Cardiology

Adversity in early life – whether preterm birth or socioeconomic disadvantage in childhood – accelerates aging, according to two recent studies, but underlying mechanisms remain unclear, and methods of investigation continue to evolve.

While one study used an established epigenetic clock to measure biological age among adults with extremely low birth weight, the other showcased a relatively new tool to measure pace of biological aging in disadvantaged children, suggesting that the metric may one day serve as a real-time measure of interventional efficacy.

These findings build upon previous studies that have demonstrated a correlation between biological age, also known as methylation age, and an increased risk of health problems later in life, according to Daniel A. Notterman, MD, professor of molecular biology at Princeton (N.J.) University.

“Finding that a person’s methylation age is greater than their chronological age has been taken as evidence of increased ‘biological age’ and perhaps a tendency to greater future morbidity,” Dr. Notterman wrote in a Pediatrics editorial. “Indeed, methylation age is advanced in association with a number of childhood and midlife adversities as well as morbidities such as atherosclerosis, cancer, and obesity.”
 

Extremely low birth weight associated with faster aging in men

For some individuals, accelerated biological aging begins at birth, or even in utero, according to Ryan J. Van Lieshout, MD, PhD, Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University, Hamilton, Ont., and colleagues.

The investigators conducted a study involving 45 extremely low birth weight (ELBW) survivors and 49 individuals born at normal birth weight. All participants were drawn from a longitudinal study conducted between 1977 and 1982 that assessed advances in neonatal intensive care. Controls were recruited at 8 years of age and matched with ELBW survivors based on family socioeconomic status, sex, and age. Follow-up continued through adulthood, allowing for the present trial to compare data from ages 8, 30, and 35.

Using samples of buccal epithelial cells, the investigators measured biological age with the Horvath epigenetic clock, the most commonly used tool of its kind, which measures cytosine-5 methylation at 353 cytosine-phosphate-guanine sites. Results were adjusted for a variety of covariates, such as smoking status, body mass index, number of chronic health conditions, and others.

Between groups, ELBW survivors trended toward older biological age, compared with adults born at normal birth weight (29.0 vs. 27.9 years), a difference that was not statistically significant. Further analysis, however, showed a significant sex-based difference between groups: Male survivors of ELBW, in adulthood, were almost 5 years biologically older than men born at normal birth weight (31.4 vs. 26.9 years; P = .01).

“[W]e provide preliminary evidence of a new link between ELBW and accelerated biological aging among men,” the investigators concluded.

In an accompanying editorial, Pam Factor-Litvak, PhD, vice chair of epidemiology at Columbia University, New York, wrote, “The findings are intriguing and open many questions for further study.”

Dr. Factor-Litvak noted that it remains unclear whether differences in biological aging were present at birth.

“[D]ifferences would provide evidence that accelerated aging begins during the in utero period, perhaps because of maternal undernutrition, stress, or another exposure,” Dr. Factor-Litvak wrote. “[R]eductions in chronic stress levels, which may begin for neonates with ELBW in utero and in the first hours of life, may provide an opportunity for interventions,” she added.

According to Calvin J. Hobel, MD, professor of pediatrics at Cedars-Sinai and professor of obstetrics and gynecology at University of California, Los Angeles, who has been studying preterm birth for more than 40 years, interventions may need to begin even earlier.

Measuring the impact of socioeconomic status on biological aging, now in real-time

A second study, by Laurel Raffington, PhD, of the University of Texas at Austin, and colleagues, evaluated the relationship between socioeconomic disadvantage in childhood and pace of biological aging.

To do so, they used the DunedinPoAm DNA methylation algorithm, a relatively new tool that was developed by analyzing changes in organ system integrity over time among adults with the same chronological age.

“Whereas epigenetic clocks quantify the amount of aging that has already occurred up to the time of measurement, DunedinPoAm quantifies how fast an individual is aging,” Dr. Raffington and colleagues wrote. “In other words, whereas epigenetic clocks tell you what time it is, pace-of-aging measures tell you how fast the clock is ticking.”

The investigators measured pace of aging in 600 children and adolescents (8-18 years of age) from the Texas Twin Project, “an ongoing longitudinal study that includes the collection of salivary samples.” The final dataset included 457 participants who identified as White, 77 who identified as Latinx, and 61 who identified as both White and Latinx.

The investigators evaluated pace of aging compared with family-level and neighborhood-level socioeconomic status, and tested for confounding by tobacco exposure, BMI, and pubertal development.

This analysis revealed that children experiencing socioeconomic disadvantage were aging more quickly than their peers, in terms of both family-level and neighborhood-level inequity (both levels, r = 0.18; P = .001).

Children who identified as Latinx aged faster than did those who identified as White only or White and Latinx, “consistent with higher levels of disadvantage in this group,” the investigators wrote. “Thus, our findings are consistent with observations that racial and/or ethnic socioeconomic disparities are an important contributor to racial and/or ethnic disparities in health.”

Higher BMI, greater tobacco exposure, and more advanced pubertal development were also associated with more rapid aging. After adjustment for these covariates, however, the significant correlation between socioeconomic disadvantage and rapid aging remained, the investigators noted.

“Our results suggest that salivary DNA methylation measures of pace of aging may provide a surrogate or intermediate endpoint for understanding the health impacts of [childhood] interventions,” the investigators concluded. “Such applications may prove particularly useful for evaluating the effectiveness of health-promoting interventions in at-risk groups.”

Still, more work is needed to understand exactly how socioeconomic disadvantage is associated with accelerated aging.

“Ultimately, not only longitudinal repeated-measures studies but also natural experiment studies and randomized controlled trials of social programs are needed to establish causal effects of social disadvantage on DunedinPoAm-measured pace of aging and to establish DunedinPoAm as a mediator of the process through which childhood disadvantage leads to aging-related health conditions,” the investigators wrote.

In his editorial, Dr. Notterman emphasized this point.

“[I]t is worth remembering that associations with either methylation age or pace of aging and health or longevity may represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (low socioeconomic status, adversity) to health outcome (i.e., cancer, vascular disease),” he wrote.

Paul Chung, MD, professor and chair of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., and adjunct professor at the University of California, Los Angeles, called the findings “preliminary,” but noted that confirmation through further research could “fill in some really important gaps.

“Right now, to some degree, we’re at a little bit of an impasse,” Dr. Chung said.

Adverse childhood experiences are “associated very strongly” with mental and physical health issues, Dr. Chung said, “but we don’t know exactly why, and because of that, it’s really hard to come up with social policy solutions that aren’t anything but extremely sort of blunt-ended. We just say, ‘Well, I guess you gotta fix everything.’ And it’s a hard place to be, I think, in the field.”

Although the present study doesn’t resolve this issue, Dr. Chung suggested that the findings “really open the door to a lot of really exciting research that could have a lot of impacts on practice and policy.”

“Sometimes the only way to get people to pay attention enough to generate the level of excitement that would allow you to even do these sorts of studies ... is to generate some initial exploratory data that makes people perk up their ears, and makes people go, ‘Hey, wow, maybe we should be looking into this.’ ”

The study by Dr. Raffington and colleagues was funded by the National Institutes of Health and the Jacobs Foundation, with additional support from the German Research Foundation, Russell Sage Foundation Biology and Social Science Grant, the Canadian Institute for Advanced Research Child and Brain Development Network, and others. The study by Dr. Lieshout and colleagues was supported by Canadian Institutes of Health Research. Dr. Factor-Litvak and Dr. Notterman reported funding from the National Institutes of Health. All of the investigators and interviewees reported no conflicts of interest.

Adversity in early life – whether preterm birth or socioeconomic disadvantage in childhood – accelerates aging, according to two recent studies, but underlying mechanisms remain unclear, and methods of investigation continue to evolve.

While one study used an established epigenetic clock to measure biological age among adults with extremely low birth weight, the other showcased a relatively new tool to measure pace of biological aging in disadvantaged children, suggesting that the metric may one day serve as a real-time measure of interventional efficacy.

These findings build upon previous studies that have demonstrated a correlation between biological age, also known as methylation age, and an increased risk of health problems later in life, according to Daniel A. Notterman, MD, professor of molecular biology at Princeton (N.J.) University.

“Finding that a person’s methylation age is greater than their chronological age has been taken as evidence of increased ‘biological age’ and perhaps a tendency to greater future morbidity,” Dr. Notterman wrote in a Pediatrics editorial. “Indeed, methylation age is advanced in association with a number of childhood and midlife adversities as well as morbidities such as atherosclerosis, cancer, and obesity.”
 

Extremely low birth weight associated with faster aging in men

For some individuals, accelerated biological aging begins at birth, or even in utero, according to Ryan J. Van Lieshout, MD, PhD, Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University, Hamilton, Ont., and colleagues.

The investigators conducted a study involving 45 extremely low birth weight (ELBW) survivors and 49 individuals born at normal birth weight. All participants were drawn from a longitudinal study conducted between 1977 and 1982 that assessed advances in neonatal intensive care. Controls were recruited at 8 years of age and matched with ELBW survivors based on family socioeconomic status, sex, and age. Follow-up continued through adulthood, allowing for the present trial to compare data from ages 8, 30, and 35.

Using samples of buccal epithelial cells, the investigators measured biological age with the Horvath epigenetic clock, the most commonly used tool of its kind, which measures cytosine-5 methylation at 353 cytosine-phosphate-guanine sites. Results were adjusted for a variety of covariates, such as smoking status, body mass index, number of chronic health conditions, and others.

Between groups, ELBW survivors trended toward older biological age, compared with adults born at normal birth weight (29.0 vs. 27.9 years), a difference that was not statistically significant. Further analysis, however, showed a significant sex-based difference between groups: Male survivors of ELBW, in adulthood, were almost 5 years biologically older than men born at normal birth weight (31.4 vs. 26.9 years; P = .01).

“[W]e provide preliminary evidence of a new link between ELBW and accelerated biological aging among men,” the investigators concluded.

In an accompanying editorial, Pam Factor-Litvak, PhD, vice chair of epidemiology at Columbia University, New York, wrote, “The findings are intriguing and open many questions for further study.”

Dr. Factor-Litvak noted that it remains unclear whether differences in biological aging were present at birth.

“[D]ifferences would provide evidence that accelerated aging begins during the in utero period, perhaps because of maternal undernutrition, stress, or another exposure,” Dr. Factor-Litvak wrote. “[R]eductions in chronic stress levels, which may begin for neonates with ELBW in utero and in the first hours of life, may provide an opportunity for interventions,” she added.

According to Calvin J. Hobel, MD, professor of pediatrics at Cedars-Sinai and professor of obstetrics and gynecology at University of California, Los Angeles, who has been studying preterm birth for more than 40 years, interventions may need to begin even earlier.

Measuring the impact of socioeconomic status on biological aging, now in real-time

A second study, by Laurel Raffington, PhD, of the University of Texas at Austin, and colleagues, evaluated the relationship between socioeconomic disadvantage in childhood and pace of biological aging.

To do so, they used the DunedinPoAm DNA methylation algorithm, a relatively new tool that was developed by analyzing changes in organ system integrity over time among adults with the same chronological age.

“Whereas epigenetic clocks quantify the amount of aging that has already occurred up to the time of measurement, DunedinPoAm quantifies how fast an individual is aging,” Dr. Raffington and colleagues wrote. “In other words, whereas epigenetic clocks tell you what time it is, pace-of-aging measures tell you how fast the clock is ticking.”

The investigators measured pace of aging in 600 children and adolescents (8-18 years of age) from the Texas Twin Project, “an ongoing longitudinal study that includes the collection of salivary samples.” The final dataset included 457 participants who identified as White, 77 who identified as Latinx, and 61 who identified as both White and Latinx.

The investigators evaluated pace of aging compared with family-level and neighborhood-level socioeconomic status, and tested for confounding by tobacco exposure, BMI, and pubertal development.

This analysis revealed that children experiencing socioeconomic disadvantage were aging more quickly than their peers, in terms of both family-level and neighborhood-level inequity (both levels, r = 0.18; P = .001).

Children who identified as Latinx aged faster than did those who identified as White only or White and Latinx, “consistent with higher levels of disadvantage in this group,” the investigators wrote. “Thus, our findings are consistent with observations that racial and/or ethnic socioeconomic disparities are an important contributor to racial and/or ethnic disparities in health.”

Higher BMI, greater tobacco exposure, and more advanced pubertal development were also associated with more rapid aging. After adjustment for these covariates, however, the significant correlation between socioeconomic disadvantage and rapid aging remained, the investigators noted.

“Our results suggest that salivary DNA methylation measures of pace of aging may provide a surrogate or intermediate endpoint for understanding the health impacts of [childhood] interventions,” the investigators concluded. “Such applications may prove particularly useful for evaluating the effectiveness of health-promoting interventions in at-risk groups.”

Still, more work is needed to understand exactly how socioeconomic disadvantage is associated with accelerated aging.

“Ultimately, not only longitudinal repeated-measures studies but also natural experiment studies and randomized controlled trials of social programs are needed to establish causal effects of social disadvantage on DunedinPoAm-measured pace of aging and to establish DunedinPoAm as a mediator of the process through which childhood disadvantage leads to aging-related health conditions,” the investigators wrote.

In his editorial, Dr. Notterman emphasized this point.

“[I]t is worth remembering that associations with either methylation age or pace of aging and health or longevity may represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (low socioeconomic status, adversity) to health outcome (i.e., cancer, vascular disease),” he wrote.

Paul Chung, MD, professor and chair of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., and adjunct professor at the University of California, Los Angeles, called the findings “preliminary,” but noted that confirmation through further research could “fill in some really important gaps.

“Right now, to some degree, we’re at a little bit of an impasse,” Dr. Chung said.

Adverse childhood experiences are “associated very strongly” with mental and physical health issues, Dr. Chung said, “but we don’t know exactly why, and because of that, it’s really hard to come up with social policy solutions that aren’t anything but extremely sort of blunt-ended. We just say, ‘Well, I guess you gotta fix everything.’ And it’s a hard place to be, I think, in the field.”

Although the present study doesn’t resolve this issue, Dr. Chung suggested that the findings “really open the door to a lot of really exciting research that could have a lot of impacts on practice and policy.”

“Sometimes the only way to get people to pay attention enough to generate the level of excitement that would allow you to even do these sorts of studies ... is to generate some initial exploratory data that makes people perk up their ears, and makes people go, ‘Hey, wow, maybe we should be looking into this.’ ”

The study by Dr. Raffington and colleagues was funded by the National Institutes of Health and the Jacobs Foundation, with additional support from the German Research Foundation, Russell Sage Foundation Biology and Social Science Grant, the Canadian Institute for Advanced Research Child and Brain Development Network, and others. The study by Dr. Lieshout and colleagues was supported by Canadian Institutes of Health Research. Dr. Factor-Litvak and Dr. Notterman reported funding from the National Institutes of Health. All of the investigators and interviewees reported no conflicts of interest.

Adversity in early life – whether preterm birth or socioeconomic disadvantage in childhood – accelerates aging, according to two recent studies, but underlying mechanisms remain unclear, and methods of investigation continue to evolve.

While one study used an established epigenetic clock to measure biological age among adults with extremely low birth weight, the other showcased a relatively new tool to measure pace of biological aging in disadvantaged children, suggesting that the metric may one day serve as a real-time measure of interventional efficacy.

These findings build upon previous studies that have demonstrated a correlation between biological age, also known as methylation age, and an increased risk of health problems later in life, according to Daniel A. Notterman, MD, professor of molecular biology at Princeton (N.J.) University.

“Finding that a person’s methylation age is greater than their chronological age has been taken as evidence of increased ‘biological age’ and perhaps a tendency to greater future morbidity,” Dr. Notterman wrote in a Pediatrics editorial. “Indeed, methylation age is advanced in association with a number of childhood and midlife adversities as well as morbidities such as atherosclerosis, cancer, and obesity.”
 

Extremely low birth weight associated with faster aging in men

For some individuals, accelerated biological aging begins at birth, or even in utero, according to Ryan J. Van Lieshout, MD, PhD, Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University, Hamilton, Ont., and colleagues.

The investigators conducted a study involving 45 extremely low birth weight (ELBW) survivors and 49 individuals born at normal birth weight. All participants were drawn from a longitudinal study conducted between 1977 and 1982 that assessed advances in neonatal intensive care. Controls were recruited at 8 years of age and matched with ELBW survivors based on family socioeconomic status, sex, and age. Follow-up continued through adulthood, allowing for the present trial to compare data from ages 8, 30, and 35.

Using samples of buccal epithelial cells, the investigators measured biological age with the Horvath epigenetic clock, the most commonly used tool of its kind, which measures cytosine-5 methylation at 353 cytosine-phosphate-guanine sites. Results were adjusted for a variety of covariates, such as smoking status, body mass index, number of chronic health conditions, and others.

Between groups, ELBW survivors trended toward older biological age, compared with adults born at normal birth weight (29.0 vs. 27.9 years), a difference that was not statistically significant. Further analysis, however, showed a significant sex-based difference between groups: Male survivors of ELBW, in adulthood, were almost 5 years biologically older than men born at normal birth weight (31.4 vs. 26.9 years; P = .01).

“[W]e provide preliminary evidence of a new link between ELBW and accelerated biological aging among men,” the investigators concluded.

In an accompanying editorial, Pam Factor-Litvak, PhD, vice chair of epidemiology at Columbia University, New York, wrote, “The findings are intriguing and open many questions for further study.”

Dr. Factor-Litvak noted that it remains unclear whether differences in biological aging were present at birth.

“[D]ifferences would provide evidence that accelerated aging begins during the in utero period, perhaps because of maternal undernutrition, stress, or another exposure,” Dr. Factor-Litvak wrote. “[R]eductions in chronic stress levels, which may begin for neonates with ELBW in utero and in the first hours of life, may provide an opportunity for interventions,” she added.

According to Calvin J. Hobel, MD, professor of pediatrics at Cedars-Sinai and professor of obstetrics and gynecology at University of California, Los Angeles, who has been studying preterm birth for more than 40 years, interventions may need to begin even earlier.

Measuring the impact of socioeconomic status on biological aging, now in real-time

A second study, by Laurel Raffington, PhD, of the University of Texas at Austin, and colleagues, evaluated the relationship between socioeconomic disadvantage in childhood and pace of biological aging.

To do so, they used the DunedinPoAm DNA methylation algorithm, a relatively new tool that was developed by analyzing changes in organ system integrity over time among adults with the same chronological age.

“Whereas epigenetic clocks quantify the amount of aging that has already occurred up to the time of measurement, DunedinPoAm quantifies how fast an individual is aging,” Dr. Raffington and colleagues wrote. “In other words, whereas epigenetic clocks tell you what time it is, pace-of-aging measures tell you how fast the clock is ticking.”

The investigators measured pace of aging in 600 children and adolescents (8-18 years of age) from the Texas Twin Project, “an ongoing longitudinal study that includes the collection of salivary samples.” The final dataset included 457 participants who identified as White, 77 who identified as Latinx, and 61 who identified as both White and Latinx.

The investigators evaluated pace of aging compared with family-level and neighborhood-level socioeconomic status, and tested for confounding by tobacco exposure, BMI, and pubertal development.

This analysis revealed that children experiencing socioeconomic disadvantage were aging more quickly than their peers, in terms of both family-level and neighborhood-level inequity (both levels, r = 0.18; P = .001).

Children who identified as Latinx aged faster than did those who identified as White only or White and Latinx, “consistent with higher levels of disadvantage in this group,” the investigators wrote. “Thus, our findings are consistent with observations that racial and/or ethnic socioeconomic disparities are an important contributor to racial and/or ethnic disparities in health.”

Higher BMI, greater tobacco exposure, and more advanced pubertal development were also associated with more rapid aging. After adjustment for these covariates, however, the significant correlation between socioeconomic disadvantage and rapid aging remained, the investigators noted.

“Our results suggest that salivary DNA methylation measures of pace of aging may provide a surrogate or intermediate endpoint for understanding the health impacts of [childhood] interventions,” the investigators concluded. “Such applications may prove particularly useful for evaluating the effectiveness of health-promoting interventions in at-risk groups.”

Still, more work is needed to understand exactly how socioeconomic disadvantage is associated with accelerated aging.

“Ultimately, not only longitudinal repeated-measures studies but also natural experiment studies and randomized controlled trials of social programs are needed to establish causal effects of social disadvantage on DunedinPoAm-measured pace of aging and to establish DunedinPoAm as a mediator of the process through which childhood disadvantage leads to aging-related health conditions,” the investigators wrote.

In his editorial, Dr. Notterman emphasized this point.

“[I]t is worth remembering that associations with either methylation age or pace of aging and health or longevity may represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (low socioeconomic status, adversity) to health outcome (i.e., cancer, vascular disease),” he wrote.

Paul Chung, MD, professor and chair of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., and adjunct professor at the University of California, Los Angeles, called the findings “preliminary,” but noted that confirmation through further research could “fill in some really important gaps.

“Right now, to some degree, we’re at a little bit of an impasse,” Dr. Chung said.

Adverse childhood experiences are “associated very strongly” with mental and physical health issues, Dr. Chung said, “but we don’t know exactly why, and because of that, it’s really hard to come up with social policy solutions that aren’t anything but extremely sort of blunt-ended. We just say, ‘Well, I guess you gotta fix everything.’ And it’s a hard place to be, I think, in the field.”

Although the present study doesn’t resolve this issue, Dr. Chung suggested that the findings “really open the door to a lot of really exciting research that could have a lot of impacts on practice and policy.”

“Sometimes the only way to get people to pay attention enough to generate the level of excitement that would allow you to even do these sorts of studies ... is to generate some initial exploratory data that makes people perk up their ears, and makes people go, ‘Hey, wow, maybe we should be looking into this.’ ”

The study by Dr. Raffington and colleagues was funded by the National Institutes of Health and the Jacobs Foundation, with additional support from the German Research Foundation, Russell Sage Foundation Biology and Social Science Grant, the Canadian Institute for Advanced Research Child and Brain Development Network, and others. The study by Dr. Lieshout and colleagues was supported by Canadian Institutes of Health Research. Dr. Factor-Litvak and Dr. Notterman reported funding from the National Institutes of Health. All of the investigators and interviewees reported no conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The benefits of COVID-19 vaccination “enormously outweigh” the rare possible risk for heart-related complications, including myocarditis, the American Heart Association/American Stroke Association (ASA) says in new statement.

The message follows a Centers for Disease Control and Prevention report that the agency is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.

The “relatively few” reported cases myocarditis in adolescents or young adults have involved males more often than females, more often followed the second dose rather than the first, and were usually seen in the 4 days after vaccination, the CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) found.

“Most cases appear to be mild, and follow-up of cases is ongoing,” the CDC says. “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

In their statement, the AHA/ASA “strongly urge” all adults and children 12 years and older to receive a COVID-19 vaccine as soon as possible.

“The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection,” the groups say.

Although the investigation of cases of myocarditis related to COVID-19 vaccination is ongoing, the AHA/ASA notes that myocarditis is typically the result of an actual viral infection, “and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

“We’ve lost hundreds of children, and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis,” Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF), said today on ABC’s Good Morning America.

Still, “from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine,” said Dr. Besser, former acting director of the CDC.

The symptoms that can occur after COVID-19 vaccination include tiredness, headache, muscle pain, chills, fever, and nausea, reminds the AHA/ASA statement. Such symptoms would “typically appear within 24-48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All health care providers should be aware of the “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation, it says.

“Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly,” the statement advises.

 A version of this article first appeared on Medscape.com.

The benefits of COVID-19 vaccination “enormously outweigh” the rare possible risk for heart-related complications, including myocarditis, the American Heart Association/American Stroke Association (ASA) says in new statement.

The message follows a Centers for Disease Control and Prevention report that the agency is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.

The “relatively few” reported cases myocarditis in adolescents or young adults have involved males more often than females, more often followed the second dose rather than the first, and were usually seen in the 4 days after vaccination, the CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) found.

“Most cases appear to be mild, and follow-up of cases is ongoing,” the CDC says. “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

In their statement, the AHA/ASA “strongly urge” all adults and children 12 years and older to receive a COVID-19 vaccine as soon as possible.

“The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection,” the groups say.

Although the investigation of cases of myocarditis related to COVID-19 vaccination is ongoing, the AHA/ASA notes that myocarditis is typically the result of an actual viral infection, “and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

“We’ve lost hundreds of children, and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis,” Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF), said today on ABC’s Good Morning America.

Still, “from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine,” said Dr. Besser, former acting director of the CDC.

The symptoms that can occur after COVID-19 vaccination include tiredness, headache, muscle pain, chills, fever, and nausea, reminds the AHA/ASA statement. Such symptoms would “typically appear within 24-48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All health care providers should be aware of the “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation, it says.

“Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly,” the statement advises.

 A version of this article first appeared on Medscape.com.

The benefits of COVID-19 vaccination “enormously outweigh” the rare possible risk for heart-related complications, including myocarditis, the American Heart Association/American Stroke Association (ASA) says in new statement.

The message follows a Centers for Disease Control and Prevention report that the agency is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.

The “relatively few” reported cases myocarditis in adolescents or young adults have involved males more often than females, more often followed the second dose rather than the first, and were usually seen in the 4 days after vaccination, the CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) found.

“Most cases appear to be mild, and follow-up of cases is ongoing,” the CDC says. “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

In their statement, the AHA/ASA “strongly urge” all adults and children 12 years and older to receive a COVID-19 vaccine as soon as possible.

“The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection,” the groups say.

Although the investigation of cases of myocarditis related to COVID-19 vaccination is ongoing, the AHA/ASA notes that myocarditis is typically the result of an actual viral infection, “and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

“We’ve lost hundreds of children, and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis,” Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF), said today on ABC’s Good Morning America.

Still, “from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine,” said Dr. Besser, former acting director of the CDC.

The symptoms that can occur after COVID-19 vaccination include tiredness, headache, muscle pain, chills, fever, and nausea, reminds the AHA/ASA statement. Such symptoms would “typically appear within 24-48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All health care providers should be aware of the “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation, it says.

“Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly,” the statement advises.

 A version of this article first appeared on Medscape.com.

For the first readers of Family Practice News, it started with this: “How safe is the pill? An extensive epidemiologic study being carried out in the United Kingdom by the Royal College of General Practitioners is expected to provide definitive answers to this question within the next few years.”

MDedge News

That was the first paragraph of the lead article on the front page of our very first issue, published in October 1971. The report on oral contraceptives, coming from the annual meeting of the British Medical Association in Leicester, largely focused on recruiting – noting that “all women in the study are married” – and data-gathering methods.

That first issue also covered such topics as the effect of “early and frequent coitus” on cervical dysplasia incidence (p. 4), breast cancer in men (p. 13), and treatment of prostate inflammation in patients with impotence (p. 34).

Our April 2021 issue included five articles related to the COVID-19 pandemic, starting on the front page and featuring a photo – a physician sitting at a computer, wearing a mask – and a topic – vaccine-hesitant patients.


 

Business of medicine today vs. in 1971

At the time of publication of our first issue the United States was in the midst of a 90-day freeze on wages and prices ordered by President Richard Nixon. Two articles in that first issue discussed the subject: “Freeze clouds future of health insurance plans” and “Freeze lets physicians ‘stabilize’ office fees.”

Besides COVID-19, here are some other topics covered in April 2021 but not in 1971: lessons learned from an electronic health records conversion, competition for physicians in the form of a “virtual primary care service” offered by United Healthcare, and the sleep effects of smartphone “addiction.”

Technology, clearly, plays a much larger role in physicians’ lives these days.
 

Similarities between issues

Not everything has changed, of course. We were informing physicians about heart disease in 1971 with “Primary MD can treat most vascular cases” and “Job satisfaction can help prevent heart disease.”

A look at the latest issue uncovered “Link clinched between high-glycemic index diets and cardiovascular disease events” and “Ultraprocessed ‘healthy’ foods raise cardiovascular disease events risk.” Diabetes is another topic that we have began covering since day one and continue to consider to be relevant to practicing family medicine. “Family attitude key to diabetic’s state” was published in our first issue and “Type 1 diabetes prevention moves toward reality as studies published” ran in our April 2021 issue.

The photos in that first issue, however, present a somewhat jarring counterpoint to our latest issue. The faces that look back from 50 years ago are men’s faces: 29 men, to be exact. There were no photos of women physicians in that issue.

That was not the case in April of 2021. Of the 26 physicians or research scientists who appeared in photos in that issue, 8 were women. Plus, three of those women appeared on the cover.

Among the photos from 1971 were 6 of the 14 founding members of our editorial advisory board, who were, again, all men. Our current board consists of 13 men and 8 women.

Times have changed.

rfranki@mdedge.com

This article was updated 5/27/21.

For the first readers of Family Practice News, it started with this: “How safe is the pill? An extensive epidemiologic study being carried out in the United Kingdom by the Royal College of General Practitioners is expected to provide definitive answers to this question within the next few years.”

MDedge News

That was the first paragraph of the lead article on the front page of our very first issue, published in October 1971. The report on oral contraceptives, coming from the annual meeting of the British Medical Association in Leicester, largely focused on recruiting – noting that “all women in the study are married” – and data-gathering methods.

That first issue also covered such topics as the effect of “early and frequent coitus” on cervical dysplasia incidence (p. 4), breast cancer in men (p. 13), and treatment of prostate inflammation in patients with impotence (p. 34).

Our April 2021 issue included five articles related to the COVID-19 pandemic, starting on the front page and featuring a photo – a physician sitting at a computer, wearing a mask – and a topic – vaccine-hesitant patients.


 

Business of medicine today vs. in 1971

At the time of publication of our first issue the United States was in the midst of a 90-day freeze on wages and prices ordered by President Richard Nixon. Two articles in that first issue discussed the subject: “Freeze clouds future of health insurance plans” and “Freeze lets physicians ‘stabilize’ office fees.”

Besides COVID-19, here are some other topics covered in April 2021 but not in 1971: lessons learned from an electronic health records conversion, competition for physicians in the form of a “virtual primary care service” offered by United Healthcare, and the sleep effects of smartphone “addiction.”

Technology, clearly, plays a much larger role in physicians’ lives these days.
 

Similarities between issues

Not everything has changed, of course. We were informing physicians about heart disease in 1971 with “Primary MD can treat most vascular cases” and “Job satisfaction can help prevent heart disease.”

A look at the latest issue uncovered “Link clinched between high-glycemic index diets and cardiovascular disease events” and “Ultraprocessed ‘healthy’ foods raise cardiovascular disease events risk.” Diabetes is another topic that we have began covering since day one and continue to consider to be relevant to practicing family medicine. “Family attitude key to diabetic’s state” was published in our first issue and “Type 1 diabetes prevention moves toward reality as studies published” ran in our April 2021 issue.

The photos in that first issue, however, present a somewhat jarring counterpoint to our latest issue. The faces that look back from 50 years ago are men’s faces: 29 men, to be exact. There were no photos of women physicians in that issue.

That was not the case in April of 2021. Of the 26 physicians or research scientists who appeared in photos in that issue, 8 were women. Plus, three of those women appeared on the cover.

Among the photos from 1971 were 6 of the 14 founding members of our editorial advisory board, who were, again, all men. Our current board consists of 13 men and 8 women.

Times have changed.

rfranki@mdedge.com

This article was updated 5/27/21.

For the first readers of Family Practice News, it started with this: “How safe is the pill? An extensive epidemiologic study being carried out in the United Kingdom by the Royal College of General Practitioners is expected to provide definitive answers to this question within the next few years.”

MDedge News

That was the first paragraph of the lead article on the front page of our very first issue, published in October 1971. The report on oral contraceptives, coming from the annual meeting of the British Medical Association in Leicester, largely focused on recruiting – noting that “all women in the study are married” – and data-gathering methods.

That first issue also covered such topics as the effect of “early and frequent coitus” on cervical dysplasia incidence (p. 4), breast cancer in men (p. 13), and treatment of prostate inflammation in patients with impotence (p. 34).

Our April 2021 issue included five articles related to the COVID-19 pandemic, starting on the front page and featuring a photo – a physician sitting at a computer, wearing a mask – and a topic – vaccine-hesitant patients.


 

Business of medicine today vs. in 1971

At the time of publication of our first issue the United States was in the midst of a 90-day freeze on wages and prices ordered by President Richard Nixon. Two articles in that first issue discussed the subject: “Freeze clouds future of health insurance plans” and “Freeze lets physicians ‘stabilize’ office fees.”

Besides COVID-19, here are some other topics covered in April 2021 but not in 1971: lessons learned from an electronic health records conversion, competition for physicians in the form of a “virtual primary care service” offered by United Healthcare, and the sleep effects of smartphone “addiction.”

Technology, clearly, plays a much larger role in physicians’ lives these days.
 

Similarities between issues

Not everything has changed, of course. We were informing physicians about heart disease in 1971 with “Primary MD can treat most vascular cases” and “Job satisfaction can help prevent heart disease.”

A look at the latest issue uncovered “Link clinched between high-glycemic index diets and cardiovascular disease events” and “Ultraprocessed ‘healthy’ foods raise cardiovascular disease events risk.” Diabetes is another topic that we have began covering since day one and continue to consider to be relevant to practicing family medicine. “Family attitude key to diabetic’s state” was published in our first issue and “Type 1 diabetes prevention moves toward reality as studies published” ran in our April 2021 issue.

The photos in that first issue, however, present a somewhat jarring counterpoint to our latest issue. The faces that look back from 50 years ago are men’s faces: 29 men, to be exact. There were no photos of women physicians in that issue.

That was not the case in April of 2021. Of the 26 physicians or research scientists who appeared in photos in that issue, 8 were women. Plus, three of those women appeared on the cover.

Among the photos from 1971 were 6 of the 14 founding members of our editorial advisory board, who were, again, all men. Our current board consists of 13 men and 8 women.

Times have changed.

rfranki@mdedge.com

This article was updated 5/27/21.

The greatest relative benefit from omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, is produced in heart failure patients with the lowest left ventricular ejection fraction (LVEF), a new analysis of the recently published phase 3 GALACTIC-HF trial has found.

The findings reinforce the potential for this drug to be helpful in the management of the most advanced stages of heart failure with reduced ejection fraction (HFrEF), reported John R. Teerlink, MD, director of heart failure at San Francisco Veterans Affairs Medical Center, at the annual scientific sessions of the American College of Cardiology.

The phase 3 multinational GALACTIC-HF trial, published earlier this year, linked omecamtiv mecarbil with an 8% reduction in the risk of a heart failure–related events or cardiovascular death, relative to placebo, which was the primary outcome. For entry, HFrEF patients were required to have a LVEF of 35% or less.

Drilling down on ejection fraction

The new analysis divided participants into quartiles of baseline LVEF and then compared relative outcomes and safety.

In the lowest quartile, defined by a LVEF of 22% or lower, the reduction in risk of events reached 17% (hazard ratio, 0.83; 95% confidence interval, 0.73-0.95) for omecamtiv mecarbil relative to placebo. In the highest, defined by a LVEF of 33% or greater, the benefit fell short of significance (HR 0.99; 95% CI, 0.84-1.16). Across quartiles, LVEF was the “strongest modifier of the treatment effect,” emerging in this analysis as a statistically significant (P = .004) continuous variable.

The comparison by LVEF quartiles also provided an opportunity to show that omecamtiv mecarbil was as safe and well tolerated in those with the most advanced disease as in those less sick. At the lowest levels of LVEF, like the higher levels, omecamtiv mecarbil did not produce any adverse effects on blood pressure, heart rate, potassium homeostasis, or renal function.

In GALACTIC-HF, 8,256 HFrEF patients with LVEF 35% or less were randomized to omecamtiv mecarbil or placebo. The primary composite outcome of hospitalization or urgent visit for heart failure or death from cardiovascular causes was evaluated after a median of 21.8 months on therapy.

When incidence rate per 100 patient years was graphed against the range of LVEF, the relative advantage of omecamtiv mecarbil became visible just below an LVEF of 30%, climbing steadily even to the lowest LVEF, which reached 10%.

Perhaps relevant to the reduction in events, there were also greater relative reductions in NT-proBNP (NT-proB-type natriuretic peptide) for omecamtiv mecarbil at lower relative to higher LVEF. Although omecamtiv mecarbil is not associated with any direct vascular, electrophysiologic, or neurohormonal effects, according to Dr. Teerlink, the indirect effects of selective binding to cardiac myosin has been associated with lower NT-proBNP and other biomarkers of cardiac remodeling in prior clinical studies.

Although Dr. Teerlink acknowledged that relatively few patients in GALACTIC-HF received an angiotensin-receptor neprilysin inhibitor (ARNI) or a sodium glucose cotransporter-2 (SGLT2) inhibitor, he said there is “every reason to believe that omecamtiv mecarbil would be complementary to these therapies.” He said the mechanism of action of omecamtiv mecarbil, which improves systolic function, has no overlap with these drugs.

Importantly, there is a particular need for new treatment options in patients with advanced LVEF, according to Dr. Teerlink, who cited evidence, for example, that “the beneficial effect of [the ARNI] sacubitril valsartan, while still significant, decreases in patients with LVEF less than 35%.”

Overall, based on these results, “we believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejection fraction, which are the very patients that are most challenging for us to treat,” Dr. Teerlink said.
 

Omecamtiv mecarbil may ‘buy you some time’

Ileana Piña, MD, clinical professor of medicine, Central Michigan University, Mount Pleasant, Mich., agreed. She said that omecamtiv mecarbil, if approved, will be an option for the type of HFrEF patients who are being considered for heart transplant or mechanical-assist devices.

“We are very loath to use inotropes in this population, because we know that ultimately the inotrope is not going to do well,” said Dr. Piña, calling these therapies a “Band-Aid.” Based on the evidence from GALACTIC-HF, she thinks that omecamtiv mecarbil will be more versatile.

“This drug does not increase myocardial oxygen demand as do the inotropes, and it can be given in the outpatient setting if need be, so I see this as a real advance,” Dr. Piña said. Although Dr. Piña acknowledged that omecamtiv mecarbil did not reduce mortality in the GALACTIC-HF trial, “at least it will buy you some time.”

Dr. Teerlink has financial relationships with multiple pharmaceutical companies, including Amgen, Cytogenetics, and Servier, which provided funding for the GALACTIC-HF trial. Dr. Piña reports no potential conflicts of interest.

The greatest relative benefit from omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, is produced in heart failure patients with the lowest left ventricular ejection fraction (LVEF), a new analysis of the recently published phase 3 GALACTIC-HF trial has found.

The findings reinforce the potential for this drug to be helpful in the management of the most advanced stages of heart failure with reduced ejection fraction (HFrEF), reported John R. Teerlink, MD, director of heart failure at San Francisco Veterans Affairs Medical Center, at the annual scientific sessions of the American College of Cardiology.

The phase 3 multinational GALACTIC-HF trial, published earlier this year, linked omecamtiv mecarbil with an 8% reduction in the risk of a heart failure–related events or cardiovascular death, relative to placebo, which was the primary outcome. For entry, HFrEF patients were required to have a LVEF of 35% or less.

Drilling down on ejection fraction

The new analysis divided participants into quartiles of baseline LVEF and then compared relative outcomes and safety.

In the lowest quartile, defined by a LVEF of 22% or lower, the reduction in risk of events reached 17% (hazard ratio, 0.83; 95% confidence interval, 0.73-0.95) for omecamtiv mecarbil relative to placebo. In the highest, defined by a LVEF of 33% or greater, the benefit fell short of significance (HR 0.99; 95% CI, 0.84-1.16). Across quartiles, LVEF was the “strongest modifier of the treatment effect,” emerging in this analysis as a statistically significant (P = .004) continuous variable.

The comparison by LVEF quartiles also provided an opportunity to show that omecamtiv mecarbil was as safe and well tolerated in those with the most advanced disease as in those less sick. At the lowest levels of LVEF, like the higher levels, omecamtiv mecarbil did not produce any adverse effects on blood pressure, heart rate, potassium homeostasis, or renal function.

In GALACTIC-HF, 8,256 HFrEF patients with LVEF 35% or less were randomized to omecamtiv mecarbil or placebo. The primary composite outcome of hospitalization or urgent visit for heart failure or death from cardiovascular causes was evaluated after a median of 21.8 months on therapy.

When incidence rate per 100 patient years was graphed against the range of LVEF, the relative advantage of omecamtiv mecarbil became visible just below an LVEF of 30%, climbing steadily even to the lowest LVEF, which reached 10%.

Perhaps relevant to the reduction in events, there were also greater relative reductions in NT-proBNP (NT-proB-type natriuretic peptide) for omecamtiv mecarbil at lower relative to higher LVEF. Although omecamtiv mecarbil is not associated with any direct vascular, electrophysiologic, or neurohormonal effects, according to Dr. Teerlink, the indirect effects of selective binding to cardiac myosin has been associated with lower NT-proBNP and other biomarkers of cardiac remodeling in prior clinical studies.

Although Dr. Teerlink acknowledged that relatively few patients in GALACTIC-HF received an angiotensin-receptor neprilysin inhibitor (ARNI) or a sodium glucose cotransporter-2 (SGLT2) inhibitor, he said there is “every reason to believe that omecamtiv mecarbil would be complementary to these therapies.” He said the mechanism of action of omecamtiv mecarbil, which improves systolic function, has no overlap with these drugs.

Importantly, there is a particular need for new treatment options in patients with advanced LVEF, according to Dr. Teerlink, who cited evidence, for example, that “the beneficial effect of [the ARNI] sacubitril valsartan, while still significant, decreases in patients with LVEF less than 35%.”

Overall, based on these results, “we believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejection fraction, which are the very patients that are most challenging for us to treat,” Dr. Teerlink said.
 

Omecamtiv mecarbil may ‘buy you some time’

Ileana Piña, MD, clinical professor of medicine, Central Michigan University, Mount Pleasant, Mich., agreed. She said that omecamtiv mecarbil, if approved, will be an option for the type of HFrEF patients who are being considered for heart transplant or mechanical-assist devices.

“We are very loath to use inotropes in this population, because we know that ultimately the inotrope is not going to do well,” said Dr. Piña, calling these therapies a “Band-Aid.” Based on the evidence from GALACTIC-HF, she thinks that omecamtiv mecarbil will be more versatile.

“This drug does not increase myocardial oxygen demand as do the inotropes, and it can be given in the outpatient setting if need be, so I see this as a real advance,” Dr. Piña said. Although Dr. Piña acknowledged that omecamtiv mecarbil did not reduce mortality in the GALACTIC-HF trial, “at least it will buy you some time.”

Dr. Teerlink has financial relationships with multiple pharmaceutical companies, including Amgen, Cytogenetics, and Servier, which provided funding for the GALACTIC-HF trial. Dr. Piña reports no potential conflicts of interest.

The greatest relative benefit from omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, is produced in heart failure patients with the lowest left ventricular ejection fraction (LVEF), a new analysis of the recently published phase 3 GALACTIC-HF trial has found.

The findings reinforce the potential for this drug to be helpful in the management of the most advanced stages of heart failure with reduced ejection fraction (HFrEF), reported John R. Teerlink, MD, director of heart failure at San Francisco Veterans Affairs Medical Center, at the annual scientific sessions of the American College of Cardiology.

The phase 3 multinational GALACTIC-HF trial, published earlier this year, linked omecamtiv mecarbil with an 8% reduction in the risk of a heart failure–related events or cardiovascular death, relative to placebo, which was the primary outcome. For entry, HFrEF patients were required to have a LVEF of 35% or less.

Drilling down on ejection fraction

The new analysis divided participants into quartiles of baseline LVEF and then compared relative outcomes and safety.

In the lowest quartile, defined by a LVEF of 22% or lower, the reduction in risk of events reached 17% (hazard ratio, 0.83; 95% confidence interval, 0.73-0.95) for omecamtiv mecarbil relative to placebo. In the highest, defined by a LVEF of 33% or greater, the benefit fell short of significance (HR 0.99; 95% CI, 0.84-1.16). Across quartiles, LVEF was the “strongest modifier of the treatment effect,” emerging in this analysis as a statistically significant (P = .004) continuous variable.

The comparison by LVEF quartiles also provided an opportunity to show that omecamtiv mecarbil was as safe and well tolerated in those with the most advanced disease as in those less sick. At the lowest levels of LVEF, like the higher levels, omecamtiv mecarbil did not produce any adverse effects on blood pressure, heart rate, potassium homeostasis, or renal function.

In GALACTIC-HF, 8,256 HFrEF patients with LVEF 35% or less were randomized to omecamtiv mecarbil or placebo. The primary composite outcome of hospitalization or urgent visit for heart failure or death from cardiovascular causes was evaluated after a median of 21.8 months on therapy.

When incidence rate per 100 patient years was graphed against the range of LVEF, the relative advantage of omecamtiv mecarbil became visible just below an LVEF of 30%, climbing steadily even to the lowest LVEF, which reached 10%.

Perhaps relevant to the reduction in events, there were also greater relative reductions in NT-proBNP (NT-proB-type natriuretic peptide) for omecamtiv mecarbil at lower relative to higher LVEF. Although omecamtiv mecarbil is not associated with any direct vascular, electrophysiologic, or neurohormonal effects, according to Dr. Teerlink, the indirect effects of selective binding to cardiac myosin has been associated with lower NT-proBNP and other biomarkers of cardiac remodeling in prior clinical studies.

Although Dr. Teerlink acknowledged that relatively few patients in GALACTIC-HF received an angiotensin-receptor neprilysin inhibitor (ARNI) or a sodium glucose cotransporter-2 (SGLT2) inhibitor, he said there is “every reason to believe that omecamtiv mecarbil would be complementary to these therapies.” He said the mechanism of action of omecamtiv mecarbil, which improves systolic function, has no overlap with these drugs.

Importantly, there is a particular need for new treatment options in patients with advanced LVEF, according to Dr. Teerlink, who cited evidence, for example, that “the beneficial effect of [the ARNI] sacubitril valsartan, while still significant, decreases in patients with LVEF less than 35%.”

Overall, based on these results, “we believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejection fraction, which are the very patients that are most challenging for us to treat,” Dr. Teerlink said.
 

Omecamtiv mecarbil may ‘buy you some time’

Ileana Piña, MD, clinical professor of medicine, Central Michigan University, Mount Pleasant, Mich., agreed. She said that omecamtiv mecarbil, if approved, will be an option for the type of HFrEF patients who are being considered for heart transplant or mechanical-assist devices.

“We are very loath to use inotropes in this population, because we know that ultimately the inotrope is not going to do well,” said Dr. Piña, calling these therapies a “Band-Aid.” Based on the evidence from GALACTIC-HF, she thinks that omecamtiv mecarbil will be more versatile.

“This drug does not increase myocardial oxygen demand as do the inotropes, and it can be given in the outpatient setting if need be, so I see this as a real advance,” Dr. Piña said. Although Dr. Piña acknowledged that omecamtiv mecarbil did not reduce mortality in the GALACTIC-HF trial, “at least it will buy you some time.”

Dr. Teerlink has financial relationships with multiple pharmaceutical companies, including Amgen, Cytogenetics, and Servier, which provided funding for the GALACTIC-HF trial. Dr. Piña reports no potential conflicts of interest.

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

mzoler@mdedge.com

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

mzoler@mdedge.com

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

mzoler@mdedge.com

Individuals at increased risk for dementia because of family history can reduce that risk by adopting healthy lifestyle behaviors, data from more than 300,000 adults aged 50-73 years suggest.

Having a parent or sibling with dementia can increase a person’s risk of developing dementia themselves by nearly 75%, compared with someone with no first-degree family history of dementia, according to Angelique Brellenthin, PhD, of Iowa State University, Ames, and colleagues.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association, the researchers reviewed information for 302,239 men and women who were enrolled in the U.K. Biobank, a population-based study of more than 500,000 individuals in the United Kingdom, between 2006 and 2010.

The study participants had no evidence of dementia at baseline, and completed questionnaires about family history and lifestyle. The questions included details about six healthy lifestyle behaviors: eating a healthy diet, engaging in at least 150 minutes of moderate to vigorous physical activity per week, sleeping 6-9 hours each night, drinking alcohol in moderation, not smoking, and maintaining a body mass index below the obese level (less than 30 kg/m²).

The researchers identified 1,698 participants (0.6%) who developed dementia over an average follow-up period of 8 years. Those with a family history (first-degree relative) of dementia had a 70% increased risk of dementia, compared with those who had no such family history.

Overall, individuals who engaged in all six healthy behaviors reduced their risk of dementia by about half, compared with those who engaged in two or fewer healthy behaviors. Engaging in three healthy behaviors reduced the risk of dementia by 30%, compared with engaging in two or fewer healthy behaviors, and this association held after controlling not only for family history of dementia, but also for other dementia risk factors such as age, sex, race, and education level, as well as high blood pressure, high cholesterol, and the presence of type 2 diabetes.

Similarly, among participants with a family history of dementia, those who engaged in three healthy lifestyle behaviors showed a 25%-35% reduction in dementia risk, compared with those who engaged in two or fewer healthy behaviors.

The study findings were limited by several factors including the inability to prove that lifestyle can cause or prevent dementia, only to show an association, the researchers noted. Also, the findings were limited by the reliance on self-reports, rather than genetic data, to confirm familial dementia.

However, the findings were strengthened by the large sample size, and the results suggest that a healthy lifestyle can impact cognitive health, and support the value of encouraging healthy behaviors in general, and especially among individuals with a family history of dementia, they said.
 

Small changes may promote prevention

The study is important now because, as the population ages, many individuals have a family member who has had dementia, said lead author Dr. Brellenthin, in an interview. “It’s important to understand how lifestyle behaviors affect the risk of dementia when it runs in families,” she said.

Dr. Brellenthin said she was surprised by some of the findings. “It was surprising to see that the risk of dementia was reduced with just three healthy behaviors [but was further reduced as you added more behaviors] compared to two or fewer behaviors. However, it was not surprising to see that these same lifestyle behaviors that tend to be good for the heart and body are also good for the brain.”

The evidence that following just three healthy behaviors can reduce the risk of dementia by 25%-35% for individuals with a familial history of dementia has clinical implications, Dr. Brellenthin said. “Many people are already following some of these behaviors like not smoking, so it might be possible to focus on adding just one more behavior, like getting enough sleep, and going from there.”

Commenting on the study, AHA President Mitchell S. V. Elkind, MD, said that the study “tells us that, yes, family history is important [in determining the risk of dementia], and much of that may be driven by genetic factors, but some of that impact can be mitigated or decreased by engaging in those important behaviors that we know are good to maintain brain health.

“The tricky thing, of course, is getting people to engage in these behaviors. That’s where a lot of work in the future will be: changing people’s behavior to become more healthy, and figuring out exactly which behaviors may be the easiest to engage in and be most likely to have public health impact,” added Dr. Elkind, professor of neurology and epidemiology at Columbia University and attending neurologist at New York–Presbyterian/Columbia University Irving Medical Center, New York.

The study received no outside funding, but the was research was conducted using the U.K. Biobank resources. The researchers had no financial conflicts to disclose.

Individuals at increased risk for dementia because of family history can reduce that risk by adopting healthy lifestyle behaviors, data from more than 300,000 adults aged 50-73 years suggest.

Having a parent or sibling with dementia can increase a person’s risk of developing dementia themselves by nearly 75%, compared with someone with no first-degree family history of dementia, according to Angelique Brellenthin, PhD, of Iowa State University, Ames, and colleagues.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association, the researchers reviewed information for 302,239 men and women who were enrolled in the U.K. Biobank, a population-based study of more than 500,000 individuals in the United Kingdom, between 2006 and 2010.

The study participants had no evidence of dementia at baseline, and completed questionnaires about family history and lifestyle. The questions included details about six healthy lifestyle behaviors: eating a healthy diet, engaging in at least 150 minutes of moderate to vigorous physical activity per week, sleeping 6-9 hours each night, drinking alcohol in moderation, not smoking, and maintaining a body mass index below the obese level (less than 30 kg/m²).

The researchers identified 1,698 participants (0.6%) who developed dementia over an average follow-up period of 8 years. Those with a family history (first-degree relative) of dementia had a 70% increased risk of dementia, compared with those who had no such family history.

Overall, individuals who engaged in all six healthy behaviors reduced their risk of dementia by about half, compared with those who engaged in two or fewer healthy behaviors. Engaging in three healthy behaviors reduced the risk of dementia by 30%, compared with engaging in two or fewer healthy behaviors, and this association held after controlling not only for family history of dementia, but also for other dementia risk factors such as age, sex, race, and education level, as well as high blood pressure, high cholesterol, and the presence of type 2 diabetes.

Similarly, among participants with a family history of dementia, those who engaged in three healthy lifestyle behaviors showed a 25%-35% reduction in dementia risk, compared with those who engaged in two or fewer healthy behaviors.

The study findings were limited by several factors including the inability to prove that lifestyle can cause or prevent dementia, only to show an association, the researchers noted. Also, the findings were limited by the reliance on self-reports, rather than genetic data, to confirm familial dementia.

However, the findings were strengthened by the large sample size, and the results suggest that a healthy lifestyle can impact cognitive health, and support the value of encouraging healthy behaviors in general, and especially among individuals with a family history of dementia, they said.
 

Small changes may promote prevention

The study is important now because, as the population ages, many individuals have a family member who has had dementia, said lead author Dr. Brellenthin, in an interview. “It’s important to understand how lifestyle behaviors affect the risk of dementia when it runs in families,” she said.

Dr. Brellenthin said she was surprised by some of the findings. “It was surprising to see that the risk of dementia was reduced with just three healthy behaviors [but was further reduced as you added more behaviors] compared to two or fewer behaviors. However, it was not surprising to see that these same lifestyle behaviors that tend to be good for the heart and body are also good for the brain.”

The evidence that following just three healthy behaviors can reduce the risk of dementia by 25%-35% for individuals with a familial history of dementia has clinical implications, Dr. Brellenthin said. “Many people are already following some of these behaviors like not smoking, so it might be possible to focus on adding just one more behavior, like getting enough sleep, and going from there.”

Commenting on the study, AHA President Mitchell S. V. Elkind, MD, said that the study “tells us that, yes, family history is important [in determining the risk of dementia], and much of that may be driven by genetic factors, but some of that impact can be mitigated or decreased by engaging in those important behaviors that we know are good to maintain brain health.

“The tricky thing, of course, is getting people to engage in these behaviors. That’s where a lot of work in the future will be: changing people’s behavior to become more healthy, and figuring out exactly which behaviors may be the easiest to engage in and be most likely to have public health impact,” added Dr. Elkind, professor of neurology and epidemiology at Columbia University and attending neurologist at New York–Presbyterian/Columbia University Irving Medical Center, New York.

The study received no outside funding, but the was research was conducted using the U.K. Biobank resources. The researchers had no financial conflicts to disclose.

Individuals at increased risk for dementia because of family history can reduce that risk by adopting healthy lifestyle behaviors, data from more than 300,000 adults aged 50-73 years suggest.

Having a parent or sibling with dementia can increase a person’s risk of developing dementia themselves by nearly 75%, compared with someone with no first-degree family history of dementia, according to Angelique Brellenthin, PhD, of Iowa State University, Ames, and colleagues.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association, the researchers reviewed information for 302,239 men and women who were enrolled in the U.K. Biobank, a population-based study of more than 500,000 individuals in the United Kingdom, between 2006 and 2010.

The study participants had no evidence of dementia at baseline, and completed questionnaires about family history and lifestyle. The questions included details about six healthy lifestyle behaviors: eating a healthy diet, engaging in at least 150 minutes of moderate to vigorous physical activity per week, sleeping 6-9 hours each night, drinking alcohol in moderation, not smoking, and maintaining a body mass index below the obese level (less than 30 kg/m²).

The researchers identified 1,698 participants (0.6%) who developed dementia over an average follow-up period of 8 years. Those with a family history (first-degree relative) of dementia had a 70% increased risk of dementia, compared with those who had no such family history.

Overall, individuals who engaged in all six healthy behaviors reduced their risk of dementia by about half, compared with those who engaged in two or fewer healthy behaviors. Engaging in three healthy behaviors reduced the risk of dementia by 30%, compared with engaging in two or fewer healthy behaviors, and this association held after controlling not only for family history of dementia, but also for other dementia risk factors such as age, sex, race, and education level, as well as high blood pressure, high cholesterol, and the presence of type 2 diabetes.

Similarly, among participants with a family history of dementia, those who engaged in three healthy lifestyle behaviors showed a 25%-35% reduction in dementia risk, compared with those who engaged in two or fewer healthy behaviors.

The study findings were limited by several factors including the inability to prove that lifestyle can cause or prevent dementia, only to show an association, the researchers noted. Also, the findings were limited by the reliance on self-reports, rather than genetic data, to confirm familial dementia.

However, the findings were strengthened by the large sample size, and the results suggest that a healthy lifestyle can impact cognitive health, and support the value of encouraging healthy behaviors in general, and especially among individuals with a family history of dementia, they said.
 

Small changes may promote prevention

The study is important now because, as the population ages, many individuals have a family member who has had dementia, said lead author Dr. Brellenthin, in an interview. “It’s important to understand how lifestyle behaviors affect the risk of dementia when it runs in families,” she said.

Dr. Brellenthin said she was surprised by some of the findings. “It was surprising to see that the risk of dementia was reduced with just three healthy behaviors [but was further reduced as you added more behaviors] compared to two or fewer behaviors. However, it was not surprising to see that these same lifestyle behaviors that tend to be good for the heart and body are also good for the brain.”

The evidence that following just three healthy behaviors can reduce the risk of dementia by 25%-35% for individuals with a familial history of dementia has clinical implications, Dr. Brellenthin said. “Many people are already following some of these behaviors like not smoking, so it might be possible to focus on adding just one more behavior, like getting enough sleep, and going from there.”

Commenting on the study, AHA President Mitchell S. V. Elkind, MD, said that the study “tells us that, yes, family history is important [in determining the risk of dementia], and much of that may be driven by genetic factors, but some of that impact can be mitigated or decreased by engaging in those important behaviors that we know are good to maintain brain health.

“The tricky thing, of course, is getting people to engage in these behaviors. That’s where a lot of work in the future will be: changing people’s behavior to become more healthy, and figuring out exactly which behaviors may be the easiest to engage in and be most likely to have public health impact,” added Dr. Elkind, professor of neurology and epidemiology at Columbia University and attending neurologist at New York–Presbyterian/Columbia University Irving Medical Center, New York.

The study received no outside funding, but the was research was conducted using the U.K. Biobank resources. The researchers had no financial conflicts to disclose.

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

A version of this article first appeared on Medscape.com.

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

A version of this article first appeared on Medscape.com.

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

A version of this article first appeared on Medscape.com.

Final results from the landmark SPRINT study confirm that aggressive blood pressure (BP) management, targeting a systolic blood pressure (SBP) below 120 mm Hg, significantly reduces the risk for heart disease, stroke, and death from these diseases, as well as death from all causes.

The results include data on some outcome events from the trial that had yet to be adjudicated when the primary analysis was released in 2015, as well as posttrial observational follow-up data collected through July 2016.

The data confirm and enhance the earlier findings and show that “lower is better” when it comes to blood pressure, primary investigator Cora E. Lewis, MD, professor and chair, department of epidemiology, University of Alabama at Birmingham, said in an interview.

Final results of the Systolic Blood Pressure Intervention Trial (SPRINT) were published in the May 20 issue of the New England Journal of Medicine.

For the trial, researchers enrolled 9,361 adults 50 years and older with a SBP between 130 and 180 mm Hg who were at increased risk for cardiovascular disease (CVD) but did not have a history of diabetes or stroke. Patients were randomly assigned to an intensive treatment target (SBP < 120 mm Hg) or a standard treatment target (SBP < 140 mm Hg).

In the final analysis, the rate of the primary outcome was 1.77% per year in the intensive-treatment group and 2.40% per year in the standard-treatment group (hazard ratio [HR], 0.73; 95% confidence interval [CR], 0.63-0.86; P < .001), similar to the earlier SPRINT findings.

All-cause mortality was 1.06% per year in the intensive-treatment group and 1.41% per year in the standard-treatment group (HR, 0.75; 95% CI, 0.61-0.92; P = .006), again similar to the previous findings.

“These results were highly statistically significant. It is remarkable in a trial powered for a composite CVD outcome to obtain a significant benefit for total mortality,” Dr. Lewis said.

She noted that one criticism of the initial SPRINT results was that, for the components of the primary outcome, only heart failure and death due to CVD were significantly lower in the intensively treated group.

“Heart failure can be difficult to diagnose from records in a clinical trial, and the critiques were that this was shaky evidence, given that more participants treated to less than 120 were on diuretics, which could decrease swelling, a key symptom of heart failure,” she explained.

“In these final results, SPRINT found that risk of myocardial infarction, heart failure, and death from CVD were significantly lower in the group treated to less than 120, and risk of the primary outcome, excluding heart failure, was still significantly lower in the more intensively treated group,” she noted.

After the trial phase ended, blood pressure treatment was returned to the participants’ usual source of medical care and the trial treatment goals were no longer pursued. SPRINT continued to collect data on the outcomes through July 2016. During this time, SBP rose 6.9 mm Hg in the intensive-treatment group and 2.6 mm Hg in the standard-treatment group.

“Putting all the data together from the trial phase and the phase after randomized interventions had been stopped, there was still a significant benefit for the more intensive treatment on the primary outcome and on death from all causes,” Dr. Lewis said.

In addition, a separate new analysis based on all the data showed significantly fewer first and recurrent primary outcome events with intensive treatment than with standard treatment (435 vs. 552; HR, 0.78; 95% CI, 0.69-0.89; P < .001).
 

Manageable risk

The pattern of safety events in the final analysis was similar to the 2015 report. In the intervention period, rates of serious adverse events overall did not differ significantly between the groups. However, rates of hypotension, electrolyte abnormalities, syncope (none leading to injurious falls), and acute kidney injury were higher in the intensive-treatment group.

As in other SPRINT reports, “acute kidney injury safety events were generally mild and there was nearly complete recovery of kidney function within 1 year,” Dr. Lewis said. “This and other analyses we have published indicate this is probably a hemodynamic effect.”

“Intensive treatment can be well tolerated and is generally safe with proper patient selection and monitoring. There are advantages to intensive therapy, and some risks, but I don’t think the risks are such that we should just throw the idea of more intensive treatment out the window,” Dr. Lewis said.

Reached for comment, Carlos G. Santos-Gallego, MD, from the Icahn School of Medicine at Mount Sinai in New York, said there has been “controversy” over whether intensive blood pressure control targeting systolic to below 120 mm Hg is beneficial.

“The original SPRINT trial is incredibly important, in that it conclusively demonstrated that among patients with hypertension and increased cardiovascular risk, targeting systolic blood pressure to below 120 mm Hg resulted in lower rates of adverse cardiovascular events and, importantly, all-cause mortality," compared with the conventional target of 140 mm Hg, he said in an interview.

“This final report of the SPRINT trial basically consolidates, confirms, and corroborates the original SPRINT data,” he noted. However, the final data are “more robust, with additional primary outcome events and all events having been adjudicated by a central committee, and there is an additional observation period of 1 extra year in which the treatment has been discontinued,” he said.

“Over time, we are becoming more and more certain that lower is better with blood pressure. We still have a long way to go, but the cardiology community is slowly becoming more intense in our treatment of blood pressure for our patients,” Dr. Santos-Gallego said.

The potential adverse effects of intensive blood pressure control are “very manageable,” he added.

Support for SPRINT was provided by the National Institutes of Health. Full disclosures for authors are available in the original article. Dr. Santos-Gallego has no relevant disclosures.

A version of this article first appeared on Medscape.com.

Final results from the landmark SPRINT study confirm that aggressive blood pressure (BP) management, targeting a systolic blood pressure (SBP) below 120 mm Hg, significantly reduces the risk for heart disease, stroke, and death from these diseases, as well as death from all causes.

The results include data on some outcome events from the trial that had yet to be adjudicated when the primary analysis was released in 2015, as well as posttrial observational follow-up data collected through July 2016.

The data confirm and enhance the earlier findings and show that “lower is better” when it comes to blood pressure, primary investigator Cora E. Lewis, MD, professor and chair, department of epidemiology, University of Alabama at Birmingham, said in an interview.

Final results of the Systolic Blood Pressure Intervention Trial (SPRINT) were published in the May 20 issue of the New England Journal of Medicine.

For the trial, researchers enrolled 9,361 adults 50 years and older with a SBP between 130 and 180 mm Hg who were at increased risk for cardiovascular disease (CVD) but did not have a history of diabetes or stroke. Patients were randomly assigned to an intensive treatment target (SBP < 120 mm Hg) or a standard treatment target (SBP < 140 mm Hg).

In the final analysis, the rate of the primary outcome was 1.77% per year in the intensive-treatment group and 2.40% per year in the standard-treatment group (hazard ratio [HR], 0.73; 95% confidence interval [CR], 0.63-0.86; P < .001), similar to the earlier SPRINT findings.

All-cause mortality was 1.06% per year in the intensive-treatment group and 1.41% per year in the standard-treatment group (HR, 0.75; 95% CI, 0.61-0.92; P = .006), again similar to the previous findings.

“These results were highly statistically significant. It is remarkable in a trial powered for a composite CVD outcome to obtain a significant benefit for total mortality,” Dr. Lewis said.

She noted that one criticism of the initial SPRINT results was that, for the components of the primary outcome, only heart failure and death due to CVD were significantly lower in the intensively treated group.

“Heart failure can be difficult to diagnose from records in a clinical trial, and the critiques were that this was shaky evidence, given that more participants treated to less than 120 were on diuretics, which could decrease swelling, a key symptom of heart failure,” she explained.

“In these final results, SPRINT found that risk of myocardial infarction, heart failure, and death from CVD were significantly lower in the group treated to less than 120, and risk of the primary outcome, excluding heart failure, was still significantly lower in the more intensively treated group,” she noted.

After the trial phase ended, blood pressure treatment was returned to the participants’ usual source of medical care and the trial treatment goals were no longer pursued. SPRINT continued to collect data on the outcomes through July 2016. During this time, SBP rose 6.9 mm Hg in the intensive-treatment group and 2.6 mm Hg in the standard-treatment group.

“Putting all the data together from the trial phase and the phase after randomized interventions had been stopped, there was still a significant benefit for the more intensive treatment on the primary outcome and on death from all causes,” Dr. Lewis said.

In addition, a separate new analysis based on all the data showed significantly fewer first and recurrent primary outcome events with intensive treatment than with standard treatment (435 vs. 552; HR, 0.78; 95% CI, 0.69-0.89; P < .001).
 

Manageable risk

The pattern of safety events in the final analysis was similar to the 2015 report. In the intervention period, rates of serious adverse events overall did not differ significantly between the groups. However, rates of hypotension, electrolyte abnormalities, syncope (none leading to injurious falls), and acute kidney injury were higher in the intensive-treatment group.

As in other SPRINT reports, “acute kidney injury safety events were generally mild and there was nearly complete recovery of kidney function within 1 year,” Dr. Lewis said. “This and other analyses we have published indicate this is probably a hemodynamic effect.”

“Intensive treatment can be well tolerated and is generally safe with proper patient selection and monitoring. There are advantages to intensive therapy, and some risks, but I don’t think the risks are such that we should just throw the idea of more intensive treatment out the window,” Dr. Lewis said.

Reached for comment, Carlos G. Santos-Gallego, MD, from the Icahn School of Medicine at Mount Sinai in New York, said there has been “controversy” over whether intensive blood pressure control targeting systolic to below 120 mm Hg is beneficial.

“The original SPRINT trial is incredibly important, in that it conclusively demonstrated that among patients with hypertension and increased cardiovascular risk, targeting systolic blood pressure to below 120 mm Hg resulted in lower rates of adverse cardiovascular events and, importantly, all-cause mortality," compared with the conventional target of 140 mm Hg, he said in an interview.

“This final report of the SPRINT trial basically consolidates, confirms, and corroborates the original SPRINT data,” he noted. However, the final data are “more robust, with additional primary outcome events and all events having been adjudicated by a central committee, and there is an additional observation period of 1 extra year in which the treatment has been discontinued,” he said.

“Over time, we are becoming more and more certain that lower is better with blood pressure. We still have a long way to go, but the cardiology community is slowly becoming more intense in our treatment of blood pressure for our patients,” Dr. Santos-Gallego said.

The potential adverse effects of intensive blood pressure control are “very manageable,” he added.

Support for SPRINT was provided by the National Institutes of Health. Full disclosures for authors are available in the original article. Dr. Santos-Gallego has no relevant disclosures.

A version of this article first appeared on Medscape.com.

Final results from the landmark SPRINT study confirm that aggressive blood pressure (BP) management, targeting a systolic blood pressure (SBP) below 120 mm Hg, significantly reduces the risk for heart disease, stroke, and death from these diseases, as well as death from all causes.

The results include data on some outcome events from the trial that had yet to be adjudicated when the primary analysis was released in 2015, as well as posttrial observational follow-up data collected through July 2016.

The data confirm and enhance the earlier findings and show that “lower is better” when it comes to blood pressure, primary investigator Cora E. Lewis, MD, professor and chair, department of epidemiology, University of Alabama at Birmingham, said in an interview.

Final results of the Systolic Blood Pressure Intervention Trial (SPRINT) were published in the May 20 issue of the New England Journal of Medicine.

For the trial, researchers enrolled 9,361 adults 50 years and older with a SBP between 130 and 180 mm Hg who were at increased risk for cardiovascular disease (CVD) but did not have a history of diabetes or stroke. Patients were randomly assigned to an intensive treatment target (SBP < 120 mm Hg) or a standard treatment target (SBP < 140 mm Hg).

In the final analysis, the rate of the primary outcome was 1.77% per year in the intensive-treatment group and 2.40% per year in the standard-treatment group (hazard ratio [HR], 0.73; 95% confidence interval [CR], 0.63-0.86; P < .001), similar to the earlier SPRINT findings.

All-cause mortality was 1.06% per year in the intensive-treatment group and 1.41% per year in the standard-treatment group (HR, 0.75; 95% CI, 0.61-0.92; P = .006), again similar to the previous findings.

“These results were highly statistically significant. It is remarkable in a trial powered for a composite CVD outcome to obtain a significant benefit for total mortality,” Dr. Lewis said.

She noted that one criticism of the initial SPRINT results was that, for the components of the primary outcome, only heart failure and death due to CVD were significantly lower in the intensively treated group.

“Heart failure can be difficult to diagnose from records in a clinical trial, and the critiques were that this was shaky evidence, given that more participants treated to less than 120 were on diuretics, which could decrease swelling, a key symptom of heart failure,” she explained.

“In these final results, SPRINT found that risk of myocardial infarction, heart failure, and death from CVD were significantly lower in the group treated to less than 120, and risk of the primary outcome, excluding heart failure, was still significantly lower in the more intensively treated group,” she noted.

After the trial phase ended, blood pressure treatment was returned to the participants’ usual source of medical care and the trial treatment goals were no longer pursued. SPRINT continued to collect data on the outcomes through July 2016. During this time, SBP rose 6.9 mm Hg in the intensive-treatment group and 2.6 mm Hg in the standard-treatment group.

“Putting all the data together from the trial phase and the phase after randomized interventions had been stopped, there was still a significant benefit for the more intensive treatment on the primary outcome and on death from all causes,” Dr. Lewis said.

In addition, a separate new analysis based on all the data showed significantly fewer first and recurrent primary outcome events with intensive treatment than with standard treatment (435 vs. 552; HR, 0.78; 95% CI, 0.69-0.89; P < .001).
 

Manageable risk

The pattern of safety events in the final analysis was similar to the 2015 report. In the intervention period, rates of serious adverse events overall did not differ significantly between the groups. However, rates of hypotension, electrolyte abnormalities, syncope (none leading to injurious falls), and acute kidney injury were higher in the intensive-treatment group.

As in other SPRINT reports, “acute kidney injury safety events were generally mild and there was nearly complete recovery of kidney function within 1 year,” Dr. Lewis said. “This and other analyses we have published indicate this is probably a hemodynamic effect.”

“Intensive treatment can be well tolerated and is generally safe with proper patient selection and monitoring. There are advantages to intensive therapy, and some risks, but I don’t think the risks are such that we should just throw the idea of more intensive treatment out the window,” Dr. Lewis said.

Reached for comment, Carlos G. Santos-Gallego, MD, from the Icahn School of Medicine at Mount Sinai in New York, said there has been “controversy” over whether intensive blood pressure control targeting systolic to below 120 mm Hg is beneficial.

“The original SPRINT trial is incredibly important, in that it conclusively demonstrated that among patients with hypertension and increased cardiovascular risk, targeting systolic blood pressure to below 120 mm Hg resulted in lower rates of adverse cardiovascular events and, importantly, all-cause mortality," compared with the conventional target of 140 mm Hg, he said in an interview.

“This final report of the SPRINT trial basically consolidates, confirms, and corroborates the original SPRINT data,” he noted. However, the final data are “more robust, with additional primary outcome events and all events having been adjudicated by a central committee, and there is an additional observation period of 1 extra year in which the treatment has been discontinued,” he said.

“Over time, we are becoming more and more certain that lower is better with blood pressure. We still have a long way to go, but the cardiology community is slowly becoming more intense in our treatment of blood pressure for our patients,” Dr. Santos-Gallego said.

The potential adverse effects of intensive blood pressure control are “very manageable,” he added.

Support for SPRINT was provided by the National Institutes of Health. Full disclosures for authors are available in the original article. Dr. Santos-Gallego has no relevant disclosures.

A version of this article first appeared on Medscape.com.