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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
VIDEO: Early caffeine did not help, may harm preemies
BALTIMORE – Early initiation of caffeine treatment in premature neonates on mechanical ventilation did not cut the time to when these babies could successfully wean off the ventilator, according to findings of a single-center, randomized controlled study of 83 children.
The results also showed an “unexpected” trend toward increased mortality among the neonates who received early caffeine treatment, Dr. Cynthia M. Amaro reported at the annual meeting of the Pediatric Academic Societies. This signal of elevated mortality with caffeine treatment prompted the study’s data and safety monitoring board to prematurely stop the trial, limiting enrollment to just 75% of the number originally planned in the study’s design, thereby raising questions about the reliability of the primary-endpoint finding that early caffeine treatment did not result in the benefit of a reduced time to extubation.
Dr. Amaro said that she and her associates ran the study to address what had emerged as a significant area of doubt in routine U.S. practice on how to best use caffeine treatment in this neonatal population following publication of findings from the landmark Caffeine for Apnea of Prematurity (CAP) Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Results from the CAP Trial had shown in nearly 2,000 randomized, premature infants that treatment with caffeine led to significantly fewer episodes of bronchopulmonary dysplasia as well as quicker time to extubation of mechanical ventilation. Caffeine or other methylxanthines stimulate an infant’s respiratory center to allow faster extubation.
Ever since that publication a decade ago, “clinicians have been using caffeine earlier and more liberally, without really good data to support its early use in mechanically-ventilated preterm babies,” explained Dr. Amaro, a neonatologist at the University of Miami and Holtz Children’s Hospital in Miami.
Based on the new findings from the study she reported, “we are now not routinely initiating caffeine in mechanically ventilated preterm babies and just using caffeine immediately before extubation to treat apnea of prematurity. This returns caffeine treatment to the way it was used in the CAP Trial,” she said. “Further studies are needed before we can say what is best for early treatment of these preterm babies,” Dr. Amaro said in a video interview.
Her report led to a flurry of comments during the question period, with several pediatricians voicing concern about the reliability of results from a study that followed only 83 patients because of its premature termination.
“The data and safety monitoring board’s decision is a big issue,” said Dr. Carl E. Hunt, a pediatrician at the Uniformed Services University of the Health Sciences in Bethesda, Md. “There is a literature that shows results of studies can be very different when they stop early. It’s unfortunate because we don’t have other prospective data, and it may now be hard to do a large randomized, controlled trial” of early caffeine treatment, Dr. Hunt said.
While Dr. Amaro conceded that premature termination limited her study’s size, she also asserted that her analyses confirmed the validity of the finding of no benefit from early caffeine treatment. “We projected to full enrollment, and there still was no difference in the time to first successful extubation,” she said.
Her study enrolled preterm infants during January 2013–December 2015 born at 23-30 weeks’ gestation who required mechanical ventilation during their first 5 days. Randomization assigned 41 infants to receive a 20-mg/kg bolus of caffeine, followed by a maintenance dosage of 5 mg/kg that continued until extubation, while 42 patients received placebo and did not get caffeine until just before attempted extubation. The bolus and maintenance caffeine dosages tested were identical to those used in the CAP Trial.
The researchers defined successful extubation as keeping a child off restart of mechanical ventilation for more than 24 hours. The average gestational age of the enrolled neonates was 26 weeks, their average weight was 700 g, and intubation started an average of 3 hours after delivery.
The study’s primary endpoint, age at first successful extubation, was an average of 24 days among the neonates treated with caffeine and 20 days in those on placebo, Dr. Amaro reported. Mortality occurred at an average of 30 days after delivery in the caffeine recipients and after an average of 10 days in the controls. The incidence of death was 22% in those on early caffeine and 12% among those in the placebo group, an excess of four deaths in the intervention arm that was not statically significant.
A recent review of more than 29,000 matched very-low-birth-weight infants managed in routine practice showed that neonates who received early caffeine had an adjusted mortality risk that was 23% higher than that of matched infants not receiving early caffeine, Dr. Amaro noted (J Pediatrics. 2014 May;164[5]:992-8).
The incidence of bronchopulmonary dysplasia also did not show a statistically significant difference between the two study arms, 46% among those on early caffeine and 53% in the placebo group. Patients on early caffeine also had higher rates of necrotizing enterocolitis, more episodes of necrotizing enterocolitis requiring surgery, and more intraventricular hemorrhages, but none of these differences reached statistical significance.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Dr. Susan Millard, FCCP, comments: Apnea of prematurity is a very common occurrence. We are excited to have new data but I am in agreement that a larger multicenter study is extremely important before instituting a protocol change.
Dr. Susan Millard, FCCP, comments: Apnea of prematurity is a very common occurrence. We are excited to have new data but I am in agreement that a larger multicenter study is extremely important before instituting a protocol change.
Dr. Susan Millard, FCCP, comments: Apnea of prematurity is a very common occurrence. We are excited to have new data but I am in agreement that a larger multicenter study is extremely important before instituting a protocol change.
BALTIMORE – Early initiation of caffeine treatment in premature neonates on mechanical ventilation did not cut the time to when these babies could successfully wean off the ventilator, according to findings of a single-center, randomized controlled study of 83 children.
The results also showed an “unexpected” trend toward increased mortality among the neonates who received early caffeine treatment, Dr. Cynthia M. Amaro reported at the annual meeting of the Pediatric Academic Societies. This signal of elevated mortality with caffeine treatment prompted the study’s data and safety monitoring board to prematurely stop the trial, limiting enrollment to just 75% of the number originally planned in the study’s design, thereby raising questions about the reliability of the primary-endpoint finding that early caffeine treatment did not result in the benefit of a reduced time to extubation.
Dr. Amaro said that she and her associates ran the study to address what had emerged as a significant area of doubt in routine U.S. practice on how to best use caffeine treatment in this neonatal population following publication of findings from the landmark Caffeine for Apnea of Prematurity (CAP) Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Results from the CAP Trial had shown in nearly 2,000 randomized, premature infants that treatment with caffeine led to significantly fewer episodes of bronchopulmonary dysplasia as well as quicker time to extubation of mechanical ventilation. Caffeine or other methylxanthines stimulate an infant’s respiratory center to allow faster extubation.
Ever since that publication a decade ago, “clinicians have been using caffeine earlier and more liberally, without really good data to support its early use in mechanically-ventilated preterm babies,” explained Dr. Amaro, a neonatologist at the University of Miami and Holtz Children’s Hospital in Miami.
Based on the new findings from the study she reported, “we are now not routinely initiating caffeine in mechanically ventilated preterm babies and just using caffeine immediately before extubation to treat apnea of prematurity. This returns caffeine treatment to the way it was used in the CAP Trial,” she said. “Further studies are needed before we can say what is best for early treatment of these preterm babies,” Dr. Amaro said in a video interview.
Her report led to a flurry of comments during the question period, with several pediatricians voicing concern about the reliability of results from a study that followed only 83 patients because of its premature termination.
“The data and safety monitoring board’s decision is a big issue,” said Dr. Carl E. Hunt, a pediatrician at the Uniformed Services University of the Health Sciences in Bethesda, Md. “There is a literature that shows results of studies can be very different when they stop early. It’s unfortunate because we don’t have other prospective data, and it may now be hard to do a large randomized, controlled trial” of early caffeine treatment, Dr. Hunt said.
While Dr. Amaro conceded that premature termination limited her study’s size, she also asserted that her analyses confirmed the validity of the finding of no benefit from early caffeine treatment. “We projected to full enrollment, and there still was no difference in the time to first successful extubation,” she said.
Her study enrolled preterm infants during January 2013–December 2015 born at 23-30 weeks’ gestation who required mechanical ventilation during their first 5 days. Randomization assigned 41 infants to receive a 20-mg/kg bolus of caffeine, followed by a maintenance dosage of 5 mg/kg that continued until extubation, while 42 patients received placebo and did not get caffeine until just before attempted extubation. The bolus and maintenance caffeine dosages tested were identical to those used in the CAP Trial.
The researchers defined successful extubation as keeping a child off restart of mechanical ventilation for more than 24 hours. The average gestational age of the enrolled neonates was 26 weeks, their average weight was 700 g, and intubation started an average of 3 hours after delivery.
The study’s primary endpoint, age at first successful extubation, was an average of 24 days among the neonates treated with caffeine and 20 days in those on placebo, Dr. Amaro reported. Mortality occurred at an average of 30 days after delivery in the caffeine recipients and after an average of 10 days in the controls. The incidence of death was 22% in those on early caffeine and 12% among those in the placebo group, an excess of four deaths in the intervention arm that was not statically significant.
A recent review of more than 29,000 matched very-low-birth-weight infants managed in routine practice showed that neonates who received early caffeine had an adjusted mortality risk that was 23% higher than that of matched infants not receiving early caffeine, Dr. Amaro noted (J Pediatrics. 2014 May;164[5]:992-8).
The incidence of bronchopulmonary dysplasia also did not show a statistically significant difference between the two study arms, 46% among those on early caffeine and 53% in the placebo group. Patients on early caffeine also had higher rates of necrotizing enterocolitis, more episodes of necrotizing enterocolitis requiring surgery, and more intraventricular hemorrhages, but none of these differences reached statistical significance.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
BALTIMORE – Early initiation of caffeine treatment in premature neonates on mechanical ventilation did not cut the time to when these babies could successfully wean off the ventilator, according to findings of a single-center, randomized controlled study of 83 children.
The results also showed an “unexpected” trend toward increased mortality among the neonates who received early caffeine treatment, Dr. Cynthia M. Amaro reported at the annual meeting of the Pediatric Academic Societies. This signal of elevated mortality with caffeine treatment prompted the study’s data and safety monitoring board to prematurely stop the trial, limiting enrollment to just 75% of the number originally planned in the study’s design, thereby raising questions about the reliability of the primary-endpoint finding that early caffeine treatment did not result in the benefit of a reduced time to extubation.
Dr. Amaro said that she and her associates ran the study to address what had emerged as a significant area of doubt in routine U.S. practice on how to best use caffeine treatment in this neonatal population following publication of findings from the landmark Caffeine for Apnea of Prematurity (CAP) Trial (N Engl J Med. 2006 May 18;354[20]:2112-21). Results from the CAP Trial had shown in nearly 2,000 randomized, premature infants that treatment with caffeine led to significantly fewer episodes of bronchopulmonary dysplasia as well as quicker time to extubation of mechanical ventilation. Caffeine or other methylxanthines stimulate an infant’s respiratory center to allow faster extubation.
Ever since that publication a decade ago, “clinicians have been using caffeine earlier and more liberally, without really good data to support its early use in mechanically-ventilated preterm babies,” explained Dr. Amaro, a neonatologist at the University of Miami and Holtz Children’s Hospital in Miami.
Based on the new findings from the study she reported, “we are now not routinely initiating caffeine in mechanically ventilated preterm babies and just using caffeine immediately before extubation to treat apnea of prematurity. This returns caffeine treatment to the way it was used in the CAP Trial,” she said. “Further studies are needed before we can say what is best for early treatment of these preterm babies,” Dr. Amaro said in a video interview.
Her report led to a flurry of comments during the question period, with several pediatricians voicing concern about the reliability of results from a study that followed only 83 patients because of its premature termination.
“The data and safety monitoring board’s decision is a big issue,” said Dr. Carl E. Hunt, a pediatrician at the Uniformed Services University of the Health Sciences in Bethesda, Md. “There is a literature that shows results of studies can be very different when they stop early. It’s unfortunate because we don’t have other prospective data, and it may now be hard to do a large randomized, controlled trial” of early caffeine treatment, Dr. Hunt said.
While Dr. Amaro conceded that premature termination limited her study’s size, she also asserted that her analyses confirmed the validity of the finding of no benefit from early caffeine treatment. “We projected to full enrollment, and there still was no difference in the time to first successful extubation,” she said.
Her study enrolled preterm infants during January 2013–December 2015 born at 23-30 weeks’ gestation who required mechanical ventilation during their first 5 days. Randomization assigned 41 infants to receive a 20-mg/kg bolus of caffeine, followed by a maintenance dosage of 5 mg/kg that continued until extubation, while 42 patients received placebo and did not get caffeine until just before attempted extubation. The bolus and maintenance caffeine dosages tested were identical to those used in the CAP Trial.
The researchers defined successful extubation as keeping a child off restart of mechanical ventilation for more than 24 hours. The average gestational age of the enrolled neonates was 26 weeks, their average weight was 700 g, and intubation started an average of 3 hours after delivery.
The study’s primary endpoint, age at first successful extubation, was an average of 24 days among the neonates treated with caffeine and 20 days in those on placebo, Dr. Amaro reported. Mortality occurred at an average of 30 days after delivery in the caffeine recipients and after an average of 10 days in the controls. The incidence of death was 22% in those on early caffeine and 12% among those in the placebo group, an excess of four deaths in the intervention arm that was not statically significant.
A recent review of more than 29,000 matched very-low-birth-weight infants managed in routine practice showed that neonates who received early caffeine had an adjusted mortality risk that was 23% higher than that of matched infants not receiving early caffeine, Dr. Amaro noted (J Pediatrics. 2014 May;164[5]:992-8).
The incidence of bronchopulmonary dysplasia also did not show a statistically significant difference between the two study arms, 46% among those on early caffeine and 53% in the placebo group. Patients on early caffeine also had higher rates of necrotizing enterocolitis, more episodes of necrotizing enterocolitis requiring surgery, and more intraventricular hemorrhages, but none of these differences reached statistical significance.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Implanted phrenic-nerve stimulator improves central sleep apnea
FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.
Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.
This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.
Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.
The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled.
Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.
Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.
The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.
But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.
“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”
Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”
She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.
Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.
The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m2.
In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.
Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
 |
| Dr. David Schulman |
Dr. David A. Schulman, FCCP, comments: Phrenic nerve and diaphragmatic pacing have historically been used in patients with respiratory failure due to neuromuscular disease to decrease the need for mechanical ventilation. Its role in the management of central sleep apnea, however, remains unclear. It is certainly unsurprising that the frequency of central sleep apnea events improves with phrenic nerve pacing. It is also encouraging that a subjective benefit to sleep quality results from such therapy. That noted, improvement in sleep quality does not necessarily predict improvement in health. While central sleep apnea has been associated with worsened outcome in several disease states, there is no evidence to date that treatment of the sleep-disordered breathing helps to improve those outcomes. Until such evidence exists, it may be difficult to justify an invasive surgical intervention to treat central sleep apnea.
|
| Dr. David Schulman |
Dr. David A. Schulman, FCCP, comments: Phrenic nerve and diaphragmatic pacing have historically been used in patients with respiratory failure due to neuromuscular disease to decrease the need for mechanical ventilation. Its role in the management of central sleep apnea, however, remains unclear. It is certainly unsurprising that the frequency of central sleep apnea events improves with phrenic nerve pacing. It is also encouraging that a subjective benefit to sleep quality results from such therapy. That noted, improvement in sleep quality does not necessarily predict improvement in health. While central sleep apnea has been associated with worsened outcome in several disease states, there is no evidence to date that treatment of the sleep-disordered breathing helps to improve those outcomes. Until such evidence exists, it may be difficult to justify an invasive surgical intervention to treat central sleep apnea.
|
| Dr. David Schulman |
Dr. David A. Schulman, FCCP, comments: Phrenic nerve and diaphragmatic pacing have historically been used in patients with respiratory failure due to neuromuscular disease to decrease the need for mechanical ventilation. Its role in the management of central sleep apnea, however, remains unclear. It is certainly unsurprising that the frequency of central sleep apnea events improves with phrenic nerve pacing. It is also encouraging that a subjective benefit to sleep quality results from such therapy. That noted, improvement in sleep quality does not necessarily predict improvement in health. While central sleep apnea has been associated with worsened outcome in several disease states, there is no evidence to date that treatment of the sleep-disordered breathing helps to improve those outcomes. Until such evidence exists, it may be difficult to justify an invasive surgical intervention to treat central sleep apnea.
FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.
Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.
This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.
Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.
The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled.
Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.
Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.
The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.
But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.
“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”
Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”
She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.
Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.
The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m2.
In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.
Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.
Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.
This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.
Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.
The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled.
Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.
Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.
The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.
But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.
“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”
Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”
She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.
Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.
The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m2.
In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.
Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT HEART FAILURE 2016
Hydroxychloroquine, abatacept linked with reduced type 2 diabetes
LONDON – U.S. rheumatoid arthritis patients had a significantly reduced incidence of type 2 diabetes when on treatment with either hydroxychloroquine or abatacept in an analysis of more than 13,000 patients enrolled in a U.S. national registry during 2000-2015.
The same analysis also showed statistically significant increases in the risk for new-onset type 2 diabetes in rheumatoid arthritis (RA) patients treated with a glucocorticoid or a statin, Kaleb Michaud, Ph.D., reported in a poster at the European Congress of Rheumatology.
“Our findings can inform clinicians about determining appropriate treatment decisions in rheumatoid arthritis patients at increased risk for developing type 2 diabetes,” said Dr. Michaud, an epidemiologist at the University of Nebraska in Omaha and also codirector of the National Data Bank for Rheumatic Diseases in Wichita, Kan., the source of the data used in his study.
Hydroxychloroquine, a relatively inexpensive drug that’s often used in RA patients in combination with other drugs, might be a good agent to consider adding to the therapeutic mix of RA patients at risk for developing type 2 diabetes, he said in an interview. Although the implications of this finding for the use of abatacept (Orencia) are less clear, it is a signal of a novel benefit from the drug that merits further study, Dr. Michaud said.
The findings also suggest that, when rheumatoid arthritis patients receive statin treatment, they are candidates for more intensive monitoring of diabetes onset, he added.
His analysis focused on the 13,669 RA patients who participated in the National Data Bank for Rheumatic Diseases for at least a year during 2000-2015 and had not been diagnosed as having diabetes of any type at the time they entered the registry. During a median 4.6 years of follow-up, 1,139 patients either self-reported receiving a new diagnosis of type 2 diabetes or began treatment with a hypoglycemic medication. Patients averaged about 59 years old at the time they entered the registry, and about 80% were women.
Dr. Michaud and his associates assessed the incidence rate of type 2 diabetes according to six categories of RA treatment: methotrexate monotherapy, which they used as the reference group; any treatment with abatacept with or without methotrexate; any treatment with hydroxychloroquine; any treatment with a glucocorticoid; treatment with any other disease-modifying antirheumatic drug (DMARD) with methotrexate; and treatment with any other DMARD without methotrexate or no DMARD treatment. A seventh treatment category was treatment with a statin.
A series of time-varying Cox proportional hazard models that adjusted for sociodemographic variables, comorbidities, body mass index, and measures of RA severity showed that, when compared with methotrexate monotherapy, patients treated with abatacept had a statistically significant 48% reduced rate of developing diabetes, and those treated with hydroxychloroquine had a statistically significant 33% reduced diabetes incidence, they reported.
In contrast, compared with methotrexate monotherapy, treatment with a glucocorticoid linked with a statistically significant 31% increased rate of type 2 diabetes, and treatment with a statin linked with a statistically significant 56% increased rate of diabetes. Other forms of DMARD treatment, including tumor necrosis factor inhibitors and other biologic DMARDs, had no statistically significant link with diabetes development.
Dr. Michaud also reported additional analyses that further defined the associations between hydroxychloroquine treatment and reduced diabetes incidence: The reduction in diabetes incidence became statistically significant in patients only when they had received the drug for at least 2 years. The link with reduced diabetes incidence seemed dose dependent, with a stronger protective effect in patients who received at least 400 mg/day. Also, the strength of the protection waned in patients who had discontinued hydroxychloroquine for at least 6 months, and the protective effect completely disappeared once patients were off hydroxychloroquine for at least 1 year. Finally, the link between hydroxychloroquine use and reduced diabetes incidence also was statistically significant in patients who concurrently received a glucocorticoid, but a significant protective association disappeared in patients who received a statin as well as hydroxychloroquine.
Dr. Michaud had no disclosures. The study received no commercial support.
On Twitter @mitchelzoler
LONDON – U.S. rheumatoid arthritis patients had a significantly reduced incidence of type 2 diabetes when on treatment with either hydroxychloroquine or abatacept in an analysis of more than 13,000 patients enrolled in a U.S. national registry during 2000-2015.
The same analysis also showed statistically significant increases in the risk for new-onset type 2 diabetes in rheumatoid arthritis (RA) patients treated with a glucocorticoid or a statin, Kaleb Michaud, Ph.D., reported in a poster at the European Congress of Rheumatology.
“Our findings can inform clinicians about determining appropriate treatment decisions in rheumatoid arthritis patients at increased risk for developing type 2 diabetes,” said Dr. Michaud, an epidemiologist at the University of Nebraska in Omaha and also codirector of the National Data Bank for Rheumatic Diseases in Wichita, Kan., the source of the data used in his study.
Hydroxychloroquine, a relatively inexpensive drug that’s often used in RA patients in combination with other drugs, might be a good agent to consider adding to the therapeutic mix of RA patients at risk for developing type 2 diabetes, he said in an interview. Although the implications of this finding for the use of abatacept (Orencia) are less clear, it is a signal of a novel benefit from the drug that merits further study, Dr. Michaud said.
The findings also suggest that, when rheumatoid arthritis patients receive statin treatment, they are candidates for more intensive monitoring of diabetes onset, he added.
His analysis focused on the 13,669 RA patients who participated in the National Data Bank for Rheumatic Diseases for at least a year during 2000-2015 and had not been diagnosed as having diabetes of any type at the time they entered the registry. During a median 4.6 years of follow-up, 1,139 patients either self-reported receiving a new diagnosis of type 2 diabetes or began treatment with a hypoglycemic medication. Patients averaged about 59 years old at the time they entered the registry, and about 80% were women.
Dr. Michaud and his associates assessed the incidence rate of type 2 diabetes according to six categories of RA treatment: methotrexate monotherapy, which they used as the reference group; any treatment with abatacept with or without methotrexate; any treatment with hydroxychloroquine; any treatment with a glucocorticoid; treatment with any other disease-modifying antirheumatic drug (DMARD) with methotrexate; and treatment with any other DMARD without methotrexate or no DMARD treatment. A seventh treatment category was treatment with a statin.
A series of time-varying Cox proportional hazard models that adjusted for sociodemographic variables, comorbidities, body mass index, and measures of RA severity showed that, when compared with methotrexate monotherapy, patients treated with abatacept had a statistically significant 48% reduced rate of developing diabetes, and those treated with hydroxychloroquine had a statistically significant 33% reduced diabetes incidence, they reported.
In contrast, compared with methotrexate monotherapy, treatment with a glucocorticoid linked with a statistically significant 31% increased rate of type 2 diabetes, and treatment with a statin linked with a statistically significant 56% increased rate of diabetes. Other forms of DMARD treatment, including tumor necrosis factor inhibitors and other biologic DMARDs, had no statistically significant link with diabetes development.
Dr. Michaud also reported additional analyses that further defined the associations between hydroxychloroquine treatment and reduced diabetes incidence: The reduction in diabetes incidence became statistically significant in patients only when they had received the drug for at least 2 years. The link with reduced diabetes incidence seemed dose dependent, with a stronger protective effect in patients who received at least 400 mg/day. Also, the strength of the protection waned in patients who had discontinued hydroxychloroquine for at least 6 months, and the protective effect completely disappeared once patients were off hydroxychloroquine for at least 1 year. Finally, the link between hydroxychloroquine use and reduced diabetes incidence also was statistically significant in patients who concurrently received a glucocorticoid, but a significant protective association disappeared in patients who received a statin as well as hydroxychloroquine.
Dr. Michaud had no disclosures. The study received no commercial support.
On Twitter @mitchelzoler
LONDON – U.S. rheumatoid arthritis patients had a significantly reduced incidence of type 2 diabetes when on treatment with either hydroxychloroquine or abatacept in an analysis of more than 13,000 patients enrolled in a U.S. national registry during 2000-2015.
The same analysis also showed statistically significant increases in the risk for new-onset type 2 diabetes in rheumatoid arthritis (RA) patients treated with a glucocorticoid or a statin, Kaleb Michaud, Ph.D., reported in a poster at the European Congress of Rheumatology.
“Our findings can inform clinicians about determining appropriate treatment decisions in rheumatoid arthritis patients at increased risk for developing type 2 diabetes,” said Dr. Michaud, an epidemiologist at the University of Nebraska in Omaha and also codirector of the National Data Bank for Rheumatic Diseases in Wichita, Kan., the source of the data used in his study.
Hydroxychloroquine, a relatively inexpensive drug that’s often used in RA patients in combination with other drugs, might be a good agent to consider adding to the therapeutic mix of RA patients at risk for developing type 2 diabetes, he said in an interview. Although the implications of this finding for the use of abatacept (Orencia) are less clear, it is a signal of a novel benefit from the drug that merits further study, Dr. Michaud said.
The findings also suggest that, when rheumatoid arthritis patients receive statin treatment, they are candidates for more intensive monitoring of diabetes onset, he added.
His analysis focused on the 13,669 RA patients who participated in the National Data Bank for Rheumatic Diseases for at least a year during 2000-2015 and had not been diagnosed as having diabetes of any type at the time they entered the registry. During a median 4.6 years of follow-up, 1,139 patients either self-reported receiving a new diagnosis of type 2 diabetes or began treatment with a hypoglycemic medication. Patients averaged about 59 years old at the time they entered the registry, and about 80% were women.
Dr. Michaud and his associates assessed the incidence rate of type 2 diabetes according to six categories of RA treatment: methotrexate monotherapy, which they used as the reference group; any treatment with abatacept with or without methotrexate; any treatment with hydroxychloroquine; any treatment with a glucocorticoid; treatment with any other disease-modifying antirheumatic drug (DMARD) with methotrexate; and treatment with any other DMARD without methotrexate or no DMARD treatment. A seventh treatment category was treatment with a statin.
A series of time-varying Cox proportional hazard models that adjusted for sociodemographic variables, comorbidities, body mass index, and measures of RA severity showed that, when compared with methotrexate monotherapy, patients treated with abatacept had a statistically significant 48% reduced rate of developing diabetes, and those treated with hydroxychloroquine had a statistically significant 33% reduced diabetes incidence, they reported.
In contrast, compared with methotrexate monotherapy, treatment with a glucocorticoid linked with a statistically significant 31% increased rate of type 2 diabetes, and treatment with a statin linked with a statistically significant 56% increased rate of diabetes. Other forms of DMARD treatment, including tumor necrosis factor inhibitors and other biologic DMARDs, had no statistically significant link with diabetes development.
Dr. Michaud also reported additional analyses that further defined the associations between hydroxychloroquine treatment and reduced diabetes incidence: The reduction in diabetes incidence became statistically significant in patients only when they had received the drug for at least 2 years. The link with reduced diabetes incidence seemed dose dependent, with a stronger protective effect in patients who received at least 400 mg/day. Also, the strength of the protection waned in patients who had discontinued hydroxychloroquine for at least 6 months, and the protective effect completely disappeared once patients were off hydroxychloroquine for at least 1 year. Finally, the link between hydroxychloroquine use and reduced diabetes incidence also was statistically significant in patients who concurrently received a glucocorticoid, but a significant protective association disappeared in patients who received a statin as well as hydroxychloroquine.
Dr. Michaud had no disclosures. The study received no commercial support.
On Twitter @mitchelzoler
AT THE EULAR 2016 CONGRESS
Key clinical point: U.S. rheumatoid arthritis patients on hydroxychloroquine or abatacept had a significantly reduced incidence of type 2 diabetes, compared with patients on methotrexate monotherapy.
Major finding: Hydroxychloroquine cut type 2 diabetes incidence by 33% and abatacept cut it by 48%, compared with patients on methotrexate monotherapy.
Data source: Analysis of data collected from 13,669 U.S. rheumatoid arthritis patients enrolled in a registry during 2000-2015.
Disclosures: Dr. Michaud had no disclosures. The study received no commercial support.
Secukinumab may slow structural ankylosing spondylitis progression
LONDON – Long-term treatment with the interleukin 17A inhibitor secukinumab showed suggestive evidence of inhibiting structural progression of spinal disease in 168 patients with ankylosing spondylitis, the first time any evidence for an effect like this has been seen with a biologic drug or any other agent used to treat ankylosing spondylitis.
However, the effect occurred in uncontrolled, 2-year open-label treatment of patients originally enrolled in one of the secukinumab pivotal trials, and the analysis did not include comparison against a historical control group, caveats that demand confirmation of this effect in additional studies, Dr. Jürgen Braun said at the European Congress of Rheumatology.
In a second, unrelated study, the oral Janus kinase inhibitor tofacitinib showed promising efficacy for controlling clinical symptoms in patients with active ankylosing spondylitis (AS) during 12 weeks of treatment in a placebo-controlled, dose-ranging phase II study.
The open-label secukinumab extension study involved patients who had been enrolled in the MEASURE 1 study, one of the pivotal trials that had established secukinumab as safe and effective for improving the clinical status of patients with active AS. The primary endpoint of MEASURE 1 had been the percentage of patients achieving at least a 20% improvement in their Assessment of Spondyloarthritis international Society (ASAS20) response after 16 weeks of treatment (New Engl J Med. 2015 Dec 24;373[26]:2534-48).
Based in part on these data the Food and Drug Administration approved secukinumab (Cosentyx) for the treatment of ankylosing spondylitis in January 2016. The new data reported by Dr. Braun assessed the level of spinal pathology in a subgroup of the MEASURE 1 patients when measured by radiography using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at baseline and after 104 weeks on secukinumab treatment.
Patients in MEASURE 1 who began on active treatment received 10 mg/kg intravenous secukinumab for 4 weeks, followed by subcutaneous dosages of either 75 mg or 150 mg every 4 weeks for 104 weeks. His analysis also included some patients who entered MEASURE 1 in the placebo group and then switched to open-label, subcutaneous secukinumab treatment after 16 or 24 weeks on placebo.
Analysis of 168 patients who started on intravenous secukinumab and later received any subcutaneous secukinumab treatment out to 104 weeks showed an average increase in mSASSS of 0.30 after 104 weeks when compared against their baseline scores, reported Dr. Braun, professor and medical director of the Ruhr Rheumatology Center of the University of Bochum, Germany.
Among an additional 89 patients who began in the placebo group and then switched to subcutaneous secukinumab, the average change in mSASSS from baseline to 104 weeks was 0.54. By comparison, Dr. Braun noted that AS patients treated with a tumor necrosis factor inhibitor have shown 2-year progression in their mSASSS of about 0.8-0.9, and AS patients not treated with an active biologic drug have shown 2-year mSASSS progression of about 1.0.
A second analysis of the data reported by Dr. Braun showed that among the 168 patients treated for the full 104 weeks with secukinumab about 80% showed no mSASSS progression, but about 20% did have some level of detectable mSASSS progression.
The phase II study of tofacitinib (Xeljanz) randomized 208 patients with active AS to either tofacitinib at daily dosages of 2 mg bid, 5 mg bid, 10 mg bid, or placebo. The study’s primary endpoint was their ASAS20 response after 12 weeks that underwent a Bayesian Emax model analysis to estimate incremental efficacy when compared against placebo.
The primary efficacy analysis showed the greatest EmaxASAS20 response among patients treated with 5 mg bid daily, 63%, which was about 23% above the placebo level, reportedDr. Désirée van der Heijde, professor of rheumatology at the Leiden University Medical Center, The Netherlands. The absolute ASAS20 response rate of the 52 patients randomized to this tofacitinib dosage was about 81%, about 40% higher than the response rate seen in the 51 patients in the placebo arm.
All dosages of tofacitinib tested were well tolerated, with safety data similar to what has previously been shown for tofacitinib, a drug that has Food and Drug Administration approval for treating rheumatoid arthritis.
On Twitter @mitchelzoler
The results on radiographic progression in ankylosing spondylitis patients who continued on secukinumab treatment for 104 weeks suggest for the first time that a biologic drug can reduce radiographic progression of ankylosing spondylitis. This effect has not been seen in patients treated with a tumor necrosis factor inhibitor. The results showed that roughly 80% of the patients maintained for 2 years on secukinumab did not have radiographic progression, although the results also showed that about 20% of these patients did have detectable radiographic progression.
This analysis has several limitations and caveats. The study did not include a control group, not even a historical control group, and it involved open-label treatment. In addition, the treatment effect observed was very close to the level of a measurement error. It would help to compare these results with a historic control group, or to run a new study that compares the effect of secukinumab on long-term radiographic progression directly with the effect of treatment with a tumor necrosis factor inhibitor.
Because of these limitations the results of this analysis are of limited immediate value. Prior results have shown that clinically the efficacy of secukinumab for treating ankylosing spondylitis is more or less the same as the efficacy of various tumor necrosis factor inhibitors. If an additional effect from secukinumab on slowing radiographic progression in these patients were proven, it would be of clear added value, but further study is needed to show this.
The phase II study assessing the impact of tofacitinib, an oral Janus kinase inhibitor, on the clinical activity of ankylosing spondylitis shows promise for this drug in this setting. Currently, the only biologic drugs with proven activity in patients with ankylosing spondylitis are tumor necrosis factor inhibitors and the interleukin 17A inhibitor secukinumab. The data reported by Dr. van der Heijde show that tofacitinib is a good candidate to move to a phase III trial. In this phase II trial the activity seen with 5 mg bid of tofacitinib for reducing disease activity was more or less the same as has been seen with other active biologic drugs.
Dr. Denis Poddubnyy is a professor of rheumatology and head of rheumatology at the Benjamin Franklin campus of Charité Medical University in Berlin. He made these comments in an interview. He has been a consultant to Novartis and to Pfizer and to several other drug companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The results on radiographic progression in ankylosing spondylitis patients who continued on secukinumab treatment for 104 weeks suggest for the first time that a biologic drug can reduce radiographic progression of ankylosing spondylitis. This effect has not been seen in patients treated with a tumor necrosis factor inhibitor. The results showed that roughly 80% of the patients maintained for 2 years on secukinumab did not have radiographic progression, although the results also showed that about 20% of these patients did have detectable radiographic progression.
This analysis has several limitations and caveats. The study did not include a control group, not even a historical control group, and it involved open-label treatment. In addition, the treatment effect observed was very close to the level of a measurement error. It would help to compare these results with a historic control group, or to run a new study that compares the effect of secukinumab on long-term radiographic progression directly with the effect of treatment with a tumor necrosis factor inhibitor.
Because of these limitations the results of this analysis are of limited immediate value. Prior results have shown that clinically the efficacy of secukinumab for treating ankylosing spondylitis is more or less the same as the efficacy of various tumor necrosis factor inhibitors. If an additional effect from secukinumab on slowing radiographic progression in these patients were proven, it would be of clear added value, but further study is needed to show this.
The phase II study assessing the impact of tofacitinib, an oral Janus kinase inhibitor, on the clinical activity of ankylosing spondylitis shows promise for this drug in this setting. Currently, the only biologic drugs with proven activity in patients with ankylosing spondylitis are tumor necrosis factor inhibitors and the interleukin 17A inhibitor secukinumab. The data reported by Dr. van der Heijde show that tofacitinib is a good candidate to move to a phase III trial. In this phase II trial the activity seen with 5 mg bid of tofacitinib for reducing disease activity was more or less the same as has been seen with other active biologic drugs.
Dr. Denis Poddubnyy is a professor of rheumatology and head of rheumatology at the Benjamin Franklin campus of Charité Medical University in Berlin. He made these comments in an interview. He has been a consultant to Novartis and to Pfizer and to several other drug companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The results on radiographic progression in ankylosing spondylitis patients who continued on secukinumab treatment for 104 weeks suggest for the first time that a biologic drug can reduce radiographic progression of ankylosing spondylitis. This effect has not been seen in patients treated with a tumor necrosis factor inhibitor. The results showed that roughly 80% of the patients maintained for 2 years on secukinumab did not have radiographic progression, although the results also showed that about 20% of these patients did have detectable radiographic progression.
This analysis has several limitations and caveats. The study did not include a control group, not even a historical control group, and it involved open-label treatment. In addition, the treatment effect observed was very close to the level of a measurement error. It would help to compare these results with a historic control group, or to run a new study that compares the effect of secukinumab on long-term radiographic progression directly with the effect of treatment with a tumor necrosis factor inhibitor.
Because of these limitations the results of this analysis are of limited immediate value. Prior results have shown that clinically the efficacy of secukinumab for treating ankylosing spondylitis is more or less the same as the efficacy of various tumor necrosis factor inhibitors. If an additional effect from secukinumab on slowing radiographic progression in these patients were proven, it would be of clear added value, but further study is needed to show this.
The phase II study assessing the impact of tofacitinib, an oral Janus kinase inhibitor, on the clinical activity of ankylosing spondylitis shows promise for this drug in this setting. Currently, the only biologic drugs with proven activity in patients with ankylosing spondylitis are tumor necrosis factor inhibitors and the interleukin 17A inhibitor secukinumab. The data reported by Dr. van der Heijde show that tofacitinib is a good candidate to move to a phase III trial. In this phase II trial the activity seen with 5 mg bid of tofacitinib for reducing disease activity was more or less the same as has been seen with other active biologic drugs.
Dr. Denis Poddubnyy is a professor of rheumatology and head of rheumatology at the Benjamin Franklin campus of Charité Medical University in Berlin. He made these comments in an interview. He has been a consultant to Novartis and to Pfizer and to several other drug companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
LONDON – Long-term treatment with the interleukin 17A inhibitor secukinumab showed suggestive evidence of inhibiting structural progression of spinal disease in 168 patients with ankylosing spondylitis, the first time any evidence for an effect like this has been seen with a biologic drug or any other agent used to treat ankylosing spondylitis.
However, the effect occurred in uncontrolled, 2-year open-label treatment of patients originally enrolled in one of the secukinumab pivotal trials, and the analysis did not include comparison against a historical control group, caveats that demand confirmation of this effect in additional studies, Dr. Jürgen Braun said at the European Congress of Rheumatology.
In a second, unrelated study, the oral Janus kinase inhibitor tofacitinib showed promising efficacy for controlling clinical symptoms in patients with active ankylosing spondylitis (AS) during 12 weeks of treatment in a placebo-controlled, dose-ranging phase II study.
The open-label secukinumab extension study involved patients who had been enrolled in the MEASURE 1 study, one of the pivotal trials that had established secukinumab as safe and effective for improving the clinical status of patients with active AS. The primary endpoint of MEASURE 1 had been the percentage of patients achieving at least a 20% improvement in their Assessment of Spondyloarthritis international Society (ASAS20) response after 16 weeks of treatment (New Engl J Med. 2015 Dec 24;373[26]:2534-48).
Based in part on these data the Food and Drug Administration approved secukinumab (Cosentyx) for the treatment of ankylosing spondylitis in January 2016. The new data reported by Dr. Braun assessed the level of spinal pathology in a subgroup of the MEASURE 1 patients when measured by radiography using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at baseline and after 104 weeks on secukinumab treatment.
Patients in MEASURE 1 who began on active treatment received 10 mg/kg intravenous secukinumab for 4 weeks, followed by subcutaneous dosages of either 75 mg or 150 mg every 4 weeks for 104 weeks. His analysis also included some patients who entered MEASURE 1 in the placebo group and then switched to open-label, subcutaneous secukinumab treatment after 16 or 24 weeks on placebo.
Analysis of 168 patients who started on intravenous secukinumab and later received any subcutaneous secukinumab treatment out to 104 weeks showed an average increase in mSASSS of 0.30 after 104 weeks when compared against their baseline scores, reported Dr. Braun, professor and medical director of the Ruhr Rheumatology Center of the University of Bochum, Germany.
Among an additional 89 patients who began in the placebo group and then switched to subcutaneous secukinumab, the average change in mSASSS from baseline to 104 weeks was 0.54. By comparison, Dr. Braun noted that AS patients treated with a tumor necrosis factor inhibitor have shown 2-year progression in their mSASSS of about 0.8-0.9, and AS patients not treated with an active biologic drug have shown 2-year mSASSS progression of about 1.0.
A second analysis of the data reported by Dr. Braun showed that among the 168 patients treated for the full 104 weeks with secukinumab about 80% showed no mSASSS progression, but about 20% did have some level of detectable mSASSS progression.
The phase II study of tofacitinib (Xeljanz) randomized 208 patients with active AS to either tofacitinib at daily dosages of 2 mg bid, 5 mg bid, 10 mg bid, or placebo. The study’s primary endpoint was their ASAS20 response after 12 weeks that underwent a Bayesian Emax model analysis to estimate incremental efficacy when compared against placebo.
The primary efficacy analysis showed the greatest EmaxASAS20 response among patients treated with 5 mg bid daily, 63%, which was about 23% above the placebo level, reportedDr. Désirée van der Heijde, professor of rheumatology at the Leiden University Medical Center, The Netherlands. The absolute ASAS20 response rate of the 52 patients randomized to this tofacitinib dosage was about 81%, about 40% higher than the response rate seen in the 51 patients in the placebo arm.
All dosages of tofacitinib tested were well tolerated, with safety data similar to what has previously been shown for tofacitinib, a drug that has Food and Drug Administration approval for treating rheumatoid arthritis.
On Twitter @mitchelzoler
LONDON – Long-term treatment with the interleukin 17A inhibitor secukinumab showed suggestive evidence of inhibiting structural progression of spinal disease in 168 patients with ankylosing spondylitis, the first time any evidence for an effect like this has been seen with a biologic drug or any other agent used to treat ankylosing spondylitis.
However, the effect occurred in uncontrolled, 2-year open-label treatment of patients originally enrolled in one of the secukinumab pivotal trials, and the analysis did not include comparison against a historical control group, caveats that demand confirmation of this effect in additional studies, Dr. Jürgen Braun said at the European Congress of Rheumatology.
In a second, unrelated study, the oral Janus kinase inhibitor tofacitinib showed promising efficacy for controlling clinical symptoms in patients with active ankylosing spondylitis (AS) during 12 weeks of treatment in a placebo-controlled, dose-ranging phase II study.
The open-label secukinumab extension study involved patients who had been enrolled in the MEASURE 1 study, one of the pivotal trials that had established secukinumab as safe and effective for improving the clinical status of patients with active AS. The primary endpoint of MEASURE 1 had been the percentage of patients achieving at least a 20% improvement in their Assessment of Spondyloarthritis international Society (ASAS20) response after 16 weeks of treatment (New Engl J Med. 2015 Dec 24;373[26]:2534-48).
Based in part on these data the Food and Drug Administration approved secukinumab (Cosentyx) for the treatment of ankylosing spondylitis in January 2016. The new data reported by Dr. Braun assessed the level of spinal pathology in a subgroup of the MEASURE 1 patients when measured by radiography using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at baseline and after 104 weeks on secukinumab treatment.
Patients in MEASURE 1 who began on active treatment received 10 mg/kg intravenous secukinumab for 4 weeks, followed by subcutaneous dosages of either 75 mg or 150 mg every 4 weeks for 104 weeks. His analysis also included some patients who entered MEASURE 1 in the placebo group and then switched to open-label, subcutaneous secukinumab treatment after 16 or 24 weeks on placebo.
Analysis of 168 patients who started on intravenous secukinumab and later received any subcutaneous secukinumab treatment out to 104 weeks showed an average increase in mSASSS of 0.30 after 104 weeks when compared against their baseline scores, reported Dr. Braun, professor and medical director of the Ruhr Rheumatology Center of the University of Bochum, Germany.
Among an additional 89 patients who began in the placebo group and then switched to subcutaneous secukinumab, the average change in mSASSS from baseline to 104 weeks was 0.54. By comparison, Dr. Braun noted that AS patients treated with a tumor necrosis factor inhibitor have shown 2-year progression in their mSASSS of about 0.8-0.9, and AS patients not treated with an active biologic drug have shown 2-year mSASSS progression of about 1.0.
A second analysis of the data reported by Dr. Braun showed that among the 168 patients treated for the full 104 weeks with secukinumab about 80% showed no mSASSS progression, but about 20% did have some level of detectable mSASSS progression.
The phase II study of tofacitinib (Xeljanz) randomized 208 patients with active AS to either tofacitinib at daily dosages of 2 mg bid, 5 mg bid, 10 mg bid, or placebo. The study’s primary endpoint was their ASAS20 response after 12 weeks that underwent a Bayesian Emax model analysis to estimate incremental efficacy when compared against placebo.
The primary efficacy analysis showed the greatest EmaxASAS20 response among patients treated with 5 mg bid daily, 63%, which was about 23% above the placebo level, reportedDr. Désirée van der Heijde, professor of rheumatology at the Leiden University Medical Center, The Netherlands. The absolute ASAS20 response rate of the 52 patients randomized to this tofacitinib dosage was about 81%, about 40% higher than the response rate seen in the 51 patients in the placebo arm.
All dosages of tofacitinib tested were well tolerated, with safety data similar to what has previously been shown for tofacitinib, a drug that has Food and Drug Administration approval for treating rheumatoid arthritis.
On Twitter @mitchelzoler
AT THE EULAR 2016 CONGRESS
Key clinical point: Ankylosing spondylitis patients maintained on open-label secukinumab treatment for 2 years showed a low level of structural spinal progression in an uncontrolled study. Also, in a placebo-controlled phase II study, 12 weeks’ treatment of patients with active ankylosing spondylitis with 5 mg tofacitinib bid led to significant clinical responses, compared with placebo.
Major finding: Little to no radiographic progression occurred in about 80% of ankylosing spondylitis patients maintained on secukinumab for 104 weeks.
Data source: The secukinumab study involved an open-label, nonrandomized extension of treatment in 168 of the 371 patients originally enrolled in MEASURE 1. The tofacitinib study included 208 patients.
Disclosures: Patients in the secukinumab study had been enrolled in MEASURE 1, a study sponsored by Novartis, the company that markets secukinumab (Cosentyx). Dr. Braun has been a consultant to Novartis, and several other drug companies, and three of his coauthors are Novartis employees. The tofacitinib study was sponsored by Pfizer, the company that markets tofacitinib (Xeljanz). Dr. van der Heijde has been a consultant to Pfizer and several other drug companies, and five of her coauthors are Pfizer employees.
New heart failure interventions face outcomes test
A history of trials where a well-reasoned heart failure intervention did not have the expected results is now coloring the way some clinicians view potential new treatments.
A couple of examples of this cautious, skeptical mindset cropped up during the annual meeting of the Heart Failure Association of the European Society of Cardiology in Florence, Italy, in May.
I previously reported on one of the major talks at the sessions, results from a pivotal trial of a phrenic nerve stimulation device in 151 patients with some type of cardiovascular disease (more than half had heart failure) and central sleep apnea. These patients generally had significant improvement in their apnea-hypopnea index while on active treatment with the phrenic nerve stimulator, designed to produce rhythmic contractions of the diaphragm to create negative chest pressure and enhance breathing in a way that mimics natural respiration and avoids the apparent danger from a positive-pressure intervention in patients with central sleep apnea and heart failure with reduced ejection fraction (HFrEF).
The positive-pressure danger in such patients occurred unexpectedly and dramatically in the form of significantly increased mortality among HFrEF patients with central sleep apnea enrolled in the SERVE-HF trial. Based on that chilling experience, “our understanding of central sleep apnea is imperfect,” said Dr. Martin R. Cowie, lead investigator of SERVE-HF, who rehashed his experience with that study during the recent meeting. “A really important message was that just because patients say they feel better [with the adaptive servo-ventilation tested in SERVE-HF], that doesn’t necessarily translate into benefit,” Dr. Cowie noted.
Dr. Mariell L. Jessup, a leading U.S. heart failure expert, had a similar reaction when I spoke with her during the meeting.
“A lot of things made a lot of sense, including treating central sleep apnea in a patient with HFrEF with positive air pressure that made them feel better,” she said, also invoking the specter of SERVE-HF. “We have to now demand that sleep trials show benefit in clinical outcomes,” such as reduced mortality or a cut in heart failure hospitalizations, and certainly no increase in mortality. Until that’s shown for phrenic nerve stimulation she’ll stay a skeptic, she told me.
Another intervention recently available for U.S. heart failure patients that seems on track to confront this “show-me-the-outcomes” attitude involves new drugs that cut serum potassium levels by binding to potassium in the gastrointestinal tract. This class includes patiromer (Veltassa), approved by the Food and Drug Administration in October 2015. Another potassium binder, sodium zirconium cyclosilicate (ZS-9), seems on track to soon receive FDA approval.
Several speakers at the meeting spoke of the potential to use these drugs to control the hyperkalemia that often complicates treatment of heart failure patients with an ACE inhibitor, angiotensin receptor blocker, or a mineralocorticoid receptor antagonist, especially heart failure patients with concomitant renal disease. Study results showed treatment with patiromer or ZS-9 reversed hyperkalemia, thereby allowing patients to remain on these drugs that are known to significantly cut rates of mortality and heart failure hospitalizations in heart failure patients.
“Right now, a lot of patients don’t get these lifesaving drugs” because of hyperkalemia, noted Dr. Bertram Pitt, a University of Michigan cardiologist who has been involved in several patiromer trials (and is a consultant to Relypsa, the company that markets patiromer).
The problem is that no studies of patiromer or ZS-9 treatment have so far shown that these drugs lead to reduced mortality or heart failure hospitalizations in heart failure patients. All that’s been shown is that patiromer and ZS-9 are effective at lowering potassium levels in patients with hyperkalemia out of the danger zone, levels above 5 mEq/L.
“I want to see outcome trials,” said Dr. Jessup.
Dr. Pitt agreed that outcomes data would be ideal, but also noted that currently no studies aimed at collecting these data are underway.
Without these data, clinicians need to decide whether they believe proven potassium lowering alone is a good enough reason to prescribe patiromer or ZS-9, or whether they need to see proof that these drugs give patients clinically meaningful benefits.
If they demand outcomes evidence they may need to wait quite a while.
On Twitter @mitchelzoler
A history of trials where a well-reasoned heart failure intervention did not have the expected results is now coloring the way some clinicians view potential new treatments.
A couple of examples of this cautious, skeptical mindset cropped up during the annual meeting of the Heart Failure Association of the European Society of Cardiology in Florence, Italy, in May.
I previously reported on one of the major talks at the sessions, results from a pivotal trial of a phrenic nerve stimulation device in 151 patients with some type of cardiovascular disease (more than half had heart failure) and central sleep apnea. These patients generally had significant improvement in their apnea-hypopnea index while on active treatment with the phrenic nerve stimulator, designed to produce rhythmic contractions of the diaphragm to create negative chest pressure and enhance breathing in a way that mimics natural respiration and avoids the apparent danger from a positive-pressure intervention in patients with central sleep apnea and heart failure with reduced ejection fraction (HFrEF).
The positive-pressure danger in such patients occurred unexpectedly and dramatically in the form of significantly increased mortality among HFrEF patients with central sleep apnea enrolled in the SERVE-HF trial. Based on that chilling experience, “our understanding of central sleep apnea is imperfect,” said Dr. Martin R. Cowie, lead investigator of SERVE-HF, who rehashed his experience with that study during the recent meeting. “A really important message was that just because patients say they feel better [with the adaptive servo-ventilation tested in SERVE-HF], that doesn’t necessarily translate into benefit,” Dr. Cowie noted.
Dr. Mariell L. Jessup, a leading U.S. heart failure expert, had a similar reaction when I spoke with her during the meeting.
“A lot of things made a lot of sense, including treating central sleep apnea in a patient with HFrEF with positive air pressure that made them feel better,” she said, also invoking the specter of SERVE-HF. “We have to now demand that sleep trials show benefit in clinical outcomes,” such as reduced mortality or a cut in heart failure hospitalizations, and certainly no increase in mortality. Until that’s shown for phrenic nerve stimulation she’ll stay a skeptic, she told me.
Another intervention recently available for U.S. heart failure patients that seems on track to confront this “show-me-the-outcomes” attitude involves new drugs that cut serum potassium levels by binding to potassium in the gastrointestinal tract. This class includes patiromer (Veltassa), approved by the Food and Drug Administration in October 2015. Another potassium binder, sodium zirconium cyclosilicate (ZS-9), seems on track to soon receive FDA approval.
Several speakers at the meeting spoke of the potential to use these drugs to control the hyperkalemia that often complicates treatment of heart failure patients with an ACE inhibitor, angiotensin receptor blocker, or a mineralocorticoid receptor antagonist, especially heart failure patients with concomitant renal disease. Study results showed treatment with patiromer or ZS-9 reversed hyperkalemia, thereby allowing patients to remain on these drugs that are known to significantly cut rates of mortality and heart failure hospitalizations in heart failure patients.
“Right now, a lot of patients don’t get these lifesaving drugs” because of hyperkalemia, noted Dr. Bertram Pitt, a University of Michigan cardiologist who has been involved in several patiromer trials (and is a consultant to Relypsa, the company that markets patiromer).
The problem is that no studies of patiromer or ZS-9 treatment have so far shown that these drugs lead to reduced mortality or heart failure hospitalizations in heart failure patients. All that’s been shown is that patiromer and ZS-9 are effective at lowering potassium levels in patients with hyperkalemia out of the danger zone, levels above 5 mEq/L.
“I want to see outcome trials,” said Dr. Jessup.
Dr. Pitt agreed that outcomes data would be ideal, but also noted that currently no studies aimed at collecting these data are underway.
Without these data, clinicians need to decide whether they believe proven potassium lowering alone is a good enough reason to prescribe patiromer or ZS-9, or whether they need to see proof that these drugs give patients clinically meaningful benefits.
If they demand outcomes evidence they may need to wait quite a while.
On Twitter @mitchelzoler
A history of trials where a well-reasoned heart failure intervention did not have the expected results is now coloring the way some clinicians view potential new treatments.
A couple of examples of this cautious, skeptical mindset cropped up during the annual meeting of the Heart Failure Association of the European Society of Cardiology in Florence, Italy, in May.
I previously reported on one of the major talks at the sessions, results from a pivotal trial of a phrenic nerve stimulation device in 151 patients with some type of cardiovascular disease (more than half had heart failure) and central sleep apnea. These patients generally had significant improvement in their apnea-hypopnea index while on active treatment with the phrenic nerve stimulator, designed to produce rhythmic contractions of the diaphragm to create negative chest pressure and enhance breathing in a way that mimics natural respiration and avoids the apparent danger from a positive-pressure intervention in patients with central sleep apnea and heart failure with reduced ejection fraction (HFrEF).
The positive-pressure danger in such patients occurred unexpectedly and dramatically in the form of significantly increased mortality among HFrEF patients with central sleep apnea enrolled in the SERVE-HF trial. Based on that chilling experience, “our understanding of central sleep apnea is imperfect,” said Dr. Martin R. Cowie, lead investigator of SERVE-HF, who rehashed his experience with that study during the recent meeting. “A really important message was that just because patients say they feel better [with the adaptive servo-ventilation tested in SERVE-HF], that doesn’t necessarily translate into benefit,” Dr. Cowie noted.
Dr. Mariell L. Jessup, a leading U.S. heart failure expert, had a similar reaction when I spoke with her during the meeting.
“A lot of things made a lot of sense, including treating central sleep apnea in a patient with HFrEF with positive air pressure that made them feel better,” she said, also invoking the specter of SERVE-HF. “We have to now demand that sleep trials show benefit in clinical outcomes,” such as reduced mortality or a cut in heart failure hospitalizations, and certainly no increase in mortality. Until that’s shown for phrenic nerve stimulation she’ll stay a skeptic, she told me.
Another intervention recently available for U.S. heart failure patients that seems on track to confront this “show-me-the-outcomes” attitude involves new drugs that cut serum potassium levels by binding to potassium in the gastrointestinal tract. This class includes patiromer (Veltassa), approved by the Food and Drug Administration in October 2015. Another potassium binder, sodium zirconium cyclosilicate (ZS-9), seems on track to soon receive FDA approval.
Several speakers at the meeting spoke of the potential to use these drugs to control the hyperkalemia that often complicates treatment of heart failure patients with an ACE inhibitor, angiotensin receptor blocker, or a mineralocorticoid receptor antagonist, especially heart failure patients with concomitant renal disease. Study results showed treatment with patiromer or ZS-9 reversed hyperkalemia, thereby allowing patients to remain on these drugs that are known to significantly cut rates of mortality and heart failure hospitalizations in heart failure patients.
“Right now, a lot of patients don’t get these lifesaving drugs” because of hyperkalemia, noted Dr. Bertram Pitt, a University of Michigan cardiologist who has been involved in several patiromer trials (and is a consultant to Relypsa, the company that markets patiromer).
The problem is that no studies of patiromer or ZS-9 treatment have so far shown that these drugs lead to reduced mortality or heart failure hospitalizations in heart failure patients. All that’s been shown is that patiromer and ZS-9 are effective at lowering potassium levels in patients with hyperkalemia out of the danger zone, levels above 5 mEq/L.
“I want to see outcome trials,” said Dr. Jessup.
Dr. Pitt agreed that outcomes data would be ideal, but also noted that currently no studies aimed at collecting these data are underway.
Without these data, clinicians need to decide whether they believe proven potassium lowering alone is a good enough reason to prescribe patiromer or ZS-9, or whether they need to see proof that these drugs give patients clinically meaningful benefits.
If they demand outcomes evidence they may need to wait quite a while.
On Twitter @mitchelzoler
Exercise training cuts heart failure mortality
FLORENCE, ITALY – Exercise training boosts the longevity of patients with heart failure.
Although results from several prior randomized, controlled trials had already shown a mortality benefit from exercise training for heart failure patients, these findings have now been confirmed by a meta-analysis that used the original, individual patient raw data collected in 20 separate randomized, controlled trials that together involved more than 4,000 patients. The results showed that an exercise-training intervention run for at least 3 weeks produced a statistically significant, relative reduction in all-cause mortality of 18%, compared with similar patients who had been randomized to usual care without an exercise program, Oriana Ciani, Ph.D., reported at a meeting held by the Heart Failure Association of the European Society of Cardiology.
The individual patient data meta-analysis using results from randomized, controlled trials also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization in heart failure patients during at least 6 months’ follow-up of exercise programs that lasted for at least 3 weeks, said Dr. Ciani, a health technology researcher at the University of Exeter (England).
Her analysis also showed no suggestion of heterogeneity for each of these two beneficial effects from exercise programs, regardless of patients’ age, sex, or baseline levels of left ventricular ejection fraction, heart failure etiology, functional status, or exercise capacity. “No evidence was found to support a differential treatment effect from exercise-based intervention across patient subgroups,” she said.
The Exercise Training for Chronic Heart Failure (ExTraMATCH II) meta-analysis used data collected in randomized trials published through 2014 that involved at least 50 patients, used an exercise intervention for at least 3 weeks, and had follow-up for at least 6 months. Dr. Ciani and her associates identified 20 studies that included a total of 4,043 heart failure patients who fulfilled these criteria and for whom the researchers from the studies were willing to share individual patient data.
The analysis also showed a median time to all-cause mortality of 605 days among patients who received exercise training and 615 days in the controls, and a median time to first all-cause hospitalization of 229 days with exercise training and 241 days in the controls. The percentage of patients who were hospitalized during follow-up was reduced by an absolute 3.8% for those in the exercise group, compared with the controls.
Although the type of exercise intervention used varied among the 20 studies, most involved aerobic training, and some also used resistance training, Dr. Ciani said. She said she plans additional analyses of the data she has collected to examine the impact of exercise in heart failure patients on cardiovascular mortality, heart failure hospitalization, and a combined endpoint of all-cause death and all-cause hospitalization.
On Twitter @mitchelzoler
These results are a step forward in confirming the safety and efficacy of exercise training for heart failure patients. It is a good addition to the literature. Its strength is its use of an analysis of individual patient data.
 |
Dr. Theresa A. McDonagh |
The findings deliver the important message that exercise rehabilitation is important for all heart failure patients. Currently, uptake of such programs is low, involving about 20% of heart failure patients.
The analysis showed a consistent effect from exercise training across all subgroups examined. The actual reductions in adverse outcomes were meaningful, with a 2% absolute reduction in all-cause mortality and a nearly 4% absolute reduction in all-cause hospitalization. However, the findings do not tell us which type of exercise prescription works best. Future research needs to especially focus on patients with heart failure with preserved ejection fraction to determine whether exercise benefits this particular type of heart failure patient.
Dr. Theresa A. McDonagh is a professor of heart failure at King’s College, London. She made these comments as the designated discussant for the study. She had no relevant financial disclosures.
These results are a step forward in confirming the safety and efficacy of exercise training for heart failure patients. It is a good addition to the literature. Its strength is its use of an analysis of individual patient data.
|
Dr. Theresa A. McDonagh |
The findings deliver the important message that exercise rehabilitation is important for all heart failure patients. Currently, uptake of such programs is low, involving about 20% of heart failure patients.
The analysis showed a consistent effect from exercise training across all subgroups examined. The actual reductions in adverse outcomes were meaningful, with a 2% absolute reduction in all-cause mortality and a nearly 4% absolute reduction in all-cause hospitalization. However, the findings do not tell us which type of exercise prescription works best. Future research needs to especially focus on patients with heart failure with preserved ejection fraction to determine whether exercise benefits this particular type of heart failure patient.
Dr. Theresa A. McDonagh is a professor of heart failure at King’s College, London. She made these comments as the designated discussant for the study. She had no relevant financial disclosures.
These results are a step forward in confirming the safety and efficacy of exercise training for heart failure patients. It is a good addition to the literature. Its strength is its use of an analysis of individual patient data.
|
Dr. Theresa A. McDonagh |
The findings deliver the important message that exercise rehabilitation is important for all heart failure patients. Currently, uptake of such programs is low, involving about 20% of heart failure patients.
The analysis showed a consistent effect from exercise training across all subgroups examined. The actual reductions in adverse outcomes were meaningful, with a 2% absolute reduction in all-cause mortality and a nearly 4% absolute reduction in all-cause hospitalization. However, the findings do not tell us which type of exercise prescription works best. Future research needs to especially focus on patients with heart failure with preserved ejection fraction to determine whether exercise benefits this particular type of heart failure patient.
Dr. Theresa A. McDonagh is a professor of heart failure at King’s College, London. She made these comments as the designated discussant for the study. She had no relevant financial disclosures.
FLORENCE, ITALY – Exercise training boosts the longevity of patients with heart failure.
Although results from several prior randomized, controlled trials had already shown a mortality benefit from exercise training for heart failure patients, these findings have now been confirmed by a meta-analysis that used the original, individual patient raw data collected in 20 separate randomized, controlled trials that together involved more than 4,000 patients. The results showed that an exercise-training intervention run for at least 3 weeks produced a statistically significant, relative reduction in all-cause mortality of 18%, compared with similar patients who had been randomized to usual care without an exercise program, Oriana Ciani, Ph.D., reported at a meeting held by the Heart Failure Association of the European Society of Cardiology.
The individual patient data meta-analysis using results from randomized, controlled trials also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization in heart failure patients during at least 6 months’ follow-up of exercise programs that lasted for at least 3 weeks, said Dr. Ciani, a health technology researcher at the University of Exeter (England).
Her analysis also showed no suggestion of heterogeneity for each of these two beneficial effects from exercise programs, regardless of patients’ age, sex, or baseline levels of left ventricular ejection fraction, heart failure etiology, functional status, or exercise capacity. “No evidence was found to support a differential treatment effect from exercise-based intervention across patient subgroups,” she said.
The Exercise Training for Chronic Heart Failure (ExTraMATCH II) meta-analysis used data collected in randomized trials published through 2014 that involved at least 50 patients, used an exercise intervention for at least 3 weeks, and had follow-up for at least 6 months. Dr. Ciani and her associates identified 20 studies that included a total of 4,043 heart failure patients who fulfilled these criteria and for whom the researchers from the studies were willing to share individual patient data.
The analysis also showed a median time to all-cause mortality of 605 days among patients who received exercise training and 615 days in the controls, and a median time to first all-cause hospitalization of 229 days with exercise training and 241 days in the controls. The percentage of patients who were hospitalized during follow-up was reduced by an absolute 3.8% for those in the exercise group, compared with the controls.
Although the type of exercise intervention used varied among the 20 studies, most involved aerobic training, and some also used resistance training, Dr. Ciani said. She said she plans additional analyses of the data she has collected to examine the impact of exercise in heart failure patients on cardiovascular mortality, heart failure hospitalization, and a combined endpoint of all-cause death and all-cause hospitalization.
On Twitter @mitchelzoler
FLORENCE, ITALY – Exercise training boosts the longevity of patients with heart failure.
Although results from several prior randomized, controlled trials had already shown a mortality benefit from exercise training for heart failure patients, these findings have now been confirmed by a meta-analysis that used the original, individual patient raw data collected in 20 separate randomized, controlled trials that together involved more than 4,000 patients. The results showed that an exercise-training intervention run for at least 3 weeks produced a statistically significant, relative reduction in all-cause mortality of 18%, compared with similar patients who had been randomized to usual care without an exercise program, Oriana Ciani, Ph.D., reported at a meeting held by the Heart Failure Association of the European Society of Cardiology.
The individual patient data meta-analysis using results from randomized, controlled trials also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization in heart failure patients during at least 6 months’ follow-up of exercise programs that lasted for at least 3 weeks, said Dr. Ciani, a health technology researcher at the University of Exeter (England).
Her analysis also showed no suggestion of heterogeneity for each of these two beneficial effects from exercise programs, regardless of patients’ age, sex, or baseline levels of left ventricular ejection fraction, heart failure etiology, functional status, or exercise capacity. “No evidence was found to support a differential treatment effect from exercise-based intervention across patient subgroups,” she said.
The Exercise Training for Chronic Heart Failure (ExTraMATCH II) meta-analysis used data collected in randomized trials published through 2014 that involved at least 50 patients, used an exercise intervention for at least 3 weeks, and had follow-up for at least 6 months. Dr. Ciani and her associates identified 20 studies that included a total of 4,043 heart failure patients who fulfilled these criteria and for whom the researchers from the studies were willing to share individual patient data.
The analysis also showed a median time to all-cause mortality of 605 days among patients who received exercise training and 615 days in the controls, and a median time to first all-cause hospitalization of 229 days with exercise training and 241 days in the controls. The percentage of patients who were hospitalized during follow-up was reduced by an absolute 3.8% for those in the exercise group, compared with the controls.
Although the type of exercise intervention used varied among the 20 studies, most involved aerobic training, and some also used resistance training, Dr. Ciani said. She said she plans additional analyses of the data she has collected to examine the impact of exercise in heart failure patients on cardiovascular mortality, heart failure hospitalization, and a combined endpoint of all-cause death and all-cause hospitalization.
On Twitter @mitchelzoler
AT HEART FAILURE 2016
Key clinical point: A meta-analysis of 20 randomized controlled studies confirmed that an exercise training intervention in heart failure patients significantly reduces mortality and hospitalizations.
Major finding: All-cause mortality fell by a relative 18% in heart failure patients who underwent exercise training, compared with controls.
Data source: Individual patient data meta-analysis for 4,043 patients from 20 studies.
Disclosures: Dr. Ciani had no relevant financial disclosures.
Flu Vaccination Cut Hospitalizations in Heart Failure Patients
FLORENCE, ITALY – Influenza vaccination of heart failure patients cut their rate of hospitalization for cardiovascular disease by nearly a third during the year following vaccination in a study of more than 59,000 British heart failure patients.
Influenza vaccination of heart failure patients also cut their rate of hospitalization for respiratory infections by a statistically significant 16% during the year following vaccination, Dr. Kazem Rahimi said at a meeting held by the Heart Failure Association of the ESC.
“In the absence of randomized trials, this [observational] study of 59,202 heart failure patients provides the most compelling evidence to date for the protective effect of influenza vaccination on hospital admissions,” said Dr. Rahimi, a cardiologist and epidemiologist who is deputy director of the George Institute for Global Health at the University of Oxford (England).
The analysis also showed that influenza vaccination of heart failure patients had no significant effect on all-cause hospitalizations.
Dr. Rahimi and his associates analyzed electronic health records from primary and secondary care settings in England during 1990-2013, from which they identified 59,202 heart failure patients with records for at least 1 year of influenza vaccination and at least 1 year without vaccination. The patients averaged 75 years old and were divided equally among women and men.
To control for potential confounding factors, they used a self-control model in which hospitalizations for each heart failure patient during the year following an influenza vaccination were compared with an adjacent year for that same patient when no vaccination occurred.
The results showed that the incidence of hospitalizations for cardiovascular diseases fell by a statistically significant 30% in the year following an influenza vaccination, compared with one or more adjacent years without vaccination. The protection again hospitalization was strongest during the second month following vaccination and then gradually waned over the ensuing year; by about 10 months following vaccination the protection effect had disappeared.
The study also looked at influenza vaccine uptake by heart failure patients through the 24-year period examined. During that time, the vaccination uptake rate rose from a low of less than 10% in 1990 to a peak rate of just over 60% in 2006, after which the rate gradually declined to a rate of just under 50% in 2013. Dr. Rahimi attributed the rise in uptake during the period from 1990 to 2006 in part to incentives that primary care physicians in England began receiving to administer influenza vaccine to their patients. “Higher uptake of annual vaccination in heart failure patients may help alleviate the burden of influenza-related hospital admissions,” he said.
Dr. Rahimi had no disclosures.
The main problem with observational studies is confounding, and the observational studies done until now that had looked at the protective role of influenza vaccination in heart failure patients had not been very convincing. Dr. Rahimi and his associates performed a high-quality study that adds to the evidence and underlines recommendations for influenza vaccination of heart failure patients. Their study was very large, and it used a self-control approach to adjust for potential confounding. I think they did their best to eliminate confounding.
 |
Dr. Arno W. Hoes |
The newly released, updated guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure recommend annual vaccination of heart failure patients against influenza and pneumococcal disease. The data reported by Dr. Rahimi also document that only about half of heart failure patients in England currently receive an annual influenza vaccine. That percentage needs to increase.
Dr. Arno W. Hoes is professor of clinical epidemiology at the University Medical Center in Utrecht, the Netherlands. He made these comments as designated discussant for the study. He had no disclosures.
The main problem with observational studies is confounding, and the observational studies done until now that had looked at the protective role of influenza vaccination in heart failure patients had not been very convincing. Dr. Rahimi and his associates performed a high-quality study that adds to the evidence and underlines recommendations for influenza vaccination of heart failure patients. Their study was very large, and it used a self-control approach to adjust for potential confounding. I think they did their best to eliminate confounding.
|
Dr. Arno W. Hoes |
The newly released, updated guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure recommend annual vaccination of heart failure patients against influenza and pneumococcal disease. The data reported by Dr. Rahimi also document that only about half of heart failure patients in England currently receive an annual influenza vaccine. That percentage needs to increase.
Dr. Arno W. Hoes is professor of clinical epidemiology at the University Medical Center in Utrecht, the Netherlands. He made these comments as designated discussant for the study. He had no disclosures.
The main problem with observational studies is confounding, and the observational studies done until now that had looked at the protective role of influenza vaccination in heart failure patients had not been very convincing. Dr. Rahimi and his associates performed a high-quality study that adds to the evidence and underlines recommendations for influenza vaccination of heart failure patients. Their study was very large, and it used a self-control approach to adjust for potential confounding. I think they did their best to eliminate confounding.
|
Dr. Arno W. Hoes |
The newly released, updated guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure recommend annual vaccination of heart failure patients against influenza and pneumococcal disease. The data reported by Dr. Rahimi also document that only about half of heart failure patients in England currently receive an annual influenza vaccine. That percentage needs to increase.
Dr. Arno W. Hoes is professor of clinical epidemiology at the University Medical Center in Utrecht, the Netherlands. He made these comments as designated discussant for the study. He had no disclosures.
FLORENCE, ITALY – Influenza vaccination of heart failure patients cut their rate of hospitalization for cardiovascular disease by nearly a third during the year following vaccination in a study of more than 59,000 British heart failure patients.
Influenza vaccination of heart failure patients also cut their rate of hospitalization for respiratory infections by a statistically significant 16% during the year following vaccination, Dr. Kazem Rahimi said at a meeting held by the Heart Failure Association of the ESC.
“In the absence of randomized trials, this [observational] study of 59,202 heart failure patients provides the most compelling evidence to date for the protective effect of influenza vaccination on hospital admissions,” said Dr. Rahimi, a cardiologist and epidemiologist who is deputy director of the George Institute for Global Health at the University of Oxford (England).
The analysis also showed that influenza vaccination of heart failure patients had no significant effect on all-cause hospitalizations.
Dr. Rahimi and his associates analyzed electronic health records from primary and secondary care settings in England during 1990-2013, from which they identified 59,202 heart failure patients with records for at least 1 year of influenza vaccination and at least 1 year without vaccination. The patients averaged 75 years old and were divided equally among women and men.
To control for potential confounding factors, they used a self-control model in which hospitalizations for each heart failure patient during the year following an influenza vaccination were compared with an adjacent year for that same patient when no vaccination occurred.
The results showed that the incidence of hospitalizations for cardiovascular diseases fell by a statistically significant 30% in the year following an influenza vaccination, compared with one or more adjacent years without vaccination. The protection again hospitalization was strongest during the second month following vaccination and then gradually waned over the ensuing year; by about 10 months following vaccination the protection effect had disappeared.
The study also looked at influenza vaccine uptake by heart failure patients through the 24-year period examined. During that time, the vaccination uptake rate rose from a low of less than 10% in 1990 to a peak rate of just over 60% in 2006, after which the rate gradually declined to a rate of just under 50% in 2013. Dr. Rahimi attributed the rise in uptake during the period from 1990 to 2006 in part to incentives that primary care physicians in England began receiving to administer influenza vaccine to their patients. “Higher uptake of annual vaccination in heart failure patients may help alleviate the burden of influenza-related hospital admissions,” he said.
Dr. Rahimi had no disclosures.
FLORENCE, ITALY – Influenza vaccination of heart failure patients cut their rate of hospitalization for cardiovascular disease by nearly a third during the year following vaccination in a study of more than 59,000 British heart failure patients.
Influenza vaccination of heart failure patients also cut their rate of hospitalization for respiratory infections by a statistically significant 16% during the year following vaccination, Dr. Kazem Rahimi said at a meeting held by the Heart Failure Association of the ESC.
“In the absence of randomized trials, this [observational] study of 59,202 heart failure patients provides the most compelling evidence to date for the protective effect of influenza vaccination on hospital admissions,” said Dr. Rahimi, a cardiologist and epidemiologist who is deputy director of the George Institute for Global Health at the University of Oxford (England).
The analysis also showed that influenza vaccination of heart failure patients had no significant effect on all-cause hospitalizations.
Dr. Rahimi and his associates analyzed electronic health records from primary and secondary care settings in England during 1990-2013, from which they identified 59,202 heart failure patients with records for at least 1 year of influenza vaccination and at least 1 year without vaccination. The patients averaged 75 years old and were divided equally among women and men.
To control for potential confounding factors, they used a self-control model in which hospitalizations for each heart failure patient during the year following an influenza vaccination were compared with an adjacent year for that same patient when no vaccination occurred.
The results showed that the incidence of hospitalizations for cardiovascular diseases fell by a statistically significant 30% in the year following an influenza vaccination, compared with one or more adjacent years without vaccination. The protection again hospitalization was strongest during the second month following vaccination and then gradually waned over the ensuing year; by about 10 months following vaccination the protection effect had disappeared.
The study also looked at influenza vaccine uptake by heart failure patients through the 24-year period examined. During that time, the vaccination uptake rate rose from a low of less than 10% in 1990 to a peak rate of just over 60% in 2006, after which the rate gradually declined to a rate of just under 50% in 2013. Dr. Rahimi attributed the rise in uptake during the period from 1990 to 2006 in part to incentives that primary care physicians in England began receiving to administer influenza vaccine to their patients. “Higher uptake of annual vaccination in heart failure patients may help alleviate the burden of influenza-related hospital admissions,” he said.
Dr. Rahimi had no disclosures.
AT HEART FAILURE 2016
Flu vaccination cut hospitalizations in heart failure patients
FLORENCE, ITALY – Influenza vaccination of heart failure patients cut their rate of hospitalization for cardiovascular disease by nearly a third during the year following vaccination in a study of more than 59,000 British heart failure patients.
Influenza vaccination of heart failure patients also cut their rate of hospitalization for respiratory infections by a statistically significant 16% during the year following vaccination, Dr. Kazem Rahimi said at a meeting held by the Heart Failure Association of the ESC.
“In the absence of randomized trials, this [observational] study of 59,202 heart failure patients provides the most compelling evidence to date for the protective effect of influenza vaccination on hospital admissions,” said Dr. Rahimi, a cardiologist and epidemiologist who is deputy director of the George Institute for Global Health at the University of Oxford (England).
The analysis also showed that influenza vaccination of heart failure patients had no significant effect on all-cause hospitalizations.
Dr. Rahimi and his associates analyzed electronic health records from primary and secondary care settings in England during 1990-2013, from which they identified 59,202 heart failure patients with records for at least 1 year of influenza vaccination and at least 1 year without vaccination. The patients averaged 75 years old and were divided equally among women and men.
To control for potential confounding factors, they used a self-control model in which hospitalizations for each heart failure patient during the year following an influenza vaccination were compared with an adjacent year for that same patient when no vaccination occurred.
The results showed that the incidence of hospitalizations for cardiovascular diseases fell by a statistically significant 30% in the year following an influenza vaccination, compared with one or more adjacent years without vaccination. The protection again hospitalization was strongest during the second month following vaccination and then gradually waned over the ensuing year; by about 10 months following vaccination the protection effect had disappeared.
The study also looked at influenza vaccine uptake by heart failure patients through the 24-year period examined. During that time, the vaccination uptake rate rose from a low of less than 10% in 1990 to a peak rate of just over 60% in 2006, after which the rate gradually declined to a rate of just under 50% in 2013. Dr. Rahimi attributed the rise in uptake during the period from 1990 to 2006 in part to incentives that primary care physicians in England began receiving to administer influenza vaccine to their patients. “Higher uptake of annual vaccination in heart failure patients may help alleviate the burden of influenza-related hospital admissions,” he said.
Dr. Rahimi had no disclosures.
On Twitter @mitchelzoler
The main problem with observational studies is confounding, and the observational studies done until now that had looked at the protective role of influenza vaccination in heart failure patients had not been very convincing. Dr. Rahimi and his associates performed a high-quality study that adds to the evidence and underlines recommendations for influenza vaccination of heart failure patients. Their study was very large, and it used a self-control approach to adjust for potential confounding. I think they did their best to eliminate confounding.
|
Dr. Arno W. Hoes |
The newly released, updated guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure recommend annual vaccination of heart failure patients against influenza and pneumococcal disease. The data reported by Dr. Rahimi also document that only about half of heart failure patients in England currently receive an annual influenza vaccine. That percentage needs to increase.
Dr. Arno W. Hoes is professor of clinical epidemiology at the University Medical Center in Utrecht, the Netherlands. He made these comments as designated discussant for the study. He had no disclosures.
The main problem with observational studies is confounding, and the observational studies done until now that had looked at the protective role of influenza vaccination in heart failure patients had not been very convincing. Dr. Rahimi and his associates performed a high-quality study that adds to the evidence and underlines recommendations for influenza vaccination of heart failure patients. Their study was very large, and it used a self-control approach to adjust for potential confounding. I think they did their best to eliminate confounding.
|
Dr. Arno W. Hoes |
The newly released, updated guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure recommend annual vaccination of heart failure patients against influenza and pneumococcal disease. The data reported by Dr. Rahimi also document that only about half of heart failure patients in England currently receive an annual influenza vaccine. That percentage needs to increase.
Dr. Arno W. Hoes is professor of clinical epidemiology at the University Medical Center in Utrecht, the Netherlands. He made these comments as designated discussant for the study. He had no disclosures.
The main problem with observational studies is confounding, and the observational studies done until now that had looked at the protective role of influenza vaccination in heart failure patients had not been very convincing. Dr. Rahimi and his associates performed a high-quality study that adds to the evidence and underlines recommendations for influenza vaccination of heart failure patients. Their study was very large, and it used a self-control approach to adjust for potential confounding. I think they did their best to eliminate confounding.
|
Dr. Arno W. Hoes |
The newly released, updated guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure recommend annual vaccination of heart failure patients against influenza and pneumococcal disease. The data reported by Dr. Rahimi also document that only about half of heart failure patients in England currently receive an annual influenza vaccine. That percentage needs to increase.
Dr. Arno W. Hoes is professor of clinical epidemiology at the University Medical Center in Utrecht, the Netherlands. He made these comments as designated discussant for the study. He had no disclosures.
FLORENCE, ITALY – Influenza vaccination of heart failure patients cut their rate of hospitalization for cardiovascular disease by nearly a third during the year following vaccination in a study of more than 59,000 British heart failure patients.
Influenza vaccination of heart failure patients also cut their rate of hospitalization for respiratory infections by a statistically significant 16% during the year following vaccination, Dr. Kazem Rahimi said at a meeting held by the Heart Failure Association of the ESC.
“In the absence of randomized trials, this [observational] study of 59,202 heart failure patients provides the most compelling evidence to date for the protective effect of influenza vaccination on hospital admissions,” said Dr. Rahimi, a cardiologist and epidemiologist who is deputy director of the George Institute for Global Health at the University of Oxford (England).
The analysis also showed that influenza vaccination of heart failure patients had no significant effect on all-cause hospitalizations.
Dr. Rahimi and his associates analyzed electronic health records from primary and secondary care settings in England during 1990-2013, from which they identified 59,202 heart failure patients with records for at least 1 year of influenza vaccination and at least 1 year without vaccination. The patients averaged 75 years old and were divided equally among women and men.
To control for potential confounding factors, they used a self-control model in which hospitalizations for each heart failure patient during the year following an influenza vaccination were compared with an adjacent year for that same patient when no vaccination occurred.
The results showed that the incidence of hospitalizations for cardiovascular diseases fell by a statistically significant 30% in the year following an influenza vaccination, compared with one or more adjacent years without vaccination. The protection again hospitalization was strongest during the second month following vaccination and then gradually waned over the ensuing year; by about 10 months following vaccination the protection effect had disappeared.
The study also looked at influenza vaccine uptake by heart failure patients through the 24-year period examined. During that time, the vaccination uptake rate rose from a low of less than 10% in 1990 to a peak rate of just over 60% in 2006, after which the rate gradually declined to a rate of just under 50% in 2013. Dr. Rahimi attributed the rise in uptake during the period from 1990 to 2006 in part to incentives that primary care physicians in England began receiving to administer influenza vaccine to their patients. “Higher uptake of annual vaccination in heart failure patients may help alleviate the burden of influenza-related hospital admissions,” he said.
Dr. Rahimi had no disclosures.
On Twitter @mitchelzoler
FLORENCE, ITALY – Influenza vaccination of heart failure patients cut their rate of hospitalization for cardiovascular disease by nearly a third during the year following vaccination in a study of more than 59,000 British heart failure patients.
Influenza vaccination of heart failure patients also cut their rate of hospitalization for respiratory infections by a statistically significant 16% during the year following vaccination, Dr. Kazem Rahimi said at a meeting held by the Heart Failure Association of the ESC.
“In the absence of randomized trials, this [observational] study of 59,202 heart failure patients provides the most compelling evidence to date for the protective effect of influenza vaccination on hospital admissions,” said Dr. Rahimi, a cardiologist and epidemiologist who is deputy director of the George Institute for Global Health at the University of Oxford (England).
The analysis also showed that influenza vaccination of heart failure patients had no significant effect on all-cause hospitalizations.
Dr. Rahimi and his associates analyzed electronic health records from primary and secondary care settings in England during 1990-2013, from which they identified 59,202 heart failure patients with records for at least 1 year of influenza vaccination and at least 1 year without vaccination. The patients averaged 75 years old and were divided equally among women and men.
To control for potential confounding factors, they used a self-control model in which hospitalizations for each heart failure patient during the year following an influenza vaccination were compared with an adjacent year for that same patient when no vaccination occurred.
The results showed that the incidence of hospitalizations for cardiovascular diseases fell by a statistically significant 30% in the year following an influenza vaccination, compared with one or more adjacent years without vaccination. The protection again hospitalization was strongest during the second month following vaccination and then gradually waned over the ensuing year; by about 10 months following vaccination the protection effect had disappeared.
The study also looked at influenza vaccine uptake by heart failure patients through the 24-year period examined. During that time, the vaccination uptake rate rose from a low of less than 10% in 1990 to a peak rate of just over 60% in 2006, after which the rate gradually declined to a rate of just under 50% in 2013. Dr. Rahimi attributed the rise in uptake during the period from 1990 to 2006 in part to incentives that primary care physicians in England began receiving to administer influenza vaccine to their patients. “Higher uptake of annual vaccination in heart failure patients may help alleviate the burden of influenza-related hospital admissions,” he said.
Dr. Rahimi had no disclosures.
On Twitter @mitchelzoler
AT HEART FAILURE 2016
Key clinical point: When heart failure patients received an influenza vaccination, their rate of hospitalization for cardiovascular disease and for respiratory infection fell significantly during the year following vaccination.
Major finding: Cardiovascular hospitalizations fell by 30% in the year following influenza vaccination, compared with adjacent years with no vaccination.
Data source: Review of electronic health records for 59,202 heart failure patients in England during 1990-2013.
Disclosures: Dr. Rahimi had no disclosures.
Implanted phrenic-nerve stimulator improves central sleep apnea
FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.
Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.
This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.
Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.
The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled. Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.
Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.
The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.
But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.
“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”
Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”
She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.
Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.
The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m2.
In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.
Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
On Twitter @mitchelzoler
This is a really interesting and provocative study that tests a concept that flies in the face of conventional wisdom. In the past, we tried our best to avoid phrenic nerve stimulation when implanting pacemakers or other devices; it was considered a side effect. With the approach studied in this new trial, phrenic-nerve stimulation is the goal.
 |
Dr. Frank Ruschitzka |
I see inherent drawbacks with a treatment that requires implantation of a device. Implanted devices never deliver an unmitigated good; there is always a downside. I am very interested in seeing more complete safety data to better judge the potential risks from this treatment. The report from the SERVE-HF trial last year (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), which showed excess mortality from a different treatment for central sleep apnea, further highlighted the importance of fully evaluating safety when treating central sleep apnea.
Another important issue is does the reduction in apnea-hypopnea index seen in this trial translate into a clinically-meaningful benefit? Ultimately that is what is important, but so far it hasn’t been shown. The treatment did, on average, decrease the apnea-hypopnea index, but does it decrease outcomes like hospitalizations or deaths? We need to see is more data specifically in heart failure patients. When judging the value of a device what we want to see are no safety concerns and fewer clinical events.
Dr. Frank Ruschitzka is professor of cardiology and head of the heart failure unit at University Hospital in Zurich. He made these comments in an interview. He had no disclosures.
This is a really interesting and provocative study that tests a concept that flies in the face of conventional wisdom. In the past, we tried our best to avoid phrenic nerve stimulation when implanting pacemakers or other devices; it was considered a side effect. With the approach studied in this new trial, phrenic-nerve stimulation is the goal.
|
Dr. Frank Ruschitzka |
I see inherent drawbacks with a treatment that requires implantation of a device. Implanted devices never deliver an unmitigated good; there is always a downside. I am very interested in seeing more complete safety data to better judge the potential risks from this treatment. The report from the SERVE-HF trial last year (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), which showed excess mortality from a different treatment for central sleep apnea, further highlighted the importance of fully evaluating safety when treating central sleep apnea.
Another important issue is does the reduction in apnea-hypopnea index seen in this trial translate into a clinically-meaningful benefit? Ultimately that is what is important, but so far it hasn’t been shown. The treatment did, on average, decrease the apnea-hypopnea index, but does it decrease outcomes like hospitalizations or deaths? We need to see is more data specifically in heart failure patients. When judging the value of a device what we want to see are no safety concerns and fewer clinical events.
Dr. Frank Ruschitzka is professor of cardiology and head of the heart failure unit at University Hospital in Zurich. He made these comments in an interview. He had no disclosures.
This is a really interesting and provocative study that tests a concept that flies in the face of conventional wisdom. In the past, we tried our best to avoid phrenic nerve stimulation when implanting pacemakers or other devices; it was considered a side effect. With the approach studied in this new trial, phrenic-nerve stimulation is the goal.
|
Dr. Frank Ruschitzka |
I see inherent drawbacks with a treatment that requires implantation of a device. Implanted devices never deliver an unmitigated good; there is always a downside. I am very interested in seeing more complete safety data to better judge the potential risks from this treatment. The report from the SERVE-HF trial last year (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), which showed excess mortality from a different treatment for central sleep apnea, further highlighted the importance of fully evaluating safety when treating central sleep apnea.
Another important issue is does the reduction in apnea-hypopnea index seen in this trial translate into a clinically-meaningful benefit? Ultimately that is what is important, but so far it hasn’t been shown. The treatment did, on average, decrease the apnea-hypopnea index, but does it decrease outcomes like hospitalizations or deaths? We need to see is more data specifically in heart failure patients. When judging the value of a device what we want to see are no safety concerns and fewer clinical events.
Dr. Frank Ruschitzka is professor of cardiology and head of the heart failure unit at University Hospital in Zurich. He made these comments in an interview. He had no disclosures.
FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.
Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.
This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.
Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.
The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled. Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.
Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.
The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.
But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.
“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”
Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”
She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.
Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.
The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m2.
In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.
Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
On Twitter @mitchelzoler
FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.
Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.
This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.
Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.
The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled. Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.
Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.
The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.
But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.
“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”
Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”
She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.
Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.
The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m2.
In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.
Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
On Twitter @mitchelzoler
AT HEART FAILURE 2016
Key clinical point: An implanted device that cuts patients’ apnea-hypopnea index was safe and effective, based on results from a pivotal trial.
Major finding: A 50% or greater reduction in apnea-hypopnea index was seen in 51% of patients who received a phrenic-nerve stimulation device and 11% of control patients.
Data source: Randomized, multicenter trial with 151 patients with central sleep apnea of various etiologies.
Disclosures: Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.
Nitroxl prodrug shows promise in acute heart failure
FLORENCE, ITALY – A novel intravenous prodrug that results in formation of nitroxyl once inside the body showed several potentially beneficial hemodynamic effects during a single, 6-hour infusion in a controlled proof-of-concept study with 46 patients hospitalized with advanced heart failure with reduced ejection fraction.
While receiving the drug, patients showed “statistically significant and clinically meaningful” reductions in pulmonary capillary wedge pressure and in pulmonary artery diastolic pressure, two of the studies three primary endpoints, Dr. Veselin Mitrovic said at a meeting held by the Heart Failure Association of the ESC.
For the study’s third primary endpoint, a change in cardiac index, treatment with the drug led to increased cardiac output using noninvasive measures, especially at the highest tested dose, as well as in all of the subset of treated patients in whom cardiac index was measured by thermodilution.
On the safety side, the drug appeared safe and well tolerated at all four tested doses, while causing no episodes of symptomatic hypotension and no increase in heart rate. Transient, asymptomatic reductions in blood pressure were similar in the treated and control patients.
“This is a very interesting and exciting drug that went in the right direction,” summed up Dr. Mitrovic, professor of cardiology at Goethe University in Frankfurt, Germany, and head of the department of cardiovascular research at the Kerckhoff Clinic in Bad Nauheim, Germany.
“This is the first demonstration of safety and preliminary efficacy in patients with advanced heart failure,” he said in an interview. “We had a very good clinical signal in a relatively small study. We now need a larger study.”
The drug “improved myocardial function in several ways: inotropy, lusitropy, and unloading. It also causes arterial vasodilation and increased stroke volume,” Dr. Mitrovic said. “Other drugs with a positive inotropic effect increase myocardial oxygen consumption; but with this drug, we see a neutral effect on mixed venous oxygen saturation. It balances myocardial oxygen consumption by its effect on unloading and reduced vascular resistance. This is a big advantage.”
Each molecule of nitroxyl is made from single atoms of hydrogen, nitrogen, and oxygen, and its physiologic action is distinct from nitric monoxide. Nitroxyl improves calcium efficiency and recycling without producing intracellular calcium overload, and its effects are not mediated by cyclic AMP or cyclic GMP.
The dose-ranging study enrolled 34 patients with New York Heart Association class III heart failure and 11 with class IV. All patients had to have a left ventricular ejection fraction of 40% or less, and their actual ejection fractions averaged about 25%.
When measured after 2, 4, and 6 hours of infusion, pulmonary capillary wedge pressure (PCWP) fell by an average of about 5 mm Hg, compared with baseline, among patients who received the three highest-dose infusions of the nitroxyl prodrug, known as CXL-1427, and by an average of about 3 mm Hg in those who received the lowest dose.
That effect had disappeared when PCWP was remeasured 2 hours after the end of the 6-hour infusion, and the 11 patients randomized to placebo showed no change at any time point in PCWP. The average declines in PCWP in each of the four dose groups were statistically significant changes, compared with the control patients.
All the drug-treated patients showed an average drop in pulmonary artery systolic pressure of about 5 mm Hg, compared with baseline, and about 3-4 mm Hg in pulmonary artery diastolic pressure. The patients who received the highest dose of CXL-1427 had an average drop in their right artery pressure of about 4 mm Hg. All of those decreases were statistically significant, compared with the lack of any measurable changes in the control patients.
Total peripheral resistance also showed statistically significant declines relative to baseline in all the treated patients when these decreases were compared with the controls.
CXL-1427 was initially developed by Cardioxyl Pharmaceuticals. Bristol-Myers Squibb acquired the company in late 2015. The study was sponsored by Cardioxyl. Dr. Mitrovic has been a consultant to Bayer, Cardiorentis, and Novartis.
On Twitter @mitchelzoler
Nitroxyl is a very promising and interesting drug. It had an effect on both contractility and inotropy, and also affected diastolic function and reduced afterload. The study’s inclusion criteria enrolled patients who are typical for acute heart failure. It is very important to conduct these sorts of hemodynamic studies of a drug’s effect in this setting.
This drug is obviously very powerful in reducing pulmonary capillary wedge pressure; only about 20% of patients did not respond. It also reduced both systolic and diastolic pulmonary artery pressure and right artery pressure, suggesting that it has a powerful effect on contractility in a way that not only affects the periphery by reducing systolic and diastolic pressures, but also produced little change in heart rate. What is important is that this drug acts at multiple points in the cardiovascular system.
The drug’s safety and tolerability looked very good, but it needs to undergo further study.
Dr. Petar M. Seferovic is a professor of cardiology at Belgrade University, Serbia. He made these comments as designated discussant for the report. He has been a speaker for and consultant to Berlin-Chemie, Boehringer Ingelheim, Pfizer, and Gedeon Richter.
Nitroxyl is a very promising and interesting drug. It had an effect on both contractility and inotropy, and also affected diastolic function and reduced afterload. The study’s inclusion criteria enrolled patients who are typical for acute heart failure. It is very important to conduct these sorts of hemodynamic studies of a drug’s effect in this setting.
This drug is obviously very powerful in reducing pulmonary capillary wedge pressure; only about 20% of patients did not respond. It also reduced both systolic and diastolic pulmonary artery pressure and right artery pressure, suggesting that it has a powerful effect on contractility in a way that not only affects the periphery by reducing systolic and diastolic pressures, but also produced little change in heart rate. What is important is that this drug acts at multiple points in the cardiovascular system.
The drug’s safety and tolerability looked very good, but it needs to undergo further study.
Dr. Petar M. Seferovic is a professor of cardiology at Belgrade University, Serbia. He made these comments as designated discussant for the report. He has been a speaker for and consultant to Berlin-Chemie, Boehringer Ingelheim, Pfizer, and Gedeon Richter.
Nitroxyl is a very promising and interesting drug. It had an effect on both contractility and inotropy, and also affected diastolic function and reduced afterload. The study’s inclusion criteria enrolled patients who are typical for acute heart failure. It is very important to conduct these sorts of hemodynamic studies of a drug’s effect in this setting.
This drug is obviously very powerful in reducing pulmonary capillary wedge pressure; only about 20% of patients did not respond. It also reduced both systolic and diastolic pulmonary artery pressure and right artery pressure, suggesting that it has a powerful effect on contractility in a way that not only affects the periphery by reducing systolic and diastolic pressures, but also produced little change in heart rate. What is important is that this drug acts at multiple points in the cardiovascular system.
The drug’s safety and tolerability looked very good, but it needs to undergo further study.
Dr. Petar M. Seferovic is a professor of cardiology at Belgrade University, Serbia. He made these comments as designated discussant for the report. He has been a speaker for and consultant to Berlin-Chemie, Boehringer Ingelheim, Pfizer, and Gedeon Richter.
FLORENCE, ITALY – A novel intravenous prodrug that results in formation of nitroxyl once inside the body showed several potentially beneficial hemodynamic effects during a single, 6-hour infusion in a controlled proof-of-concept study with 46 patients hospitalized with advanced heart failure with reduced ejection fraction.
While receiving the drug, patients showed “statistically significant and clinically meaningful” reductions in pulmonary capillary wedge pressure and in pulmonary artery diastolic pressure, two of the studies three primary endpoints, Dr. Veselin Mitrovic said at a meeting held by the Heart Failure Association of the ESC.
For the study’s third primary endpoint, a change in cardiac index, treatment with the drug led to increased cardiac output using noninvasive measures, especially at the highest tested dose, as well as in all of the subset of treated patients in whom cardiac index was measured by thermodilution.
On the safety side, the drug appeared safe and well tolerated at all four tested doses, while causing no episodes of symptomatic hypotension and no increase in heart rate. Transient, asymptomatic reductions in blood pressure were similar in the treated and control patients.
“This is a very interesting and exciting drug that went in the right direction,” summed up Dr. Mitrovic, professor of cardiology at Goethe University in Frankfurt, Germany, and head of the department of cardiovascular research at the Kerckhoff Clinic in Bad Nauheim, Germany.
“This is the first demonstration of safety and preliminary efficacy in patients with advanced heart failure,” he said in an interview. “We had a very good clinical signal in a relatively small study. We now need a larger study.”
The drug “improved myocardial function in several ways: inotropy, lusitropy, and unloading. It also causes arterial vasodilation and increased stroke volume,” Dr. Mitrovic said. “Other drugs with a positive inotropic effect increase myocardial oxygen consumption; but with this drug, we see a neutral effect on mixed venous oxygen saturation. It balances myocardial oxygen consumption by its effect on unloading and reduced vascular resistance. This is a big advantage.”
Each molecule of nitroxyl is made from single atoms of hydrogen, nitrogen, and oxygen, and its physiologic action is distinct from nitric monoxide. Nitroxyl improves calcium efficiency and recycling without producing intracellular calcium overload, and its effects are not mediated by cyclic AMP or cyclic GMP.
The dose-ranging study enrolled 34 patients with New York Heart Association class III heart failure and 11 with class IV. All patients had to have a left ventricular ejection fraction of 40% or less, and their actual ejection fractions averaged about 25%.
When measured after 2, 4, and 6 hours of infusion, pulmonary capillary wedge pressure (PCWP) fell by an average of about 5 mm Hg, compared with baseline, among patients who received the three highest-dose infusions of the nitroxyl prodrug, known as CXL-1427, and by an average of about 3 mm Hg in those who received the lowest dose.
That effect had disappeared when PCWP was remeasured 2 hours after the end of the 6-hour infusion, and the 11 patients randomized to placebo showed no change at any time point in PCWP. The average declines in PCWP in each of the four dose groups were statistically significant changes, compared with the control patients.
All the drug-treated patients showed an average drop in pulmonary artery systolic pressure of about 5 mm Hg, compared with baseline, and about 3-4 mm Hg in pulmonary artery diastolic pressure. The patients who received the highest dose of CXL-1427 had an average drop in their right artery pressure of about 4 mm Hg. All of those decreases were statistically significant, compared with the lack of any measurable changes in the control patients.
Total peripheral resistance also showed statistically significant declines relative to baseline in all the treated patients when these decreases were compared with the controls.
CXL-1427 was initially developed by Cardioxyl Pharmaceuticals. Bristol-Myers Squibb acquired the company in late 2015. The study was sponsored by Cardioxyl. Dr. Mitrovic has been a consultant to Bayer, Cardiorentis, and Novartis.
On Twitter @mitchelzoler
FLORENCE, ITALY – A novel intravenous prodrug that results in formation of nitroxyl once inside the body showed several potentially beneficial hemodynamic effects during a single, 6-hour infusion in a controlled proof-of-concept study with 46 patients hospitalized with advanced heart failure with reduced ejection fraction.
While receiving the drug, patients showed “statistically significant and clinically meaningful” reductions in pulmonary capillary wedge pressure and in pulmonary artery diastolic pressure, two of the studies three primary endpoints, Dr. Veselin Mitrovic said at a meeting held by the Heart Failure Association of the ESC.
For the study’s third primary endpoint, a change in cardiac index, treatment with the drug led to increased cardiac output using noninvasive measures, especially at the highest tested dose, as well as in all of the subset of treated patients in whom cardiac index was measured by thermodilution.
On the safety side, the drug appeared safe and well tolerated at all four tested doses, while causing no episodes of symptomatic hypotension and no increase in heart rate. Transient, asymptomatic reductions in blood pressure were similar in the treated and control patients.
“This is a very interesting and exciting drug that went in the right direction,” summed up Dr. Mitrovic, professor of cardiology at Goethe University in Frankfurt, Germany, and head of the department of cardiovascular research at the Kerckhoff Clinic in Bad Nauheim, Germany.
“This is the first demonstration of safety and preliminary efficacy in patients with advanced heart failure,” he said in an interview. “We had a very good clinical signal in a relatively small study. We now need a larger study.”
The drug “improved myocardial function in several ways: inotropy, lusitropy, and unloading. It also causes arterial vasodilation and increased stroke volume,” Dr. Mitrovic said. “Other drugs with a positive inotropic effect increase myocardial oxygen consumption; but with this drug, we see a neutral effect on mixed venous oxygen saturation. It balances myocardial oxygen consumption by its effect on unloading and reduced vascular resistance. This is a big advantage.”
Each molecule of nitroxyl is made from single atoms of hydrogen, nitrogen, and oxygen, and its physiologic action is distinct from nitric monoxide. Nitroxyl improves calcium efficiency and recycling without producing intracellular calcium overload, and its effects are not mediated by cyclic AMP or cyclic GMP.
The dose-ranging study enrolled 34 patients with New York Heart Association class III heart failure and 11 with class IV. All patients had to have a left ventricular ejection fraction of 40% or less, and their actual ejection fractions averaged about 25%.
When measured after 2, 4, and 6 hours of infusion, pulmonary capillary wedge pressure (PCWP) fell by an average of about 5 mm Hg, compared with baseline, among patients who received the three highest-dose infusions of the nitroxyl prodrug, known as CXL-1427, and by an average of about 3 mm Hg in those who received the lowest dose.
That effect had disappeared when PCWP was remeasured 2 hours after the end of the 6-hour infusion, and the 11 patients randomized to placebo showed no change at any time point in PCWP. The average declines in PCWP in each of the four dose groups were statistically significant changes, compared with the control patients.
All the drug-treated patients showed an average drop in pulmonary artery systolic pressure of about 5 mm Hg, compared with baseline, and about 3-4 mm Hg in pulmonary artery diastolic pressure. The patients who received the highest dose of CXL-1427 had an average drop in their right artery pressure of about 4 mm Hg. All of those decreases were statistically significant, compared with the lack of any measurable changes in the control patients.
Total peripheral resistance also showed statistically significant declines relative to baseline in all the treated patients when these decreases were compared with the controls.
CXL-1427 was initially developed by Cardioxyl Pharmaceuticals. Bristol-Myers Squibb acquired the company in late 2015. The study was sponsored by Cardioxyl. Dr. Mitrovic has been a consultant to Bayer, Cardiorentis, and Novartis.
On Twitter @mitchelzoler
AT HEART FAILURE 2016
Key clinical point: Intravenous infusion of a nitroxyl prodrug for 6 hours showed safety and several promising hemodynamic effects in a pilot, controlled study with 46 patients with advanced heart failure.
Major finding: Pulmonary capillary wedge pressure fell by about 5 mm Hg throughout a 6-hour infusion at the three highest tested doses of a nitroxyl prodrug.
Data source: A single-center, single-dose study with 46 patients hospitalized with advanced heart failure.
Disclosures: The study was sponsored by Cardioxyl, the drug’s developer, which was recently acquired by Bristol-Myers Squibb. Dr. Mitrovic has been a consultant to Bayer, Cardiorentis, and Novartis.
