rest got the 31-mm CoreValve.
Among patients in the lowest-surgical-risk and youngest subgroup – those aged 70-75 with a Society of Thoracic Surgeons risk score below 4% – the composite primary endpoint rate at 4 years was 15.6% with TAVR compared with 27.2% with SAVR. However, only 62 NOTION participants fell into this category, so the between-group difference, while sizable, didn’t achieve statistical significance, according to Dr. Sondergaard.
There was a trade-off between the two valve replacement strategies with regard to procedural complications. The rate of new-onset atrial fibrillation was far higher in the SAVR group: 59.4% at 1 year and 60.2% at 4 years of follow-up, compared with 21.2% and 24.5% at 1 and 4 years, respectively, in the TAVR group.
On the other hand, 38% of the TAVR patients got a new pacemaker within the first year of follow-up, compared with only 2.4% in the SAVR group. At 4 years, 43.7% of the TAVR group had a pacemaker, versus 9% of the SAVR group.
Turning to the hemodynamic data, the cardiologist noted that the effective orifice area in the TAVR group went from 0.71 cm2 at baseline to 1.66 at 1 year and remained steady thereafter at 1.67 cm2 through 5 years. The TAVR group’s mean gradient improved from 45.4 mm Hg at baseline to 8.6 mm Hg at 1 year and 7.9 mm Hg at 5 years. These outcomes were significantly better than in the SAVR group, where the effective orifice area went from 0.74 cm2 at baseline to 1.32 at 1 year and 1.24 cm2 at 5 years, while the mean gradient fell from 44.9 mm Hg to 12.5 at 1 year and 13.6 mm Hg at 5 years.
Moderate hemodynamic structural valve deterioration was significantly more common in the SAVR group: 20.7% at 5 years, compared with 2.9% in the TAVR patients. The opposite was true with regard to moderate paravalvular leak, which occurred in 20.9% of the TAVI group but only 1.5% of SAVR patients.
Late complications were rare following either procedure. There were no cases of valve thrombosis through 5 years. The incidence of endocarditis at 5 years was 4.3% in the TAVR patients and similar at 5.9% in the SAVR group.
Discussant Samer Mansour, MD, of the University of Montreal, remarked that the rate of new pacemaker implantation following TAVR seemed extraordinarily high.
“This was early days,” Dr. Sondergaard explained. “We had a lower threshold for putting in a pacemaker and we put the valves in a little deeper.”
About half of new pacemaker recipients didn’t use the device after the first year, he added. Also, neither getting a new pacemaker nor moderate paravalvular leak was associated with increased mortality in the TAVR group.
Dr. Mansour observed that subtle but real differences in mortality probably wouldn’t show up in a 280-patient trial. Dr. Sondergaard concurred.
“We designed the NOTION trial in 2008-2009. Knowing what we know now, we should have had a larger study, but at that time TAVR volume wasn’t that big and it wasn’t realistic as a Nordic trial to include 1,000 patients. This was the best we could do,” he said.
Follow-up in the NOTION study will continue out to 10 years.
The study is funded by Medtronic. Dr. Sondergaard reported serving as a consultant to and receiving research grant support from the company.
PARIS – Five-year hemodynamic results of the first randomized trial of transcatheter versus surgical aortic valve replacement in low-surgical-risk patients with severe aortic stenosis showed continued superior valve performance in the TAVR group, Lars Sondergaard, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
“The durability results are very encouraging. We can’t see that the TAVR patients are doing worse. So I think this is setting the scene to try to move forward in patients at low risk and also in younger patients,” declared Dr. Sondergaard, professor of cardiology at the University of Copenhagen.
He presented an update from the Nordic Aortic Valve Intervention (NOTION) trial, a prospective, multicenter, randomized, all-comers clinical trial in which 280 patients with symptomatic severe aortic stenosis at low surgical risk were assigned to surgical aortic valve replacement (SAVR) or to TAVR with the self-expanding CoreValve. Their mean age was 79 years, with an average Society of Thoracic Surgeons projected risk of mortality score of 3%. Eighty-two percent of participants had an STS score below 4%. Roughly 40% of TAVR patients got the first-generation CoreValve in the 26-mm size, 40% received the 29-mm version, and the rest got the 31-mm CoreValve.
Among patients in the lowest-surgical-risk and youngest subgroup – those aged 70-75 with a Society of Thoracic Surgeons risk score below 4% – the composite primary endpoint rate at 4 years was 15.6% with TAVR compared with 27.2% with SAVR. However, only 62 NOTION participants fell into this category, so the between-group difference, while sizable, didn’t achieve statistical significance, according to Dr. Sondergaard.
There was a trade-off between the two valve replacement strategies with regard to procedural complications. The rate of new-onset atrial fibrillation was far higher in the SAVR group: 59.4% at 1 year and 60.2% at 4 years of follow-up, compared with 21.2% and 24.5% at 1 and 4 years, respectively, in the TAVR group.
On the other hand, 38% of the TAVR patients got a new pacemaker within the first year of follow-up, compared with only 2.4% in the SAVR group. At 4 years, 43.7% of the TAVR group had a pacemaker, versus 9% of the SAVR group.
Turning to the hemodynamic data, the cardiologist noted that the effective orifice area in the TAVR group went from 0.71 cm2 at baseline to 1.66 at 1 year and remained steady thereafter at 1.67 cm2 through 5 years. The TAVR group’s mean gradient improved from 45.4 mm Hg at baseline to 8.6 mm Hg at 1 year and 7.9 mm Hg at 5 years. These outcomes were significantly better than in the SAVR group, where the effective orifice area went from 0.74 cm2 at baseline to 1.32 at 1 year and 1.24 cm2 at 5 years, while the mean gradient fell from 44.9 mm Hg to 12.5 at 1 year and 13.6 mm Hg at 5 years.
Moderate hemodynamic structural valve deterioration was significantly more common in the SAVR group: 20.7% at 5 years, compared with 2.9% in the TAVR patients. The opposite was true with regard to moderate paravalvular leak, which occurred in 20.9% of the TAVI group but only 1.5% of SAVR patients.
Late complications were rare following either procedure. There were no cases of valve thrombosis through 5 years. The incidence of endocarditis at 5 years was 4.3% in the TAVR patients and similar at 5.9% in the SAVR group.
Discussant Samer Mansour, MD, of the University of Montreal, remarked that the rate of new pacemaker implantation following TAVR seemed extraordinarily high.
“This was early days,” Dr. Sondergaard explained. “We had a lower threshold for putting in a pacemaker and we put the valves in a little deeper.”
About half of new pacemaker recipients didn’t use the device after the first year, he added. Also, neither getting a new pacemaker nor moderate paravalvular leak was associated with increased mortality in the TAVR group.
Dr. Mansour observed that subtle but real differences in mortality probably wouldn’t show up in a 280-patient trial. Dr. Sondergaard concurred.
“We designed the NOTION trial in 2008-2009. Knowing what we know now, we should have had a larger study, but at that time TAVR volume wasn’t that big and it wasn’t realistic as a Nordic trial to include 1,000 patients. This was the best we could do,” he said.
Follow-up in the NOTION study will continue out to 10 years.
The study is funded by Medtronic. Dr. Sondergaard reported serving as a consultant to and receiving research grant support from the company.
AT EuroPCR
Key clinical point:
Major finding: At 4 years of follow-up, the composite endpoint of all-cause mortality, MI, or stroke occurred in 29% of low-surgical-risk patients with severe aortic stenosis who were randomized to transcatheter aortic valve replacement (TAVR) and 30% of those who underwent surgical valve replacement.
Data source: NOTION, a prospective multicenter randomized trial in which 280 Nordic patients with symptomatic severe aortic stenosis at low surgical risk were assigned to surgical aortic valve replacement (SAVR) or to TAVR with the self-expanding CoreValve.
Disclosures: The study is funded by Medtronic. The presenter reported serving as a consultant to and receiving research grant support from the company.
E-cigarettes: A health threat or cessation tool?
DENVER –
“So far, the evidence regarding e-cigarettes’ effectiveness for smoking cessation is equivocal at best,” Alison Breland, PhD, said at the annual meeting of the Teratology Society.
But Dr. Breland noted that there is significant controversy around this topic. “I can tell you that, at the conferences I go to, where there are lots of people studying nicotine and tobacco, scientists are fighting with each other over this question,” said Dr. Breland, a psychologist and project director at the Center for the Study of Tobacco Products at Virginia Commonwealth University in Richmond.
That being said, she noted that this meta-analysis has generated unusually harsh printed comments from its critics.
“We could argue about the methodology of the studies all day. If you think all the studies are garbage then you won’t believe the odds ratio, either. But I think right now the evidence shows that e-cigarettes don’t seem to help people quit,” she said. “That may change in the future with testing of different kinds of devices.”
To be useful for smoking cessation, she explained, a device would need to consistently deliver enough nicotine to enable the smoker to fend off withdrawal symptoms but not so much that the wish to quit evaporates. It’s a matter of finding the sweet spot in what is technically termed device nicotine flux.
There is a great deal of misconception about e-cigarettes, Dr. Breland said, some of it promoted through misleading product advertising. She sought to set the record straight.
How e-cigarettes work
What are e-cigarettes? They are basically nicotine delivery devices. They use electricity to power a heating element that aerosolizes a liquid containing varying concentrations of nicotine; solvents, such as propylene glycol and vegetable glycerins; and flavorants. As a class, e-cigarettes are rapidly evolving. A vast array of devices are marketed with wide differences in design, materials, construction, amount of nicotine delivered, and electrical power – which, along with puff duration, is a key factor in how much nicotine gets into a user’s blood.
“Most of the devices have a battery, but it’s important to know that some of them can be plugged directly into a USB port on a computer,” Dr. Breland said.
E-cigarettes don’t generate a vapor, as is widely believed. It’s an aerosol, and it contains toxic byproducts. On the plus side, unlike combustible cigarettes, e-cigarettes don’t deliver carbon monoxide.
A vast array of flavorant mixtures are sold, including some that are clearly designed to be attractive to children, with names like “blue cotton candy” and “Apple Jacks.”
User demographics
Who is using e-cigarettes? Primarily adolescents and young adults in prime reproductive age. National surveys indicate e-cigarettes are now the most widely used tobacco product among U.S. high school students, well ahead of combustible cigarettes.
Of particular concern, data from the Centers for Disease Control and Prevention’s National Health Interview Survey indicate that, among 18- to 24-year-olds who use e-cigarettes, about 40% also currently use conventional cigarettes, about 20% are former cigarette smokers, and about 40% are never smokers – that is, have never smoked combustible cigarettes (MMWR Morb Mortal Wkly Rep. 2016;65:1177. doi: 10.15585/mmwr.mm6542a7).
“We don’t know what’s going to happen to these never smokers who are currently using e-cigarettes. Are they starting on a lifetime of nicotine dependence via e-cigarettes, or perhaps even worse, are they going to transition to combustible cigarettes? There’s more and more evidence showing that’s happening,” Dr. Breland said.
The CDC survey also showed that 59% of adult users of e-cigarettes are what Dr. Breland called “dualies,” individuals who also smoke conventional cigarettes.
“That really diminishes any potential benefit of e-cigarettes,” she said.
Impact on pregnancy
What is known about the impact of e-cigarettes on pregnancy and birth outcomes? Almost nothing at this point. E-cigarettes deliver nicotine to the bloodstream, and nicotine is known to cause unwelcome, long-term changes in fetal brain development and in that of adolescents as well. The other aerosolized toxicants have not been well studied. A few small surveys conducted in obstetric practices indicate some pregnant women perceive e-cigarettes as posing only minor health risks and safer than combustible cigarettes. And some pregnant women are using e-cigarettes.
“I think it’s notable that we’re not finding exclusive e-cigarette users. It’s early in the study, but so far the dual users are smoking the same number of cigarettes per day as cigarette-only users, and they have the same expired carbon monoxide levels. It makes me feel concerned in particular about dual use in pregnancy,” she said.
Regulation
One audience member asked what the point of allowing e-cigarettes is since, under a best-case scenario, their effectiveness as a smoking cessation tool is similar to a nicotine patch, and smokers already have access to the patch as well as nicotine gum.
Dr. Breland replied that the patch and gum deliver nicotine very slowly, so they are not as satisfying as smoking.
“The hope with e-cigarettes is that, since they get nicotine into your blood pretty fast – similar to a cigarette – they can more effectively suppress your withdrawal,” she said. “Whether or not that’s true isn’t known yet.”
The Food and Drug Administration has the authority to regulate e-cigarettes through several different mechanisms but, in late July 2017, announced a delay in issuing new regulations that would likely have removed many of the devices and flavorings from the marketplace.
Dr. Breland’s research is supported by the National Institute on Drug Abuse and the Food and Drug Administration. She reported having no financial conflicts of interest.
DENVER –
“So far, the evidence regarding e-cigarettes’ effectiveness for smoking cessation is equivocal at best,” Alison Breland, PhD, said at the annual meeting of the Teratology Society.
But Dr. Breland noted that there is significant controversy around this topic. “I can tell you that, at the conferences I go to, where there are lots of people studying nicotine and tobacco, scientists are fighting with each other over this question,” said Dr. Breland, a psychologist and project director at the Center for the Study of Tobacco Products at Virginia Commonwealth University in Richmond.
That being said, she noted that this meta-analysis has generated unusually harsh printed comments from its critics.
“We could argue about the methodology of the studies all day. If you think all the studies are garbage then you won’t believe the odds ratio, either. But I think right now the evidence shows that e-cigarettes don’t seem to help people quit,” she said. “That may change in the future with testing of different kinds of devices.”
To be useful for smoking cessation, she explained, a device would need to consistently deliver enough nicotine to enable the smoker to fend off withdrawal symptoms but not so much that the wish to quit evaporates. It’s a matter of finding the sweet spot in what is technically termed device nicotine flux.
There is a great deal of misconception about e-cigarettes, Dr. Breland said, some of it promoted through misleading product advertising. She sought to set the record straight.
How e-cigarettes work
What are e-cigarettes? They are basically nicotine delivery devices. They use electricity to power a heating element that aerosolizes a liquid containing varying concentrations of nicotine; solvents, such as propylene glycol and vegetable glycerins; and flavorants. As a class, e-cigarettes are rapidly evolving. A vast array of devices are marketed with wide differences in design, materials, construction, amount of nicotine delivered, and electrical power – which, along with puff duration, is a key factor in how much nicotine gets into a user’s blood.
“Most of the devices have a battery, but it’s important to know that some of them can be plugged directly into a USB port on a computer,” Dr. Breland said.
E-cigarettes don’t generate a vapor, as is widely believed. It’s an aerosol, and it contains toxic byproducts. On the plus side, unlike combustible cigarettes, e-cigarettes don’t deliver carbon monoxide.
A vast array of flavorant mixtures are sold, including some that are clearly designed to be attractive to children, with names like “blue cotton candy” and “Apple Jacks.”
User demographics
Who is using e-cigarettes? Primarily adolescents and young adults in prime reproductive age. National surveys indicate e-cigarettes are now the most widely used tobacco product among U.S. high school students, well ahead of combustible cigarettes.
Of particular concern, data from the Centers for Disease Control and Prevention’s National Health Interview Survey indicate that, among 18- to 24-year-olds who use e-cigarettes, about 40% also currently use conventional cigarettes, about 20% are former cigarette smokers, and about 40% are never smokers – that is, have never smoked combustible cigarettes (MMWR Morb Mortal Wkly Rep. 2016;65:1177. doi: 10.15585/mmwr.mm6542a7).
“We don’t know what’s going to happen to these never smokers who are currently using e-cigarettes. Are they starting on a lifetime of nicotine dependence via e-cigarettes, or perhaps even worse, are they going to transition to combustible cigarettes? There’s more and more evidence showing that’s happening,” Dr. Breland said.
The CDC survey also showed that 59% of adult users of e-cigarettes are what Dr. Breland called “dualies,” individuals who also smoke conventional cigarettes.
“That really diminishes any potential benefit of e-cigarettes,” she said.
Impact on pregnancy
What is known about the impact of e-cigarettes on pregnancy and birth outcomes? Almost nothing at this point. E-cigarettes deliver nicotine to the bloodstream, and nicotine is known to cause unwelcome, long-term changes in fetal brain development and in that of adolescents as well. The other aerosolized toxicants have not been well studied. A few small surveys conducted in obstetric practices indicate some pregnant women perceive e-cigarettes as posing only minor health risks and safer than combustible cigarettes. And some pregnant women are using e-cigarettes.
“I think it’s notable that we’re not finding exclusive e-cigarette users. It’s early in the study, but so far the dual users are smoking the same number of cigarettes per day as cigarette-only users, and they have the same expired carbon monoxide levels. It makes me feel concerned in particular about dual use in pregnancy,” she said.
Regulation
One audience member asked what the point of allowing e-cigarettes is since, under a best-case scenario, their effectiveness as a smoking cessation tool is similar to a nicotine patch, and smokers already have access to the patch as well as nicotine gum.
Dr. Breland replied that the patch and gum deliver nicotine very slowly, so they are not as satisfying as smoking.
“The hope with e-cigarettes is that, since they get nicotine into your blood pretty fast – similar to a cigarette – they can more effectively suppress your withdrawal,” she said. “Whether or not that’s true isn’t known yet.”
The Food and Drug Administration has the authority to regulate e-cigarettes through several different mechanisms but, in late July 2017, announced a delay in issuing new regulations that would likely have removed many of the devices and flavorings from the marketplace.
Dr. Breland’s research is supported by the National Institute on Drug Abuse and the Food and Drug Administration. She reported having no financial conflicts of interest.
DENVER –
“So far, the evidence regarding e-cigarettes’ effectiveness for smoking cessation is equivocal at best,” Alison Breland, PhD, said at the annual meeting of the Teratology Society.
But Dr. Breland noted that there is significant controversy around this topic. “I can tell you that, at the conferences I go to, where there are lots of people studying nicotine and tobacco, scientists are fighting with each other over this question,” said Dr. Breland, a psychologist and project director at the Center for the Study of Tobacco Products at Virginia Commonwealth University in Richmond.
That being said, she noted that this meta-analysis has generated unusually harsh printed comments from its critics.
“We could argue about the methodology of the studies all day. If you think all the studies are garbage then you won’t believe the odds ratio, either. But I think right now the evidence shows that e-cigarettes don’t seem to help people quit,” she said. “That may change in the future with testing of different kinds of devices.”
To be useful for smoking cessation, she explained, a device would need to consistently deliver enough nicotine to enable the smoker to fend off withdrawal symptoms but not so much that the wish to quit evaporates. It’s a matter of finding the sweet spot in what is technically termed device nicotine flux.
There is a great deal of misconception about e-cigarettes, Dr. Breland said, some of it promoted through misleading product advertising. She sought to set the record straight.
How e-cigarettes work
What are e-cigarettes? They are basically nicotine delivery devices. They use electricity to power a heating element that aerosolizes a liquid containing varying concentrations of nicotine; solvents, such as propylene glycol and vegetable glycerins; and flavorants. As a class, e-cigarettes are rapidly evolving. A vast array of devices are marketed with wide differences in design, materials, construction, amount of nicotine delivered, and electrical power – which, along with puff duration, is a key factor in how much nicotine gets into a user’s blood.
“Most of the devices have a battery, but it’s important to know that some of them can be plugged directly into a USB port on a computer,” Dr. Breland said.
E-cigarettes don’t generate a vapor, as is widely believed. It’s an aerosol, and it contains toxic byproducts. On the plus side, unlike combustible cigarettes, e-cigarettes don’t deliver carbon monoxide.
A vast array of flavorant mixtures are sold, including some that are clearly designed to be attractive to children, with names like “blue cotton candy” and “Apple Jacks.”
User demographics
Who is using e-cigarettes? Primarily adolescents and young adults in prime reproductive age. National surveys indicate e-cigarettes are now the most widely used tobacco product among U.S. high school students, well ahead of combustible cigarettes.
Of particular concern, data from the Centers for Disease Control and Prevention’s National Health Interview Survey indicate that, among 18- to 24-year-olds who use e-cigarettes, about 40% also currently use conventional cigarettes, about 20% are former cigarette smokers, and about 40% are never smokers – that is, have never smoked combustible cigarettes (MMWR Morb Mortal Wkly Rep. 2016;65:1177. doi: 10.15585/mmwr.mm6542a7).
“We don’t know what’s going to happen to these never smokers who are currently using e-cigarettes. Are they starting on a lifetime of nicotine dependence via e-cigarettes, or perhaps even worse, are they going to transition to combustible cigarettes? There’s more and more evidence showing that’s happening,” Dr. Breland said.
The CDC survey also showed that 59% of adult users of e-cigarettes are what Dr. Breland called “dualies,” individuals who also smoke conventional cigarettes.
“That really diminishes any potential benefit of e-cigarettes,” she said.
Impact on pregnancy
What is known about the impact of e-cigarettes on pregnancy and birth outcomes? Almost nothing at this point. E-cigarettes deliver nicotine to the bloodstream, and nicotine is known to cause unwelcome, long-term changes in fetal brain development and in that of adolescents as well. The other aerosolized toxicants have not been well studied. A few small surveys conducted in obstetric practices indicate some pregnant women perceive e-cigarettes as posing only minor health risks and safer than combustible cigarettes. And some pregnant women are using e-cigarettes.
“I think it’s notable that we’re not finding exclusive e-cigarette users. It’s early in the study, but so far the dual users are smoking the same number of cigarettes per day as cigarette-only users, and they have the same expired carbon monoxide levels. It makes me feel concerned in particular about dual use in pregnancy,” she said.
Regulation
One audience member asked what the point of allowing e-cigarettes is since, under a best-case scenario, their effectiveness as a smoking cessation tool is similar to a nicotine patch, and smokers already have access to the patch as well as nicotine gum.
Dr. Breland replied that the patch and gum deliver nicotine very slowly, so they are not as satisfying as smoking.
“The hope with e-cigarettes is that, since they get nicotine into your blood pretty fast – similar to a cigarette – they can more effectively suppress your withdrawal,” she said. “Whether or not that’s true isn’t known yet.”
The Food and Drug Administration has the authority to regulate e-cigarettes through several different mechanisms but, in late July 2017, announced a delay in issuing new regulations that would likely have removed many of the devices and flavorings from the marketplace.
Dr. Breland’s research is supported by the National Institute on Drug Abuse and the Food and Drug Administration. She reported having no financial conflicts of interest.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017