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Wildfire smoke has acute cardiorespiratory impact, but long-term effects still under study
The 2019 wildfire season is underway in many locales across the United States, exposing millions of individuals to smoky conditions that will have health consequences ranging from stinging eyes to scratchy throats to a trip to the ED for asthma or chronic obstructive pulmonary disease (COPD) exacerbation. Questions about long-term health impacts are on the minds of many, including physicians and their patients who live with cardiorespiratory conditions.
John R. Balmes, MD, a pulmonologist at the University of California, San Francisco, and an expert on the respiratory and cardiovascular effects of air pollutants, suggested that the best available published literature points to “pretty strong evidence for acute effects of wildfire smoke on respiratory health, meaning people with preexisting asthma and COPD are at risk for exacerbations, and probably for respiratory tract infections as well.” He said, “It’s a little less clear, but there’s good biological plausibility for increased risk of respiratory tract infections because when your alveolar macrophages are overloaded with carbon particles that are toxic to those cells, they don’t function as well as a first line of defense against bacterial infection, for example.”
The new normal of wildfires
Warmer, drier summers in recent years in the western United States and many other regions, attributed by climate experts to global climate change, have produced catastrophic wildfires (PNAS;2016 Oct 18;113[42]11770-5; Science 2006 Aug 18;313:940-3). The Camp Fire in Northern California broke out in November 2018, took the lives of at least 85 people, and cost more than $16 billion in damage. Smoke from that blaze reached hazardous levels in San Francisco, Sacramento, Fresno, and many other smaller towns. Other forest fires in that year caused heavy smoke conditions in Portland, Seattle, Vancouver, and Anchorage. Such events are expected to be repeated often in the coming years (Int J Environ Res Public Health. 2019 Jul 6;16[13]). 
Wildfire smoke can contain a wide range of substances, chemicals, and gases with known and unknown cardiorespiratory implications. “Smoke is composed primarily of carbon dioxide, water vapor, carbon monoxide, particulate matter, hydrocarbons and other organic chemicals, nitrogen oxides, trace minerals and several thousand other compounds,” according to the U.S. Environmental Protection Agency (Wildfire smoke: A guide for public health officials 2019. Washington, D.C.: EPA, 2019). The EPA report noted, “Particles with diameters less than 10 mcm (particulate matter, or PM10) can be inhaled into the lungs and affect the lungs, heart, and blood vessels. The smallest particles, those less than 2.5 mcm in diameter (PM2.5), are the greatest risk to public health because they can reach deep into the lungs and may even make it into the bloodstream.”
Research on health impact
In early June of 2008, Wayne Cascio, MD, awoke in his Greenville, N.C., home to the stench of smoke emanating from a large peat fire burning some 65 miles away. By the time he reached the parking lot at East Carolina University in Greenville to begin his workday as chief of cardiology, the haze of smoke had thickened to the point where he could only see a few feet in front of him.
Over the next several weeks, the fire scorched 41,000 acres and produced haze and air pollution that far exceeded National Ambient Air Quality Standards for particulate matter and blanketed rural communities in the state’s eastern region. The price tag for management of the blaze reached $20 million. Because of his interest in the health effects of wildfire smoke and because of his relationship with investigators at the EPA, Dr. Cascio initiated an epidemiology study to investigate the effects of exposure on cardiorespiratory outcomes in the population affected by the fire (Environ Health Perspect. 2011 Oct;119[10]:1415-20).
By combining satellite data with syndromic surveillance drawn from hospital records in 41 counties contained in the North Carolina Disease Event Tracking and Epidemiologic Collection Tool, he and his colleagues found that exposure to the peat wildfire smoke led to increases in the cumulative risk ratio for asthma (relative risk, 1.65), chronic obstructive pulmonary disease (RR, 1.73), and pneumonia and acute bronchitis (RR, 1.59). ED visits related to cardiopulmonary symptoms and heart failure also were significantly increased (RR, 1.23 and 1.37, respectively). “That was really the first study to strongly identify a cardiac endpoint related to wildfire smoke exposure,” said Dr. Cascio, who now directs the EPA’s National Health and Environmental Effects Research Laboratory. “It really pointed out how little we knew about the health effects of wildfire up until that time.”
Those early findings have been replicated in subsequent research about the acute health effects of exposure to wildfire smoke, which contains PM2.5 and other toxic substances from structures, electronic devices, and automobiles destroyed in the path of flames, including heavy metals and asbestos. Most of the work has focused on smoke-related cardiovascular and respiratory ED visits and hospitalizations.
A study of the 2008 California wildfire impact on ED visits accounted for ozone levels in addition to PM2.5 in the smoke. During the active fire periods, PM2.5 was significantly associated with exacerbations of asthma and COPD and these effects remained after controlling for ozone levels. PM2.5 inhalation during the wildfires was associated with increased risk of an ED visit for asthma (RR, 1.112; 95% confidence interval, 1.087-1.138) for a 10 mcg/m3 increase in PM2.5 and COPD (RR, 1.05; 95% CI, 1.019-1.0825), as well as for combined respiratory visits (RR, 1.035; 95% CI, 1.023-1.046) (Environ Int. 2109 Aug;129:291-8).
Researchers who evaluated the health impacts of wildfires in California during the 2015 fire season found an increase in all-cause cardiovascular and respiratory ED visits, especially among those aged 65 years and older during smoke days. The population-based study included 1,196,233 ED visits during May 1–Sept. 30 that year. PM2.5 concentrations were categorized as light, medium, or dense. Relative risk rose with the amount of smoke in the air. Rates of all-cause cardiovascular ED visits were elevated across levels of smoke density, with the greatest increase on dense smoke days and among those aged 65 years or older (RR,1.15; 95% CI, 1.09-1.22). All-cause cerebrovascular visits were associated with dense smoke days, especially among those aged 65 years and older (RR, 1.22; 95% CI, 1.00-1.49). Respiratory conditions also were increased on dense smoke days (RR, 1.18; 95% CI, 1.08-1.28) (J Am Heart Assoc. 2018 Apr 11;7:e007492. doi: 10.1161/JAHA.117.007492).
Long-term effects unknown
When it comes to the long-term effects of wildfire smoke on human health outcomes, much less is known. In a recent literature review, Colleen E. Reid, PhD, and Melissa May Maestas, PhD, found only one study that investigated long-term respiratory health impacts of wildfire smoke, and only a few studies that have estimated future health impacts of wildfires under likely climate change scenarios (Curr Opin Pulm Med. 2019 Mar;25:179-87).
“We know that there are immediate respiratory health effects from wildfire smoke,” said Dr. Reid of the department of geography at the University of Colorado Boulder. “What’s less known is everything else. That’s challenging, because people want to know about the long-term health effects.”
Evidence from the scientific literature suggests that exposure to air pollution adversely affects cardiovascular health, but whether exposure to wildfire smoke confers a similar risk is less clear. “Until just a few years ago we haven’t been able to study wildfire exposure measures on a large scale,” said EPA scientist Ana G. Rappold, PhD, a statistician there in the environmental public health division of the National Health and Environmental Effects Research Laboratory. “It’s also hard to predict wildfires, so it’s hard to plan for an epidemiologic study if you don’t know where they’re going to occur.”
Dr. Rappold and colleagues examined cardiopulmonary hospitalizations among adults aged 65 years and older in 692 U.S. counties within 200 km of 123 large wildfires during 2008-2010 (Environ Health Perspect. 2019;127[3]:37006. doi: 10.1289/EHP3860). They observed that an increased risk of PM2.5-related cardiopulmonary hospitalizations was similar on smoke and nonsmoke days across multiple lags and exposure metrics, while risk for asthma-related hospitalizations was higher during smoke days. “One hypothesis is that this was an older study population, so naturally if you’re inhaling smoke, the first organ that’s impacted in an older population is the lungs,” Dr. Rappold said. “If you go to the hospital for asthma, wheezing, or bronchitis, you are taken out of the risk pool for cardiovascular and other diseases. That could explain why in other studies we don’t see a clear cardiovascular signal as we have for air pollution studies in general. Another aspect to this study is, the exposure metric was PM2.5, but smoke contains many other components, particularly gases, which are respiratory irritants. It could be that this triggers a higher risk for respiratory [effects] than regular episodes of high PM2.5 exposure, just because of the additional gases that people are exposed to.”
Another complicating factor is the paucity of data about solutions to long-term exposure to wildfire smoke. “If you’re impacted by high-exposure levels for 60 days, that is not something we have experienced before,” Dr. Rappold noted. “What are the solutions for that community? What works? Can we show that by implementing community-level resilience plans with HEPA [high-efficiency particulate air] filters or other interventions, do the overall outcomes improve? Doctors are the first ones to talk with their patients about their symptoms and about how to take care of their conditions. They can clearly make a difference in emphasizing reducing exposures in a way that fits their patients individually, either reducing the amount of time spent outside, the duration of exposure, and the level of exposure. Maybe change activities based on the intensity of exposure. Don’t go for a run outside when it’s smoky, because your ventilation rate is higher and you will breathe in more smoke. Become aware of those things.”
Advising vulnerable patients
While research in this field advances, the unforgiving wildfire season looms, assuring more destruction of property and threats to cardiorespiratory health. “There are a lot of questions that research will have an opportunity to address as we go forward, including the utility and the benefit of N95 masks, the utility of HEPA filters used in the house, and even with HVAC [heating, ventilation, and air conditioning] systems,” Dr. Cascio said. “Can we really clean up the indoor air well enough to protect us from wildfire smoke?”
The way he sees it, the time is ripe for clinicians and officials in public and private practice settings to refine how they distribute information to people living in areas affected by wildfire smoke. “We can’t force people do anything, but at least if they’re informed, then they understand they can make an informed decision about how they might want to affect what they do that would limit their exposure,” he said. “As a patient, my health care system sends text and email messages to me. So, why couldn’t the hospital send out a text message or an email to all of the patients with COPD, coronary disease, and heart failure when an area is impacted by smoke, saying, ‘Check your air quality and take action if air quality is poor?’ Physicians don’t have time to do this kind of education in the office for all of their patients. I know that from experience. But if one were to only focus on those at highest risk, and encourage them to follow our guidelines, which might include doing HEPA filter treatment in the home, we probably would reduce the number of clinical events in a cost-effective way.”
The 2019 wildfire season is underway in many locales across the United States, exposing millions of individuals to smoky conditions that will have health consequences ranging from stinging eyes to scratchy throats to a trip to the ED for asthma or chronic obstructive pulmonary disease (COPD) exacerbation. Questions about long-term health impacts are on the minds of many, including physicians and their patients who live with cardiorespiratory conditions.
John R. Balmes, MD, a pulmonologist at the University of California, San Francisco, and an expert on the respiratory and cardiovascular effects of air pollutants, suggested that the best available published literature points to “pretty strong evidence for acute effects of wildfire smoke on respiratory health, meaning people with preexisting asthma and COPD are at risk for exacerbations, and probably for respiratory tract infections as well.” He said, “It’s a little less clear, but there’s good biological plausibility for increased risk of respiratory tract infections because when your alveolar macrophages are overloaded with carbon particles that are toxic to those cells, they don’t function as well as a first line of defense against bacterial infection, for example.”
The new normal of wildfires
Warmer, drier summers in recent years in the western United States and many other regions, attributed by climate experts to global climate change, have produced catastrophic wildfires (PNAS;2016 Oct 18;113[42]11770-5; Science 2006 Aug 18;313:940-3). The Camp Fire in Northern California broke out in November 2018, took the lives of at least 85 people, and cost more than $16 billion in damage. Smoke from that blaze reached hazardous levels in San Francisco, Sacramento, Fresno, and many other smaller towns. Other forest fires in that year caused heavy smoke conditions in Portland, Seattle, Vancouver, and Anchorage. Such events are expected to be repeated often in the coming years (Int J Environ Res Public Health. 2019 Jul 6;16[13]).
Wildfire smoke can contain a wide range of substances, chemicals, and gases with known and unknown cardiorespiratory implications. “Smoke is composed primarily of carbon dioxide, water vapor, carbon monoxide, particulate matter, hydrocarbons and other organic chemicals, nitrogen oxides, trace minerals and several thousand other compounds,” according to the U.S. Environmental Protection Agency (Wildfire smoke: A guide for public health officials 2019. Washington, D.C.: EPA, 2019). The EPA report noted, “Particles with diameters less than 10 mcm (particulate matter, or PM10) can be inhaled into the lungs and affect the lungs, heart, and blood vessels. The smallest particles, those less than 2.5 mcm in diameter (PM2.5), are the greatest risk to public health because they can reach deep into the lungs and may even make it into the bloodstream.”
Research on health impact
In early June of 2008, Wayne Cascio, MD, awoke in his Greenville, N.C., home to the stench of smoke emanating from a large peat fire burning some 65 miles away. By the time he reached the parking lot at East Carolina University in Greenville to begin his workday as chief of cardiology, the haze of smoke had thickened to the point where he could only see a few feet in front of him.
Over the next several weeks, the fire scorched 41,000 acres and produced haze and air pollution that far exceeded National Ambient Air Quality Standards for particulate matter and blanketed rural communities in the state’s eastern region. The price tag for management of the blaze reached $20 million. Because of his interest in the health effects of wildfire smoke and because of his relationship with investigators at the EPA, Dr. Cascio initiated an epidemiology study to investigate the effects of exposure on cardiorespiratory outcomes in the population affected by the fire (Environ Health Perspect. 2011 Oct;119[10]:1415-20).
By combining satellite data with syndromic surveillance drawn from hospital records in 41 counties contained in the North Carolina Disease Event Tracking and Epidemiologic Collection Tool, he and his colleagues found that exposure to the peat wildfire smoke led to increases in the cumulative risk ratio for asthma (relative risk, 1.65), chronic obstructive pulmonary disease (RR, 1.73), and pneumonia and acute bronchitis (RR, 1.59). ED visits related to cardiopulmonary symptoms and heart failure also were significantly increased (RR, 1.23 and 1.37, respectively). “That was really the first study to strongly identify a cardiac endpoint related to wildfire smoke exposure,” said Dr. Cascio, who now directs the EPA’s National Health and Environmental Effects Research Laboratory. “It really pointed out how little we knew about the health effects of wildfire up until that time.”
Those early findings have been replicated in subsequent research about the acute health effects of exposure to wildfire smoke, which contains PM2.5 and other toxic substances from structures, electronic devices, and automobiles destroyed in the path of flames, including heavy metals and asbestos. Most of the work has focused on smoke-related cardiovascular and respiratory ED visits and hospitalizations.
A study of the 2008 California wildfire impact on ED visits accounted for ozone levels in addition to PM2.5 in the smoke. During the active fire periods, PM2.5 was significantly associated with exacerbations of asthma and COPD and these effects remained after controlling for ozone levels. PM2.5 inhalation during the wildfires was associated with increased risk of an ED visit for asthma (RR, 1.112; 95% confidence interval, 1.087-1.138) for a 10 mcg/m3 increase in PM2.5 and COPD (RR, 1.05; 95% CI, 1.019-1.0825), as well as for combined respiratory visits (RR, 1.035; 95% CI, 1.023-1.046) (Environ Int. 2109 Aug;129:291-8).
Researchers who evaluated the health impacts of wildfires in California during the 2015 fire season found an increase in all-cause cardiovascular and respiratory ED visits, especially among those aged 65 years and older during smoke days. The population-based study included 1,196,233 ED visits during May 1–Sept. 30 that year. PM2.5 concentrations were categorized as light, medium, or dense. Relative risk rose with the amount of smoke in the air. Rates of all-cause cardiovascular ED visits were elevated across levels of smoke density, with the greatest increase on dense smoke days and among those aged 65 years or older (RR,1.15; 95% CI, 1.09-1.22). All-cause cerebrovascular visits were associated with dense smoke days, especially among those aged 65 years and older (RR, 1.22; 95% CI, 1.00-1.49). Respiratory conditions also were increased on dense smoke days (RR, 1.18; 95% CI, 1.08-1.28) (J Am Heart Assoc. 2018 Apr 11;7:e007492. doi: 10.1161/JAHA.117.007492).
Long-term effects unknown
When it comes to the long-term effects of wildfire smoke on human health outcomes, much less is known. In a recent literature review, Colleen E. Reid, PhD, and Melissa May Maestas, PhD, found only one study that investigated long-term respiratory health impacts of wildfire smoke, and only a few studies that have estimated future health impacts of wildfires under likely climate change scenarios (Curr Opin Pulm Med. 2019 Mar;25:179-87).
“We know that there are immediate respiratory health effects from wildfire smoke,” said Dr. Reid of the department of geography at the University of Colorado Boulder. “What’s less known is everything else. That’s challenging, because people want to know about the long-term health effects.”
Evidence from the scientific literature suggests that exposure to air pollution adversely affects cardiovascular health, but whether exposure to wildfire smoke confers a similar risk is less clear. “Until just a few years ago we haven’t been able to study wildfire exposure measures on a large scale,” said EPA scientist Ana G. Rappold, PhD, a statistician there in the environmental public health division of the National Health and Environmental Effects Research Laboratory. “It’s also hard to predict wildfires, so it’s hard to plan for an epidemiologic study if you don’t know where they’re going to occur.”
Dr. Rappold and colleagues examined cardiopulmonary hospitalizations among adults aged 65 years and older in 692 U.S. counties within 200 km of 123 large wildfires during 2008-2010 (Environ Health Perspect. 2019;127[3]:37006. doi: 10.1289/EHP3860). They observed that an increased risk of PM2.5-related cardiopulmonary hospitalizations was similar on smoke and nonsmoke days across multiple lags and exposure metrics, while risk for asthma-related hospitalizations was higher during smoke days. “One hypothesis is that this was an older study population, so naturally if you’re inhaling smoke, the first organ that’s impacted in an older population is the lungs,” Dr. Rappold said. “If you go to the hospital for asthma, wheezing, or bronchitis, you are taken out of the risk pool for cardiovascular and other diseases. That could explain why in other studies we don’t see a clear cardiovascular signal as we have for air pollution studies in general. Another aspect to this study is, the exposure metric was PM2.5, but smoke contains many other components, particularly gases, which are respiratory irritants. It could be that this triggers a higher risk for respiratory [effects] than regular episodes of high PM2.5 exposure, just because of the additional gases that people are exposed to.”
Another complicating factor is the paucity of data about solutions to long-term exposure to wildfire smoke. “If you’re impacted by high-exposure levels for 60 days, that is not something we have experienced before,” Dr. Rappold noted. “What are the solutions for that community? What works? Can we show that by implementing community-level resilience plans with HEPA [high-efficiency particulate air] filters or other interventions, do the overall outcomes improve? Doctors are the first ones to talk with their patients about their symptoms and about how to take care of their conditions. They can clearly make a difference in emphasizing reducing exposures in a way that fits their patients individually, either reducing the amount of time spent outside, the duration of exposure, and the level of exposure. Maybe change activities based on the intensity of exposure. Don’t go for a run outside when it’s smoky, because your ventilation rate is higher and you will breathe in more smoke. Become aware of those things.”
Advising vulnerable patients
While research in this field advances, the unforgiving wildfire season looms, assuring more destruction of property and threats to cardiorespiratory health. “There are a lot of questions that research will have an opportunity to address as we go forward, including the utility and the benefit of N95 masks, the utility of HEPA filters used in the house, and even with HVAC [heating, ventilation, and air conditioning] systems,” Dr. Cascio said. “Can we really clean up the indoor air well enough to protect us from wildfire smoke?”
The way he sees it, the time is ripe for clinicians and officials in public and private practice settings to refine how they distribute information to people living in areas affected by wildfire smoke. “We can’t force people do anything, but at least if they’re informed, then they understand they can make an informed decision about how they might want to affect what they do that would limit their exposure,” he said. “As a patient, my health care system sends text and email messages to me. So, why couldn’t the hospital send out a text message or an email to all of the patients with COPD, coronary disease, and heart failure when an area is impacted by smoke, saying, ‘Check your air quality and take action if air quality is poor?’ Physicians don’t have time to do this kind of education in the office for all of their patients. I know that from experience. But if one were to only focus on those at highest risk, and encourage them to follow our guidelines, which might include doing HEPA filter treatment in the home, we probably would reduce the number of clinical events in a cost-effective way.”
The 2019 wildfire season is underway in many locales across the United States, exposing millions of individuals to smoky conditions that will have health consequences ranging from stinging eyes to scratchy throats to a trip to the ED for asthma or chronic obstructive pulmonary disease (COPD) exacerbation. Questions about long-term health impacts are on the minds of many, including physicians and their patients who live with cardiorespiratory conditions.
John R. Balmes, MD, a pulmonologist at the University of California, San Francisco, and an expert on the respiratory and cardiovascular effects of air pollutants, suggested that the best available published literature points to “pretty strong evidence for acute effects of wildfire smoke on respiratory health, meaning people with preexisting asthma and COPD are at risk for exacerbations, and probably for respiratory tract infections as well.” He said, “It’s a little less clear, but there’s good biological plausibility for increased risk of respiratory tract infections because when your alveolar macrophages are overloaded with carbon particles that are toxic to those cells, they don’t function as well as a first line of defense against bacterial infection, for example.”
The new normal of wildfires
Warmer, drier summers in recent years in the western United States and many other regions, attributed by climate experts to global climate change, have produced catastrophic wildfires (PNAS;2016 Oct 18;113[42]11770-5; Science 2006 Aug 18;313:940-3). The Camp Fire in Northern California broke out in November 2018, took the lives of at least 85 people, and cost more than $16 billion in damage. Smoke from that blaze reached hazardous levels in San Francisco, Sacramento, Fresno, and many other smaller towns. Other forest fires in that year caused heavy smoke conditions in Portland, Seattle, Vancouver, and Anchorage. Such events are expected to be repeated often in the coming years (Int J Environ Res Public Health. 2019 Jul 6;16[13]).
Wildfire smoke can contain a wide range of substances, chemicals, and gases with known and unknown cardiorespiratory implications. “Smoke is composed primarily of carbon dioxide, water vapor, carbon monoxide, particulate matter, hydrocarbons and other organic chemicals, nitrogen oxides, trace minerals and several thousand other compounds,” according to the U.S. Environmental Protection Agency (Wildfire smoke: A guide for public health officials 2019. Washington, D.C.: EPA, 2019). The EPA report noted, “Particles with diameters less than 10 mcm (particulate matter, or PM10) can be inhaled into the lungs and affect the lungs, heart, and blood vessels. The smallest particles, those less than 2.5 mcm in diameter (PM2.5), are the greatest risk to public health because they can reach deep into the lungs and may even make it into the bloodstream.”
Research on health impact
In early June of 2008, Wayne Cascio, MD, awoke in his Greenville, N.C., home to the stench of smoke emanating from a large peat fire burning some 65 miles away. By the time he reached the parking lot at East Carolina University in Greenville to begin his workday as chief of cardiology, the haze of smoke had thickened to the point where he could only see a few feet in front of him.
Over the next several weeks, the fire scorched 41,000 acres and produced haze and air pollution that far exceeded National Ambient Air Quality Standards for particulate matter and blanketed rural communities in the state’s eastern region. The price tag for management of the blaze reached $20 million. Because of his interest in the health effects of wildfire smoke and because of his relationship with investigators at the EPA, Dr. Cascio initiated an epidemiology study to investigate the effects of exposure on cardiorespiratory outcomes in the population affected by the fire (Environ Health Perspect. 2011 Oct;119[10]:1415-20).
By combining satellite data with syndromic surveillance drawn from hospital records in 41 counties contained in the North Carolina Disease Event Tracking and Epidemiologic Collection Tool, he and his colleagues found that exposure to the peat wildfire smoke led to increases in the cumulative risk ratio for asthma (relative risk, 1.65), chronic obstructive pulmonary disease (RR, 1.73), and pneumonia and acute bronchitis (RR, 1.59). ED visits related to cardiopulmonary symptoms and heart failure also were significantly increased (RR, 1.23 and 1.37, respectively). “That was really the first study to strongly identify a cardiac endpoint related to wildfire smoke exposure,” said Dr. Cascio, who now directs the EPA’s National Health and Environmental Effects Research Laboratory. “It really pointed out how little we knew about the health effects of wildfire up until that time.”
Those early findings have been replicated in subsequent research about the acute health effects of exposure to wildfire smoke, which contains PM2.5 and other toxic substances from structures, electronic devices, and automobiles destroyed in the path of flames, including heavy metals and asbestos. Most of the work has focused on smoke-related cardiovascular and respiratory ED visits and hospitalizations.
A study of the 2008 California wildfire impact on ED visits accounted for ozone levels in addition to PM2.5 in the smoke. During the active fire periods, PM2.5 was significantly associated with exacerbations of asthma and COPD and these effects remained after controlling for ozone levels. PM2.5 inhalation during the wildfires was associated with increased risk of an ED visit for asthma (RR, 1.112; 95% confidence interval, 1.087-1.138) for a 10 mcg/m3 increase in PM2.5 and COPD (RR, 1.05; 95% CI, 1.019-1.0825), as well as for combined respiratory visits (RR, 1.035; 95% CI, 1.023-1.046) (Environ Int. 2109 Aug;129:291-8).
Researchers who evaluated the health impacts of wildfires in California during the 2015 fire season found an increase in all-cause cardiovascular and respiratory ED visits, especially among those aged 65 years and older during smoke days. The population-based study included 1,196,233 ED visits during May 1–Sept. 30 that year. PM2.5 concentrations were categorized as light, medium, or dense. Relative risk rose with the amount of smoke in the air. Rates of all-cause cardiovascular ED visits were elevated across levels of smoke density, with the greatest increase on dense smoke days and among those aged 65 years or older (RR,1.15; 95% CI, 1.09-1.22). All-cause cerebrovascular visits were associated with dense smoke days, especially among those aged 65 years and older (RR, 1.22; 95% CI, 1.00-1.49). Respiratory conditions also were increased on dense smoke days (RR, 1.18; 95% CI, 1.08-1.28) (J Am Heart Assoc. 2018 Apr 11;7:e007492. doi: 10.1161/JAHA.117.007492).
Long-term effects unknown
When it comes to the long-term effects of wildfire smoke on human health outcomes, much less is known. In a recent literature review, Colleen E. Reid, PhD, and Melissa May Maestas, PhD, found only one study that investigated long-term respiratory health impacts of wildfire smoke, and only a few studies that have estimated future health impacts of wildfires under likely climate change scenarios (Curr Opin Pulm Med. 2019 Mar;25:179-87).
“We know that there are immediate respiratory health effects from wildfire smoke,” said Dr. Reid of the department of geography at the University of Colorado Boulder. “What’s less known is everything else. That’s challenging, because people want to know about the long-term health effects.”
Evidence from the scientific literature suggests that exposure to air pollution adversely affects cardiovascular health, but whether exposure to wildfire smoke confers a similar risk is less clear. “Until just a few years ago we haven’t been able to study wildfire exposure measures on a large scale,” said EPA scientist Ana G. Rappold, PhD, a statistician there in the environmental public health division of the National Health and Environmental Effects Research Laboratory. “It’s also hard to predict wildfires, so it’s hard to plan for an epidemiologic study if you don’t know where they’re going to occur.”
Dr. Rappold and colleagues examined cardiopulmonary hospitalizations among adults aged 65 years and older in 692 U.S. counties within 200 km of 123 large wildfires during 2008-2010 (Environ Health Perspect. 2019;127[3]:37006. doi: 10.1289/EHP3860). They observed that an increased risk of PM2.5-related cardiopulmonary hospitalizations was similar on smoke and nonsmoke days across multiple lags and exposure metrics, while risk for asthma-related hospitalizations was higher during smoke days. “One hypothesis is that this was an older study population, so naturally if you’re inhaling smoke, the first organ that’s impacted in an older population is the lungs,” Dr. Rappold said. “If you go to the hospital for asthma, wheezing, or bronchitis, you are taken out of the risk pool for cardiovascular and other diseases. That could explain why in other studies we don’t see a clear cardiovascular signal as we have for air pollution studies in general. Another aspect to this study is, the exposure metric was PM2.5, but smoke contains many other components, particularly gases, which are respiratory irritants. It could be that this triggers a higher risk for respiratory [effects] than regular episodes of high PM2.5 exposure, just because of the additional gases that people are exposed to.”
Another complicating factor is the paucity of data about solutions to long-term exposure to wildfire smoke. “If you’re impacted by high-exposure levels for 60 days, that is not something we have experienced before,” Dr. Rappold noted. “What are the solutions for that community? What works? Can we show that by implementing community-level resilience plans with HEPA [high-efficiency particulate air] filters or other interventions, do the overall outcomes improve? Doctors are the first ones to talk with their patients about their symptoms and about how to take care of their conditions. They can clearly make a difference in emphasizing reducing exposures in a way that fits their patients individually, either reducing the amount of time spent outside, the duration of exposure, and the level of exposure. Maybe change activities based on the intensity of exposure. Don’t go for a run outside when it’s smoky, because your ventilation rate is higher and you will breathe in more smoke. Become aware of those things.”
Advising vulnerable patients
While research in this field advances, the unforgiving wildfire season looms, assuring more destruction of property and threats to cardiorespiratory health. “There are a lot of questions that research will have an opportunity to address as we go forward, including the utility and the benefit of N95 masks, the utility of HEPA filters used in the house, and even with HVAC [heating, ventilation, and air conditioning] systems,” Dr. Cascio said. “Can we really clean up the indoor air well enough to protect us from wildfire smoke?”
The way he sees it, the time is ripe for clinicians and officials in public and private practice settings to refine how they distribute information to people living in areas affected by wildfire smoke. “We can’t force people do anything, but at least if they’re informed, then they understand they can make an informed decision about how they might want to affect what they do that would limit their exposure,” he said. “As a patient, my health care system sends text and email messages to me. So, why couldn’t the hospital send out a text message or an email to all of the patients with COPD, coronary disease, and heart failure when an area is impacted by smoke, saying, ‘Check your air quality and take action if air quality is poor?’ Physicians don’t have time to do this kind of education in the office for all of their patients. I know that from experience. But if one were to only focus on those at highest risk, and encourage them to follow our guidelines, which might include doing HEPA filter treatment in the home, we probably would reduce the number of clinical events in a cost-effective way.”
Milrinone beats dobutamine in extending survival in HF
PHILADELPHIA – Milrinone was associated with a 50% reduction in mortality, compared with dobutamine, in patients with heart failure who were receiving home inotropes as a bridge to advanced therapies, according to results of a large U.S. registry study.
The survival profile for milrinone was more favorable than that for dobutamine across various indications for use, including bridge to transplant, bridge to mechanical support, and palliation.
The findings illustrate an “urgent need” for randomized trials that compare inotropic therapy strategies in patients with end-stage heart failure, said investigator Behram P. Mody, MD, of the division of cardiology at the University of California, San Diego, La Jolla.
“Although [there is] the possibility of selection bias and there are confounding variables, this consistent finding may reflect a true benefit of milrinone,” Dr. Mody said in a presentation at the annual scientific meeting of the Heart Failure Society of America
The evidence to support use of continuous outpatient intravenous inotropic therapy in stage D heart failure is limited and comes mainly from case series, and small, randomized trials demonstrating poor outcomes, Dr. Mody explained.
“Long-term survival associated with home inotropes in the modern era of guideline-directed medical and device therapy is poorly defined,” he said.
The retrospective study Dr. Mody presented at the meeting included 1,149 patients (mean age, 60 years; 29.9% women) who received continuous intravenous outpatient inotropic therapy (milrinone or dobutamine) from 2015 to 2017. This is possibly the largest body of data reported to date of patients receiving home inotropes, he said.
For the overall population, the estimated 1-year survival rate was 71% with milrinone, compared with 46% for dobutamine (P less than .0001), Dr. Mody reported. After adjusting for age, gender, weight, and indication, milrinone use was still significantly associated with lower mortality, compared with dobutamine (hazard ratio, 0.50; 95% confidence interval, 0.39-0.64; P less than .0001).
The survival benefit of milrinone over dobutamine was also significant in subsets of patients receiving home inotropes as bridge to transplant, bridge to mechanical support, or palliation. A similar trend, though not statistically significant, was seen for inotropes used as a bridge to decision, he added.
Mortality was generally higher in patients receiving inotropes as palliation, as opposed to bridge therapy, with 1-year survival of 55.0% and 65.6%, respectively, and median survival of 461 days and 584 days.
These findings suggest home inotropes can be “beneficial” in patients with end-stage heart failure in an era of guideline-directed medical therapy and greater defibrillator use, Dr. Mody said.
“I’m not saying that it should replace left ventricular assist devices as the bridge to transplant,” he added, “but it could be an alternative strategy for our patients.”
No funding source was given. Dr. Mody had no disclosures related to the study.
SOURCE: Mody BP et al. J Card Fail. 2019 Sep 14. doi: 10.1016/j.cardfail.2019.07.021.
PHILADELPHIA – Milrinone was associated with a 50% reduction in mortality, compared with dobutamine, in patients with heart failure who were receiving home inotropes as a bridge to advanced therapies, according to results of a large U.S. registry study.
The survival profile for milrinone was more favorable than that for dobutamine across various indications for use, including bridge to transplant, bridge to mechanical support, and palliation.
The findings illustrate an “urgent need” for randomized trials that compare inotropic therapy strategies in patients with end-stage heart failure, said investigator Behram P. Mody, MD, of the division of cardiology at the University of California, San Diego, La Jolla.
“Although [there is] the possibility of selection bias and there are confounding variables, this consistent finding may reflect a true benefit of milrinone,” Dr. Mody said in a presentation at the annual scientific meeting of the Heart Failure Society of America
The evidence to support use of continuous outpatient intravenous inotropic therapy in stage D heart failure is limited and comes mainly from case series, and small, randomized trials demonstrating poor outcomes, Dr. Mody explained.
“Long-term survival associated with home inotropes in the modern era of guideline-directed medical and device therapy is poorly defined,” he said.
The retrospective study Dr. Mody presented at the meeting included 1,149 patients (mean age, 60 years; 29.9% women) who received continuous intravenous outpatient inotropic therapy (milrinone or dobutamine) from 2015 to 2017. This is possibly the largest body of data reported to date of patients receiving home inotropes, he said.
For the overall population, the estimated 1-year survival rate was 71% with milrinone, compared with 46% for dobutamine (P less than .0001), Dr. Mody reported. After adjusting for age, gender, weight, and indication, milrinone use was still significantly associated with lower mortality, compared with dobutamine (hazard ratio, 0.50; 95% confidence interval, 0.39-0.64; P less than .0001).
The survival benefit of milrinone over dobutamine was also significant in subsets of patients receiving home inotropes as bridge to transplant, bridge to mechanical support, or palliation. A similar trend, though not statistically significant, was seen for inotropes used as a bridge to decision, he added.
Mortality was generally higher in patients receiving inotropes as palliation, as opposed to bridge therapy, with 1-year survival of 55.0% and 65.6%, respectively, and median survival of 461 days and 584 days.
These findings suggest home inotropes can be “beneficial” in patients with end-stage heart failure in an era of guideline-directed medical therapy and greater defibrillator use, Dr. Mody said.
“I’m not saying that it should replace left ventricular assist devices as the bridge to transplant,” he added, “but it could be an alternative strategy for our patients.”
No funding source was given. Dr. Mody had no disclosures related to the study.
SOURCE: Mody BP et al. J Card Fail. 2019 Sep 14. doi: 10.1016/j.cardfail.2019.07.021.
PHILADELPHIA – Milrinone was associated with a 50% reduction in mortality, compared with dobutamine, in patients with heart failure who were receiving home inotropes as a bridge to advanced therapies, according to results of a large U.S. registry study.
The survival profile for milrinone was more favorable than that for dobutamine across various indications for use, including bridge to transplant, bridge to mechanical support, and palliation.
The findings illustrate an “urgent need” for randomized trials that compare inotropic therapy strategies in patients with end-stage heart failure, said investigator Behram P. Mody, MD, of the division of cardiology at the University of California, San Diego, La Jolla.
“Although [there is] the possibility of selection bias and there are confounding variables, this consistent finding may reflect a true benefit of milrinone,” Dr. Mody said in a presentation at the annual scientific meeting of the Heart Failure Society of America
The evidence to support use of continuous outpatient intravenous inotropic therapy in stage D heart failure is limited and comes mainly from case series, and small, randomized trials demonstrating poor outcomes, Dr. Mody explained.
“Long-term survival associated with home inotropes in the modern era of guideline-directed medical and device therapy is poorly defined,” he said.
The retrospective study Dr. Mody presented at the meeting included 1,149 patients (mean age, 60 years; 29.9% women) who received continuous intravenous outpatient inotropic therapy (milrinone or dobutamine) from 2015 to 2017. This is possibly the largest body of data reported to date of patients receiving home inotropes, he said.
For the overall population, the estimated 1-year survival rate was 71% with milrinone, compared with 46% for dobutamine (P less than .0001), Dr. Mody reported. After adjusting for age, gender, weight, and indication, milrinone use was still significantly associated with lower mortality, compared with dobutamine (hazard ratio, 0.50; 95% confidence interval, 0.39-0.64; P less than .0001).
The survival benefit of milrinone over dobutamine was also significant in subsets of patients receiving home inotropes as bridge to transplant, bridge to mechanical support, or palliation. A similar trend, though not statistically significant, was seen for inotropes used as a bridge to decision, he added.
Mortality was generally higher in patients receiving inotropes as palliation, as opposed to bridge therapy, with 1-year survival of 55.0% and 65.6%, respectively, and median survival of 461 days and 584 days.
These findings suggest home inotropes can be “beneficial” in patients with end-stage heart failure in an era of guideline-directed medical therapy and greater defibrillator use, Dr. Mody said.
“I’m not saying that it should replace left ventricular assist devices as the bridge to transplant,” he added, “but it could be an alternative strategy for our patients.”
No funding source was given. Dr. Mody had no disclosures related to the study.
SOURCE: Mody BP et al. J Card Fail. 2019 Sep 14. doi: 10.1016/j.cardfail.2019.07.021.
REPORTING FROM HFSA 2019
Drug doses for heart failure could possibly be halved for women
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
FROM THE LANCET
Chemotherapy may raise CVD risk in pediatric cancer survivors
Pediatric cancer survivors have a higher likelihood of experiencing a cardiac event, developing diabetes, or having hypertension at a median 10-year follow-up, according to results from a recent research letter published in Circulation.
Ashna Khanna of the University of Toronto and colleagues identified 7,289 pediatric patients in the Pediatric Oncology Group of Ontario Networked Information System who were diagnosed with cancer at median age of 7 years old, who were treated between 1987 and 2010, and who were cancer survivors for 5 years. Each patient was matched to five cancer-free control subjects who were a median of 24 years old at the 10-year follow-up (36,205 cancer-free individuals). The researchers studied whether pediatric cancer survivors experienced cardiac events, such as heart failure, arrhythmia, pericardial disease, valvular disease, or coronary artery disease. They also evaluated the incidence of diabetes and hypertension in each group.
Of the children who survived cancer, 2.8% (n = 203) experienced at least one cardiac event versus 0.9% of controls (P less than .001). The cancer survivors experienced 3.2 cardiac events per 1,000 person-years (95% confidence interval, 2.8-3.6), compared with the control group in which there was a rate of 0.9 cardiac events per 1,000 person-years (95% CI, 0.9-1.9).
With regard to cardiovascular disease (CVD) risk, associated factors included cancer relapse or subsequent cancer (hazard ratio, 1.7; 95% CI, 1.1-2.7) and a 250-mg/m2 or greater dose of doxorubicin-equivalent anthracycline chemotherapy, compared with a dose of less than 250 mg/m2 or no anthracycline chemotherapy (HR, 2.0; 95% CI, 1.4-2.9). Patients who developed diabetes mellitus before a CVD diagnosis were also at higher risk of CVD (HR, 3.0; 95% CI, 1.6-5.8).
Heart failure risk was also statistically significant in patients with relapse and subsequent childhood cancer (HR, 2.0; 95% CI, 1.1-3.7), a 250-mg/m2 or greater dose of doxorubicin-equivalent anthracycline chemotherapy (HR, 8.6; 95% CI, 4.5-16.6), diabetes (HR, 4.3; 95% CI, 1.8-10.7), and hypertension (HR, 3.1; 95% CI, 1.3-7.9).
“While anthracycline chemotherapy may induce heart disease, many patients require this cancer treatment to survive,” Paul Nathan, MD, of the Hospital for Sick Children in Canada and a study coauthor said in a statement. “Doctors should address heart disease risk factors – such as diabetes and hypertension – that can be modified.”
This study was funded in part from a grant by the Canadian Institutes for Health Research. Several authors reported support from noncommercial sources. The other authors reported having no relevant conflicts of interest.
SOURCE: Khanna A et al. Circulation. 2019 Aug 26. doi: 10.1161/CIRCULATIONAHA.119.041403.
Pediatric cancer survivors have a higher likelihood of experiencing a cardiac event, developing diabetes, or having hypertension at a median 10-year follow-up, according to results from a recent research letter published in Circulation.
Ashna Khanna of the University of Toronto and colleagues identified 7,289 pediatric patients in the Pediatric Oncology Group of Ontario Networked Information System who were diagnosed with cancer at median age of 7 years old, who were treated between 1987 and 2010, and who were cancer survivors for 5 years. Each patient was matched to five cancer-free control subjects who were a median of 24 years old at the 10-year follow-up (36,205 cancer-free individuals). The researchers studied whether pediatric cancer survivors experienced cardiac events, such as heart failure, arrhythmia, pericardial disease, valvular disease, or coronary artery disease. They also evaluated the incidence of diabetes and hypertension in each group.
Of the children who survived cancer, 2.8% (n = 203) experienced at least one cardiac event versus 0.9% of controls (P less than .001). The cancer survivors experienced 3.2 cardiac events per 1,000 person-years (95% confidence interval, 2.8-3.6), compared with the control group in which there was a rate of 0.9 cardiac events per 1,000 person-years (95% CI, 0.9-1.9).
With regard to cardiovascular disease (CVD) risk, associated factors included cancer relapse or subsequent cancer (hazard ratio, 1.7; 95% CI, 1.1-2.7) and a 250-mg/m2 or greater dose of doxorubicin-equivalent anthracycline chemotherapy, compared with a dose of less than 250 mg/m2 or no anthracycline chemotherapy (HR, 2.0; 95% CI, 1.4-2.9). Patients who developed diabetes mellitus before a CVD diagnosis were also at higher risk of CVD (HR, 3.0; 95% CI, 1.6-5.8).
Heart failure risk was also statistically significant in patients with relapse and subsequent childhood cancer (HR, 2.0; 95% CI, 1.1-3.7), a 250-mg/m2 or greater dose of doxorubicin-equivalent anthracycline chemotherapy (HR, 8.6; 95% CI, 4.5-16.6), diabetes (HR, 4.3; 95% CI, 1.8-10.7), and hypertension (HR, 3.1; 95% CI, 1.3-7.9).
“While anthracycline chemotherapy may induce heart disease, many patients require this cancer treatment to survive,” Paul Nathan, MD, of the Hospital for Sick Children in Canada and a study coauthor said in a statement. “Doctors should address heart disease risk factors – such as diabetes and hypertension – that can be modified.”
This study was funded in part from a grant by the Canadian Institutes for Health Research. Several authors reported support from noncommercial sources. The other authors reported having no relevant conflicts of interest.
SOURCE: Khanna A et al. Circulation. 2019 Aug 26. doi: 10.1161/CIRCULATIONAHA.119.041403.
Pediatric cancer survivors have a higher likelihood of experiencing a cardiac event, developing diabetes, or having hypertension at a median 10-year follow-up, according to results from a recent research letter published in Circulation.
Ashna Khanna of the University of Toronto and colleagues identified 7,289 pediatric patients in the Pediatric Oncology Group of Ontario Networked Information System who were diagnosed with cancer at median age of 7 years old, who were treated between 1987 and 2010, and who were cancer survivors for 5 years. Each patient was matched to five cancer-free control subjects who were a median of 24 years old at the 10-year follow-up (36,205 cancer-free individuals). The researchers studied whether pediatric cancer survivors experienced cardiac events, such as heart failure, arrhythmia, pericardial disease, valvular disease, or coronary artery disease. They also evaluated the incidence of diabetes and hypertension in each group.
Of the children who survived cancer, 2.8% (n = 203) experienced at least one cardiac event versus 0.9% of controls (P less than .001). The cancer survivors experienced 3.2 cardiac events per 1,000 person-years (95% confidence interval, 2.8-3.6), compared with the control group in which there was a rate of 0.9 cardiac events per 1,000 person-years (95% CI, 0.9-1.9).
With regard to cardiovascular disease (CVD) risk, associated factors included cancer relapse or subsequent cancer (hazard ratio, 1.7; 95% CI, 1.1-2.7) and a 250-mg/m2 or greater dose of doxorubicin-equivalent anthracycline chemotherapy, compared with a dose of less than 250 mg/m2 or no anthracycline chemotherapy (HR, 2.0; 95% CI, 1.4-2.9). Patients who developed diabetes mellitus before a CVD diagnosis were also at higher risk of CVD (HR, 3.0; 95% CI, 1.6-5.8).
Heart failure risk was also statistically significant in patients with relapse and subsequent childhood cancer (HR, 2.0; 95% CI, 1.1-3.7), a 250-mg/m2 or greater dose of doxorubicin-equivalent anthracycline chemotherapy (HR, 8.6; 95% CI, 4.5-16.6), diabetes (HR, 4.3; 95% CI, 1.8-10.7), and hypertension (HR, 3.1; 95% CI, 1.3-7.9).
“While anthracycline chemotherapy may induce heart disease, many patients require this cancer treatment to survive,” Paul Nathan, MD, of the Hospital for Sick Children in Canada and a study coauthor said in a statement. “Doctors should address heart disease risk factors – such as diabetes and hypertension – that can be modified.”
This study was funded in part from a grant by the Canadian Institutes for Health Research. Several authors reported support from noncommercial sources. The other authors reported having no relevant conflicts of interest.
SOURCE: Khanna A et al. Circulation. 2019 Aug 26. doi: 10.1161/CIRCULATIONAHA.119.041403.
FROM CIRCULATION
DAPA-HF results transform dapagliflozin from antidiabetic to heart failure drug
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
REPORTING FROM THE ESC CONGRESS 2019
Key clinical point: Dapagliflozin produced multiple, statistically significant benefits in heart failure patients on top of guideline-directed therapy.
Major finding: The study’s primary endpoint fell by a statistically significant 27% with dapagliflozin compared with placebo in patients without diabetes.
Study details: DAPA-HF, a multinational study with 4,744 patients at 410 sites.
Disclosures: DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF.
Sacubitril-valsartan effect on aortic stiffness minimal
PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found , according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.
“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.
The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.
Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm 5 in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm 5 in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm 5 , ranging from -17.6 to 13.2 dyne x s/cm 5 . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.
The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.
Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.
The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.
The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.
SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.
PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found , according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.
“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.
The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.
Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm 5 in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm 5 in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm 5 , ranging from -17.6 to 13.2 dyne x s/cm 5 . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.
The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.
Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.
The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.
The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.
SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.
PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found , according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.
“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.
The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.
Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm 5 in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm 5 in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm 5 , ranging from -17.6 to 13.2 dyne x s/cm 5 . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.
The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.
Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.
The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.
The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.
SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.
AT THE ESC CONGRESS 2019
Key clinical point: Sacubitril-valsartan does not significantly reduce aortic stiffness, compared with enalapril.
Major finding: The difference in aortic characteristic impedance was -2.2 dyne x s/cm5 between treatment groups.
Study details: EVALUATE-HF is a randomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of less than 40%.
Disclosures: The study was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron.
Source: Desai AS, et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843
Weight loss surgery linked to lower CV event risk in diabetes
, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.
The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.
At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).
The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.
Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).
In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.
In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m2 or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.
The surgery was also associated with significantly greater reductions in HbA1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.
The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.
In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.
“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.
“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.
The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.
“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.
The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.
Despite a focus on reducing macrovascular events in individuals with type 2 diabetes, none of the major randomized controlled trials of glucose-lowering interventions that support current treatment guidelines have achieved this outcome. This study of bariatric surgery in obese patients with diabetes, however, does show reductions in major adverse cardiovascular events, although these outcomes should be interpreted with caution because of their observational nature and imprecise matching of the study groups.
Despite this, the many known benefits associated with bariatric surgery–induced weight loss suggest that for carefully selected, motivated patients with obesity and type 2 diabetes – who have been unable to lose weight by other means – this could be the preferred treatment option.
Dr. Edward H. Livingston is the deputy editor of JAMA and with the department of surgery at the University of California, Los Angeles. These comments are adapted from an accompanying editorial (JAMA 2019, Sept 2. DOI:10.1001/jama.2019.14577). No conflicts of interest were declared.
Despite a focus on reducing macrovascular events in individuals with type 2 diabetes, none of the major randomized controlled trials of glucose-lowering interventions that support current treatment guidelines have achieved this outcome. This study of bariatric surgery in obese patients with diabetes, however, does show reductions in major adverse cardiovascular events, although these outcomes should be interpreted with caution because of their observational nature and imprecise matching of the study groups.
Despite this, the many known benefits associated with bariatric surgery–induced weight loss suggest that for carefully selected, motivated patients with obesity and type 2 diabetes – who have been unable to lose weight by other means – this could be the preferred treatment option.
Dr. Edward H. Livingston is the deputy editor of JAMA and with the department of surgery at the University of California, Los Angeles. These comments are adapted from an accompanying editorial (JAMA 2019, Sept 2. DOI:10.1001/jama.2019.14577). No conflicts of interest were declared.
Despite a focus on reducing macrovascular events in individuals with type 2 diabetes, none of the major randomized controlled trials of glucose-lowering interventions that support current treatment guidelines have achieved this outcome. This study of bariatric surgery in obese patients with diabetes, however, does show reductions in major adverse cardiovascular events, although these outcomes should be interpreted with caution because of their observational nature and imprecise matching of the study groups.
Despite this, the many known benefits associated with bariatric surgery–induced weight loss suggest that for carefully selected, motivated patients with obesity and type 2 diabetes – who have been unable to lose weight by other means – this could be the preferred treatment option.
Dr. Edward H. Livingston is the deputy editor of JAMA and with the department of surgery at the University of California, Los Angeles. These comments are adapted from an accompanying editorial (JAMA 2019, Sept 2. DOI:10.1001/jama.2019.14577). No conflicts of interest were declared.
, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.
The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.
At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).
The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.
Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).
In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.
In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m2 or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.
The surgery was also associated with significantly greater reductions in HbA1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.
The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.
In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.
“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.
“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.
The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.
“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.
The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.
, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.
The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.
At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).
The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.
Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).
In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.
In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m2 or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.
The surgery was also associated with significantly greater reductions in HbA1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.
The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.
In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.
“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.
“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.
The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.
“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.
The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.
AT THE ESC CONGRESS 2019
Key clinical point: Bariatric surgery may reduce the risk of cardiovascular events in people with type 2 diabetes.
Major finding: Bariatric surgery is associated with a 39% reduction in risk of major cardiovascular events.
Study details: Retrospective cohort study in 13,722 individuals with type 2 diabetes and obesity.
Disclosures: The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.
Source: Aminian A et al. JAMA 2019, September 2. DOI: 10.1001/jama.2019.14231.
Dapagliflozin meets primary endpoint in the DAPA-HF trial
The SGLT2 inhibitor dapagliflozin (Farxiga) successfully met the primary endpoint of the phase 3 DAPA-HF trial in patients with heart failure, according to a press release from AstraZeneca.
DAPA-HF is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction with or without type 2 diabetes. Patients in the study received either 10 mg dapagliflozin or placebo, and the primary outcome was time to a worsening heart failure event or to cardiovascular death. Patients who received dapagliflozin had a statistically significant reduction in incidence of cardiovascular death and an increase in time to a heart failure event.
The adverse events reported for dapagliflozin in DAPA-HF matched the established safety profile for the drug, AstraZeneca noted in the press release.
“The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients,” said John McMurray, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Another dapagliflozin trial, called DELIVER, is focused on 4,700 patients with heart failure with preserved ejection fraction randomized to dapagliflozin (Farxiga) or placebo. That is due to be completed next year.
The full results from DAPA-HF will be presented at a later date.
The SGLT2 inhibitor dapagliflozin (Farxiga) successfully met the primary endpoint of the phase 3 DAPA-HF trial in patients with heart failure, according to a press release from AstraZeneca.
DAPA-HF is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction with or without type 2 diabetes. Patients in the study received either 10 mg dapagliflozin or placebo, and the primary outcome was time to a worsening heart failure event or to cardiovascular death. Patients who received dapagliflozin had a statistically significant reduction in incidence of cardiovascular death and an increase in time to a heart failure event.
The adverse events reported for dapagliflozin in DAPA-HF matched the established safety profile for the drug, AstraZeneca noted in the press release.
“The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients,” said John McMurray, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Another dapagliflozin trial, called DELIVER, is focused on 4,700 patients with heart failure with preserved ejection fraction randomized to dapagliflozin (Farxiga) or placebo. That is due to be completed next year.
The full results from DAPA-HF will be presented at a later date.
The SGLT2 inhibitor dapagliflozin (Farxiga) successfully met the primary endpoint of the phase 3 DAPA-HF trial in patients with heart failure, according to a press release from AstraZeneca.
DAPA-HF is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction with or without type 2 diabetes. Patients in the study received either 10 mg dapagliflozin or placebo, and the primary outcome was time to a worsening heart failure event or to cardiovascular death. Patients who received dapagliflozin had a statistically significant reduction in incidence of cardiovascular death and an increase in time to a heart failure event.
The adverse events reported for dapagliflozin in DAPA-HF matched the established safety profile for the drug, AstraZeneca noted in the press release.
“The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients,” said John McMurray, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Another dapagliflozin trial, called DELIVER, is focused on 4,700 patients with heart failure with preserved ejection fraction randomized to dapagliflozin (Farxiga) or placebo. That is due to be completed next year.
The full results from DAPA-HF will be presented at a later date.
Diabetes effect in heart failure varies by phenotype
Type 2 diabetes is a risk factor for heart failure and a common comorbidity in heart failure patients. New results from a large cohort study in Asia show that, for people with heart failure, having diabetes is associated with changes to the structure of the heart, lower quality of life, more readmissions to hospital, and higher risk of death.
Jonathan Yap, MBBS, MPH, of the National Heart Centre in Singapore, and colleagues, looked at data from a cohort enrolling 6,167 heart failure patients in 11 Asian countries for the prospective ASIAN-HF (Asian Sudden
Cardiac Death in Heart Failure) registry. The researchers identified 5,028 patients with heart failure and reduced left ventricle ejection fraction (LVEF; 22% women), of whom 40% had type 2 diabetes. They also looked at 1,139 patients in the registry with heart failure and preserved LVEF (51% women), of whom 45% had type 2 disease. Controls without heart failure (n = 985; 9% with diabetes) from the SHOP (Singapore Heart Failure Outcomes and Phenotypes) study were included in the analysis, which was published August 21 in the Journal of the American Heart Association.
For both heart failure phenotypes, diabetes was associated with left ventricular hypertrophy, but there was no similar association in patients without diabetes. Dr. Yap and his colleagues reported differences in cardiac remodeling based on heart failure phenotype: The reduced LVEF patients had more eccentric hypertrophy, or dilation, of the left ventricular chamber, whereas the preserved LVEF patients had more concentric hypertrophy, or thickening, of the left ventricular wall.
The researchers also reported that patients with diabetes had lower health-related quality of life scores in both heart failure groups, compared with patients without diabetes, although those in the latter group with preserved LVEF did significantly worse on some quality of life measures. Patients with diabetes had more heart failure rehospitalizations (adjusted hazard ratio, 1.27; 95% confidence interval, 1.05-1.54; P = .014) and higher 1-year rates of a combined measure of all-cause mortality and hospitalization for heart failure (aHR, 1.22; 95% CI, 1.05-1.41; P = .011). No differences were seen between phenotypes for these outcomes.
Dr. Yap and colleagues noted that this was the first large, multinational study investigating diabetes and heart failure in Asia and that “no prior studies have concomitantly included both HF types or controls without HF from the same population.” They listed among the study’s limitations a lack of uniform screening for diabetes that may have resulted in under-identification of diabetics in the cohort.
The Singapore government, the Biomedical Research Council, Boston Scientific, and Bayer sponsored the study. One coauthor disclosed receiving pharmaceutical industry support.
Source: Yap J et al. J Am Heart Assoc. 2019 Aug. doi: 10.1161/JAHA.119.013114.
Type 2 diabetes is a risk factor for heart failure and a common comorbidity in heart failure patients. New results from a large cohort study in Asia show that, for people with heart failure, having diabetes is associated with changes to the structure of the heart, lower quality of life, more readmissions to hospital, and higher risk of death.
Jonathan Yap, MBBS, MPH, of the National Heart Centre in Singapore, and colleagues, looked at data from a cohort enrolling 6,167 heart failure patients in 11 Asian countries for the prospective ASIAN-HF (Asian Sudden
Cardiac Death in Heart Failure) registry. The researchers identified 5,028 patients with heart failure and reduced left ventricle ejection fraction (LVEF; 22% women), of whom 40% had type 2 diabetes. They also looked at 1,139 patients in the registry with heart failure and preserved LVEF (51% women), of whom 45% had type 2 disease. Controls without heart failure (n = 985; 9% with diabetes) from the SHOP (Singapore Heart Failure Outcomes and Phenotypes) study were included in the analysis, which was published August 21 in the Journal of the American Heart Association.
For both heart failure phenotypes, diabetes was associated with left ventricular hypertrophy, but there was no similar association in patients without diabetes. Dr. Yap and his colleagues reported differences in cardiac remodeling based on heart failure phenotype: The reduced LVEF patients had more eccentric hypertrophy, or dilation, of the left ventricular chamber, whereas the preserved LVEF patients had more concentric hypertrophy, or thickening, of the left ventricular wall.
The researchers also reported that patients with diabetes had lower health-related quality of life scores in both heart failure groups, compared with patients without diabetes, although those in the latter group with preserved LVEF did significantly worse on some quality of life measures. Patients with diabetes had more heart failure rehospitalizations (adjusted hazard ratio, 1.27; 95% confidence interval, 1.05-1.54; P = .014) and higher 1-year rates of a combined measure of all-cause mortality and hospitalization for heart failure (aHR, 1.22; 95% CI, 1.05-1.41; P = .011). No differences were seen between phenotypes for these outcomes.
Dr. Yap and colleagues noted that this was the first large, multinational study investigating diabetes and heart failure in Asia and that “no prior studies have concomitantly included both HF types or controls without HF from the same population.” They listed among the study’s limitations a lack of uniform screening for diabetes that may have resulted in under-identification of diabetics in the cohort.
The Singapore government, the Biomedical Research Council, Boston Scientific, and Bayer sponsored the study. One coauthor disclosed receiving pharmaceutical industry support.
Source: Yap J et al. J Am Heart Assoc. 2019 Aug. doi: 10.1161/JAHA.119.013114.
Type 2 diabetes is a risk factor for heart failure and a common comorbidity in heart failure patients. New results from a large cohort study in Asia show that, for people with heart failure, having diabetes is associated with changes to the structure of the heart, lower quality of life, more readmissions to hospital, and higher risk of death.
Jonathan Yap, MBBS, MPH, of the National Heart Centre in Singapore, and colleagues, looked at data from a cohort enrolling 6,167 heart failure patients in 11 Asian countries for the prospective ASIAN-HF (Asian Sudden
Cardiac Death in Heart Failure) registry. The researchers identified 5,028 patients with heart failure and reduced left ventricle ejection fraction (LVEF; 22% women), of whom 40% had type 2 diabetes. They also looked at 1,139 patients in the registry with heart failure and preserved LVEF (51% women), of whom 45% had type 2 disease. Controls without heart failure (n = 985; 9% with diabetes) from the SHOP (Singapore Heart Failure Outcomes and Phenotypes) study were included in the analysis, which was published August 21 in the Journal of the American Heart Association.
For both heart failure phenotypes, diabetes was associated with left ventricular hypertrophy, but there was no similar association in patients without diabetes. Dr. Yap and his colleagues reported differences in cardiac remodeling based on heart failure phenotype: The reduced LVEF patients had more eccentric hypertrophy, or dilation, of the left ventricular chamber, whereas the preserved LVEF patients had more concentric hypertrophy, or thickening, of the left ventricular wall.
The researchers also reported that patients with diabetes had lower health-related quality of life scores in both heart failure groups, compared with patients without diabetes, although those in the latter group with preserved LVEF did significantly worse on some quality of life measures. Patients with diabetes had more heart failure rehospitalizations (adjusted hazard ratio, 1.27; 95% confidence interval, 1.05-1.54; P = .014) and higher 1-year rates of a combined measure of all-cause mortality and hospitalization for heart failure (aHR, 1.22; 95% CI, 1.05-1.41; P = .011). No differences were seen between phenotypes for these outcomes.
Dr. Yap and colleagues noted that this was the first large, multinational study investigating diabetes and heart failure in Asia and that “no prior studies have concomitantly included both HF types or controls without HF from the same population.” They listed among the study’s limitations a lack of uniform screening for diabetes that may have resulted in under-identification of diabetics in the cohort.
The Singapore government, the Biomedical Research Council, Boston Scientific, and Bayer sponsored the study. One coauthor disclosed receiving pharmaceutical industry support.
Source: Yap J et al. J Am Heart Assoc. 2019 Aug. doi: 10.1161/JAHA.119.013114.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point: Patients with heart failure and type 2 diabetes have smaller left ventricular ejection fractions, poorer quality of life, and increased risk for all-cause and cardiovascular death and hospitalization for heart failure.
Major finding: Heart failure with comorbid type 2 diabetes is associated with cardiac remodeling, worse clinical outcomes, and higher risk for hospitalization; type of heart failure may have a role.
Study details: A prospective, multicenter cohort of 6,167 patients with heart failure in the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry enrolled in 11 Asian countries and 965 community-based controls without heart failure recruited as part of the control arm of the SHOP (Singapore Heart Failure Outcomes and Phenotypes) study.
Disclosures: The Singapore government, the Biomedical Research Council, Boston Scientific, and Bayer sponsored the study. One coauthor disclosed receiving pharmaceutical industry support.
Source: Yap J et al. J Am Heart Assoc. 2019 Aug. doi: 10.1161/JAHA.119.013114.
FDA approves baroreflex activation for advanced HF
The Food and Drug Administration has approved the Barostim Neo System, an electronic carotid sinus baroreceptor stimulator, for advanced heart failure patients who have a regular heart rhythm, an ejection fraction of 35% or less, and who are not candidates for cardiac resynchronization.
A tiny, unilateral electrode delivers a pulse that decreases sympathetic but increases parasympathetic tone. The effect is that blood vessels relax and production of stress hormones drops. The device is powered by a small generator implanted under the collarbone.
Approval was based on BeAT-HF, a randomized trial with 408 patients on guideline-directed medical therapy with left ventricular ejection fractions at or below 35% and New York Heart Association class III disease.
At 6 months, 125 patients implanted with the device had improved about 14 points more than controls on a quality of life scale, walked about 60 meters farther in 6 minutes, and were more likely to have improved a functional class or two. The benefits corresponded with a drop in the N-terminal of the prohormone brain natriuretic peptide.
Possible complications include infection, low blood pressure, nerve damage, arterial damage, heart failure exacerbation, stroke, and death. Contraindications include certain nervous system disorders, uncontrolled and symptomatic bradycardia, and atherosclerosis or ulcerative carotid plaques near the implant zone, the FDA said.
The system, from CRVx in Minneapolis, received priority review as a breakthrough device. The agency is requiring a phase 4 investigation of its potential to reduce hospitalizations and prolong life.
The Food and Drug Administration has approved the Barostim Neo System, an electronic carotid sinus baroreceptor stimulator, for advanced heart failure patients who have a regular heart rhythm, an ejection fraction of 35% or less, and who are not candidates for cardiac resynchronization.
A tiny, unilateral electrode delivers a pulse that decreases sympathetic but increases parasympathetic tone. The effect is that blood vessels relax and production of stress hormones drops. The device is powered by a small generator implanted under the collarbone.
Approval was based on BeAT-HF, a randomized trial with 408 patients on guideline-directed medical therapy with left ventricular ejection fractions at or below 35% and New York Heart Association class III disease.
At 6 months, 125 patients implanted with the device had improved about 14 points more than controls on a quality of life scale, walked about 60 meters farther in 6 minutes, and were more likely to have improved a functional class or two. The benefits corresponded with a drop in the N-terminal of the prohormone brain natriuretic peptide.
Possible complications include infection, low blood pressure, nerve damage, arterial damage, heart failure exacerbation, stroke, and death. Contraindications include certain nervous system disorders, uncontrolled and symptomatic bradycardia, and atherosclerosis or ulcerative carotid plaques near the implant zone, the FDA said.
The system, from CRVx in Minneapolis, received priority review as a breakthrough device. The agency is requiring a phase 4 investigation of its potential to reduce hospitalizations and prolong life.
The Food and Drug Administration has approved the Barostim Neo System, an electronic carotid sinus baroreceptor stimulator, for advanced heart failure patients who have a regular heart rhythm, an ejection fraction of 35% or less, and who are not candidates for cardiac resynchronization.
A tiny, unilateral electrode delivers a pulse that decreases sympathetic but increases parasympathetic tone. The effect is that blood vessels relax and production of stress hormones drops. The device is powered by a small generator implanted under the collarbone.
Approval was based on BeAT-HF, a randomized trial with 408 patients on guideline-directed medical therapy with left ventricular ejection fractions at or below 35% and New York Heart Association class III disease.
At 6 months, 125 patients implanted with the device had improved about 14 points more than controls on a quality of life scale, walked about 60 meters farther in 6 minutes, and were more likely to have improved a functional class or two. The benefits corresponded with a drop in the N-terminal of the prohormone brain natriuretic peptide.
Possible complications include infection, low blood pressure, nerve damage, arterial damage, heart failure exacerbation, stroke, and death. Contraindications include certain nervous system disorders, uncontrolled and symptomatic bradycardia, and atherosclerosis or ulcerative carotid plaques near the implant zone, the FDA said.
The system, from CRVx in Minneapolis, received priority review as a breakthrough device. The agency is requiring a phase 4 investigation of its potential to reduce hospitalizations and prolong life.