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Frail ADHF patients benefit more from early rehab
Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.
“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”
Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.
However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”
The study was published online in JAMA Cardiology.
Interpret with caution
Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.
According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.
- The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
- It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
- It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
- It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.
For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.
At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.
The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.
A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.
Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.
“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”
To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
‘Never too old or sick to benefit’
Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”
However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.
Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.
On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”
“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.
The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.
“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”
Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.
However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”
The study was published online in JAMA Cardiology.
Interpret with caution
Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.
According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.
- The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
- It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
- It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
- It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.
For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.
At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.
The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.
A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.
Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.
“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”
To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
‘Never too old or sick to benefit’
Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”
However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.
Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.
On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”
“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.
The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.
“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”
Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.
However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”
The study was published online in JAMA Cardiology.
Interpret with caution
Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.
According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.
- The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
- It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
- It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
- It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.
For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.
At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.
The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.
A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.
Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.
“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”
To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
‘Never too old or sick to benefit’
Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”
However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.
Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.
On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”
“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.
The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Some BP meds tied to significantly lower risk for dementia, Alzheimer’s
Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.
Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.
“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.
The findings were published online in JAMA Network Open.
Medicare beneficiaries
Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.
The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.
Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.
Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.
“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.
The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.
For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.
The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.
Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
Unanswered questions
After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).
The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.
As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).
Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).
A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.
“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
Stimulators instead of inhibitors?
The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.
But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.
Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.
“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.
However, “we’re not suggesting [that all patients] have their regimen switched,” he added.
That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.
As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.
The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
‘More convincing’
Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.
“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.
However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.
As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.
For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.
He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.
Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.
“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.
Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.
Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.
She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”
The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.
Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.
“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.
The findings were published online in JAMA Network Open.
Medicare beneficiaries
Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.
The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.
Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.
Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.
“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.
The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.
For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.
The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.
Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
Unanswered questions
After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).
The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.
As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).
Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).
A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.
“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
Stimulators instead of inhibitors?
The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.
But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.
Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.
“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.
However, “we’re not suggesting [that all patients] have their regimen switched,” he added.
That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.
As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.
The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
‘More convincing’
Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.
“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.
However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.
As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.
For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.
He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.
Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.
“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.
Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.
Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.
She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”
The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.
Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.
“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.
The findings were published online in JAMA Network Open.
Medicare beneficiaries
Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.
The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.
Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.
Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.
“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.
The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.
For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.
The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.
Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
Unanswered questions
After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).
The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.
As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).
Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).
A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.
“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
Stimulators instead of inhibitors?
The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.
But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.
Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.
“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.
However, “we’re not suggesting [that all patients] have their regimen switched,” he added.
That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.
As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.
The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
‘More convincing’
Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.
“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.
However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.
As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.
For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.
He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.
Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.
“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.
Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.
Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.
She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”
The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LDL cholesterol triglycerides ‘robust’ ASCVD risk marker
High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.
“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.
The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.
LDL triglycerides carry higher ASCVD risk
In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).
In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.
The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.
Results confirm hypothesis the study sought to disprove
The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”
He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.
The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.
The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”
A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.
Next step is finding a treatment
The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator.
This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”
The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.
The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.
The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.
High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.
“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.
The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.
LDL triglycerides carry higher ASCVD risk
In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).
In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.
The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.
Results confirm hypothesis the study sought to disprove
The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”
He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.
The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.
The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”
A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.
Next step is finding a treatment
The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator.
This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”
The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.
The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.
The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.
High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.
“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.
The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.
LDL triglycerides carry higher ASCVD risk
In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).
In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.
The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.
Results confirm hypothesis the study sought to disprove
The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”
He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.
The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.
The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”
A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.
Next step is finding a treatment
The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator.
This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”
The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.
The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.
The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Spikes out: A COVID mystery
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.
To date, it has been a mystery, like “Glass Onion.” And in the spirit of all the great mysteries, to get to the bottom of this, we’ll need to round up the usual suspects.
Appearing in Circulation, a new study does a great job of systematically evaluating multiple hypotheses linking vaccination to myocarditis, and eliminating them, Poirot-style, one by one until only one remains. We’ll get there.
But first, let’s review the suspects. Why do the mRNA vaccines cause myocarditis in a small subset of people?
There are a few leading candidates.
Number one: antibody responses. There are two flavors here. The quantitative hypothesis suggests that some people simply generate too many antibodies to the vaccine, leading to increased inflammation and heart damage.
The qualitative hypothesis suggests that maybe it’s the nature of the antibodies generated rather than the amount; they might cross-react with some protein on the surface of heart cells for instance.
Or maybe it is driven by T-cell responses, which, of course, are independent of antibody levels.
There’s the idea that myocarditis is due to excessive cytokine release – sort of like what we see in the multisystem inflammatory syndrome in children.
Or it could be due to the viral antigens themselves – the spike protein the mRNA codes for that is generated after vaccination.
To tease all these possibilities apart, researchers led by Lael Yonker at Mass General performed a case-control study. Sixteen children with postvaccine myocarditis were matched by age to 45 control children who had been vaccinated without complications.
The matching was OK, but as you can see here, there were more boys in the myocarditis group, and the time from vaccination was a bit shorter in that group as well. We’ll keep that in mind as we go through the results.
OK, let’s start eliminating suspects.
First, quantitative antibodies. Seems unlikely. Absolute antibody titers were really no different in the myocarditis vs. the control group.
What about the quality of the antibodies? Would the kids with myocarditis have more self-recognizing antibodies present? It doesn’t appear so. Autoantibody levels were similar in the two groups.
Take antibodies off the list.
T-cell responses come next, and, again, no major differences here, save for one specific T-cell subtype that was moderately elevated in the myocarditis group. Not what I would call a smoking gun, frankly.
Cytokines give us a bit more to chew on. Levels of interleukin (IL)-8, IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 were all substantially higher in the kids with myocarditis.
But the thing about cytokines is that they are not particularly specific. OK, kids with myocarditis have more systemic inflammation than kids without; that’s not really surprising. It still leaves us with the question of what is causing all this inflammation? Who is the arch-villain? The kingpin? The don?
It’s the analyses of antigens – the protein products of vaccination – that may hold the key here.
In 12 out of 16 kids with myocarditis, the researchers were able to measure free spike protein in the blood – that is to say spike protein, not bound by antispike antibodies.
These free spikes were present in – wait for it – zero of the 45 control patients. That makes spike protein itself our prime suspect. J’accuse free spike protein!
Of course, all good detectives need to wrap up the case with a good story: How was it all done?
And here’s where we could use Agatha Christie’s help. How could this all work? The vaccine gets injected; mRNA is taken up into cells, where spike protein is generated and released, generating antibody and T-cell responses all the while. Those responses rapidly clear that spike protein from the system – this has been demonstrated in multiple studies – in adults, at least. But in some small number of people, apparently, spike protein is not cleared. Why? It makes no damn sense. Compels me, though. Some have suggested that inadvertent intravenous injection of vaccine, compared with the appropriate intramuscular route, might distribute the vaccine to sites with less immune surveillance. But that is definitely not proven yet.
We are on the path for sure, but this is, as Benoit Blanc would say, a twisted web – and we are not finished untangling it. Not yet.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here. He tweets @fperrywilson and his new book, “How Medicine Works and When It Doesn’t,” is available for preorder now. He reports no conflicts of interest.
A version of this article first appeared on Medscape.com.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.
To date, it has been a mystery, like “Glass Onion.” And in the spirit of all the great mysteries, to get to the bottom of this, we’ll need to round up the usual suspects.
Appearing in Circulation, a new study does a great job of systematically evaluating multiple hypotheses linking vaccination to myocarditis, and eliminating them, Poirot-style, one by one until only one remains. We’ll get there.
But first, let’s review the suspects. Why do the mRNA vaccines cause myocarditis in a small subset of people?
There are a few leading candidates.
Number one: antibody responses. There are two flavors here. The quantitative hypothesis suggests that some people simply generate too many antibodies to the vaccine, leading to increased inflammation and heart damage.
The qualitative hypothesis suggests that maybe it’s the nature of the antibodies generated rather than the amount; they might cross-react with some protein on the surface of heart cells for instance.
Or maybe it is driven by T-cell responses, which, of course, are independent of antibody levels.
There’s the idea that myocarditis is due to excessive cytokine release – sort of like what we see in the multisystem inflammatory syndrome in children.
Or it could be due to the viral antigens themselves – the spike protein the mRNA codes for that is generated after vaccination.
To tease all these possibilities apart, researchers led by Lael Yonker at Mass General performed a case-control study. Sixteen children with postvaccine myocarditis were matched by age to 45 control children who had been vaccinated without complications.
The matching was OK, but as you can see here, there were more boys in the myocarditis group, and the time from vaccination was a bit shorter in that group as well. We’ll keep that in mind as we go through the results.
OK, let’s start eliminating suspects.
First, quantitative antibodies. Seems unlikely. Absolute antibody titers were really no different in the myocarditis vs. the control group.
What about the quality of the antibodies? Would the kids with myocarditis have more self-recognizing antibodies present? It doesn’t appear so. Autoantibody levels were similar in the two groups.
Take antibodies off the list.
T-cell responses come next, and, again, no major differences here, save for one specific T-cell subtype that was moderately elevated in the myocarditis group. Not what I would call a smoking gun, frankly.
Cytokines give us a bit more to chew on. Levels of interleukin (IL)-8, IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 were all substantially higher in the kids with myocarditis.
But the thing about cytokines is that they are not particularly specific. OK, kids with myocarditis have more systemic inflammation than kids without; that’s not really surprising. It still leaves us with the question of what is causing all this inflammation? Who is the arch-villain? The kingpin? The don?
It’s the analyses of antigens – the protein products of vaccination – that may hold the key here.
In 12 out of 16 kids with myocarditis, the researchers were able to measure free spike protein in the blood – that is to say spike protein, not bound by antispike antibodies.
These free spikes were present in – wait for it – zero of the 45 control patients. That makes spike protein itself our prime suspect. J’accuse free spike protein!
Of course, all good detectives need to wrap up the case with a good story: How was it all done?
And here’s where we could use Agatha Christie’s help. How could this all work? The vaccine gets injected; mRNA is taken up into cells, where spike protein is generated and released, generating antibody and T-cell responses all the while. Those responses rapidly clear that spike protein from the system – this has been demonstrated in multiple studies – in adults, at least. But in some small number of people, apparently, spike protein is not cleared. Why? It makes no damn sense. Compels me, though. Some have suggested that inadvertent intravenous injection of vaccine, compared with the appropriate intramuscular route, might distribute the vaccine to sites with less immune surveillance. But that is definitely not proven yet.
We are on the path for sure, but this is, as Benoit Blanc would say, a twisted web – and we are not finished untangling it. Not yet.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here. He tweets @fperrywilson and his new book, “How Medicine Works and When It Doesn’t,” is available for preorder now. He reports no conflicts of interest.
A version of this article first appeared on Medscape.com.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.
To date, it has been a mystery, like “Glass Onion.” And in the spirit of all the great mysteries, to get to the bottom of this, we’ll need to round up the usual suspects.
Appearing in Circulation, a new study does a great job of systematically evaluating multiple hypotheses linking vaccination to myocarditis, and eliminating them, Poirot-style, one by one until only one remains. We’ll get there.
But first, let’s review the suspects. Why do the mRNA vaccines cause myocarditis in a small subset of people?
There are a few leading candidates.
Number one: antibody responses. There are two flavors here. The quantitative hypothesis suggests that some people simply generate too many antibodies to the vaccine, leading to increased inflammation and heart damage.
The qualitative hypothesis suggests that maybe it’s the nature of the antibodies generated rather than the amount; they might cross-react with some protein on the surface of heart cells for instance.
Or maybe it is driven by T-cell responses, which, of course, are independent of antibody levels.
There’s the idea that myocarditis is due to excessive cytokine release – sort of like what we see in the multisystem inflammatory syndrome in children.
Or it could be due to the viral antigens themselves – the spike protein the mRNA codes for that is generated after vaccination.
To tease all these possibilities apart, researchers led by Lael Yonker at Mass General performed a case-control study. Sixteen children with postvaccine myocarditis were matched by age to 45 control children who had been vaccinated without complications.
The matching was OK, but as you can see here, there were more boys in the myocarditis group, and the time from vaccination was a bit shorter in that group as well. We’ll keep that in mind as we go through the results.
OK, let’s start eliminating suspects.
First, quantitative antibodies. Seems unlikely. Absolute antibody titers were really no different in the myocarditis vs. the control group.
What about the quality of the antibodies? Would the kids with myocarditis have more self-recognizing antibodies present? It doesn’t appear so. Autoantibody levels were similar in the two groups.
Take antibodies off the list.
T-cell responses come next, and, again, no major differences here, save for one specific T-cell subtype that was moderately elevated in the myocarditis group. Not what I would call a smoking gun, frankly.
Cytokines give us a bit more to chew on. Levels of interleukin (IL)-8, IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 were all substantially higher in the kids with myocarditis.
But the thing about cytokines is that they are not particularly specific. OK, kids with myocarditis have more systemic inflammation than kids without; that’s not really surprising. It still leaves us with the question of what is causing all this inflammation? Who is the arch-villain? The kingpin? The don?
It’s the analyses of antigens – the protein products of vaccination – that may hold the key here.
In 12 out of 16 kids with myocarditis, the researchers were able to measure free spike protein in the blood – that is to say spike protein, not bound by antispike antibodies.
These free spikes were present in – wait for it – zero of the 45 control patients. That makes spike protein itself our prime suspect. J’accuse free spike protein!
Of course, all good detectives need to wrap up the case with a good story: How was it all done?
And here’s where we could use Agatha Christie’s help. How could this all work? The vaccine gets injected; mRNA is taken up into cells, where spike protein is generated and released, generating antibody and T-cell responses all the while. Those responses rapidly clear that spike protein from the system – this has been demonstrated in multiple studies – in adults, at least. But in some small number of people, apparently, spike protein is not cleared. Why? It makes no damn sense. Compels me, though. Some have suggested that inadvertent intravenous injection of vaccine, compared with the appropriate intramuscular route, might distribute the vaccine to sites with less immune surveillance. But that is definitely not proven yet.
We are on the path for sure, but this is, as Benoit Blanc would say, a twisted web – and we are not finished untangling it. Not yet.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here. He tweets @fperrywilson and his new book, “How Medicine Works and When It Doesn’t,” is available for preorder now. He reports no conflicts of interest.
A version of this article first appeared on Medscape.com.
Atrial fibrillation: Sex differences and modifiable risk factors
This transcript has been edited for clarity.
Hello. This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital.
We looked at these questions in our vitamin D and omega-3 trial VITAL in an ancillary study called VITAL Rhythm, led by Dr. Christine Albert at Cedars-Sinai. And this particular project was led by Dr. Hasan Siddiqi at Vanderbilt.
As you know, AF is the most common arrhythmia in the world, and it’s burgeoning in numbers, primarily because of the aging of the population. It’s also a major cause of stroke, heart failure, and cardiovascular mortality. Although women are known to have lower rates of AF than men, they’re also known to have a higher risk for cardiovascular complications and sequelae, such as higher risk for stroke and CVD mortality. Therefore, we thought that understanding sex differences in risk and modifiable risk factors for AF that could reduce the burden of disease would be important.
It’s known that greater height is a risk factor for AF, but the extent to which it explains the differences in AF risk between men and women isn’t really known. So we looked at these questions in the VITAL cohort. VITAL has more than 25,000 participants. It’s a large, diverse, nationwide cohort. About 51% are women, and all are aged 50 years or older, with a mean age of 67. All were free of known clinical cardiovascular disease at the start of the study.
AF reports were confirmed by medical records and also supplemented by Medicare CMS linkage for fuller ascertainment of outcomes. We had 900 incident cases of AF in the study, and we did see that women were less likely to be diagnosed with AF. They had a 32% lower risk – strongly statistically significant compared with men, with a P < .001. Women were also more likely to be symptomatic: About 77% of women vs. 63% of men had symptoms prior to or at diagnosis.
It was very interesting that adjustment for height eliminated the lower risk for AF in women compared with men. After accounting for height, there was not only no reduction in risk for AF among the women, there was actually a reversal of the association so that there was a slightly higher risk for AF in the women. Other risk factors for AF in the cohort included older age, higher body mass index, hypertension, and higher consumption of alcohol. We did not see an association between diabetes and higher risk for AF. We also saw no clear association with physical activity, although very strenuous physical activity has been linked to AF in some other studies.
We looked at the interventions of vitamin D (2,000 IU/day) and omega-3 fatty acids (460 mg/day of EPA and 380 mg/day of DHA) and found no association with AF, although some other studies have seen increased risk for AF with higher doses of the marine omega-3s > 1 g/day and certainly at doses of 4 g/day. So overall, the findings highlight the fact that many of the risk factors for AF do seem to be modifiable, and it is really important to identify and try to reduce these risk factors in order to reduce the burden of AF. This may be particularly important in women because women are more likely to have stroke and cardiovascular mortality in these adverse cardiovascular outcomes.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital.
We looked at these questions in our vitamin D and omega-3 trial VITAL in an ancillary study called VITAL Rhythm, led by Dr. Christine Albert at Cedars-Sinai. And this particular project was led by Dr. Hasan Siddiqi at Vanderbilt.
As you know, AF is the most common arrhythmia in the world, and it’s burgeoning in numbers, primarily because of the aging of the population. It’s also a major cause of stroke, heart failure, and cardiovascular mortality. Although women are known to have lower rates of AF than men, they’re also known to have a higher risk for cardiovascular complications and sequelae, such as higher risk for stroke and CVD mortality. Therefore, we thought that understanding sex differences in risk and modifiable risk factors for AF that could reduce the burden of disease would be important.
It’s known that greater height is a risk factor for AF, but the extent to which it explains the differences in AF risk between men and women isn’t really known. So we looked at these questions in the VITAL cohort. VITAL has more than 25,000 participants. It’s a large, diverse, nationwide cohort. About 51% are women, and all are aged 50 years or older, with a mean age of 67. All were free of known clinical cardiovascular disease at the start of the study.
AF reports were confirmed by medical records and also supplemented by Medicare CMS linkage for fuller ascertainment of outcomes. We had 900 incident cases of AF in the study, and we did see that women were less likely to be diagnosed with AF. They had a 32% lower risk – strongly statistically significant compared with men, with a P < .001. Women were also more likely to be symptomatic: About 77% of women vs. 63% of men had symptoms prior to or at diagnosis.
It was very interesting that adjustment for height eliminated the lower risk for AF in women compared with men. After accounting for height, there was not only no reduction in risk for AF among the women, there was actually a reversal of the association so that there was a slightly higher risk for AF in the women. Other risk factors for AF in the cohort included older age, higher body mass index, hypertension, and higher consumption of alcohol. We did not see an association between diabetes and higher risk for AF. We also saw no clear association with physical activity, although very strenuous physical activity has been linked to AF in some other studies.
We looked at the interventions of vitamin D (2,000 IU/day) and omega-3 fatty acids (460 mg/day of EPA and 380 mg/day of DHA) and found no association with AF, although some other studies have seen increased risk for AF with higher doses of the marine omega-3s > 1 g/day and certainly at doses of 4 g/day. So overall, the findings highlight the fact that many of the risk factors for AF do seem to be modifiable, and it is really important to identify and try to reduce these risk factors in order to reduce the burden of AF. This may be particularly important in women because women are more likely to have stroke and cardiovascular mortality in these adverse cardiovascular outcomes.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital.
We looked at these questions in our vitamin D and omega-3 trial VITAL in an ancillary study called VITAL Rhythm, led by Dr. Christine Albert at Cedars-Sinai. And this particular project was led by Dr. Hasan Siddiqi at Vanderbilt.
As you know, AF is the most common arrhythmia in the world, and it’s burgeoning in numbers, primarily because of the aging of the population. It’s also a major cause of stroke, heart failure, and cardiovascular mortality. Although women are known to have lower rates of AF than men, they’re also known to have a higher risk for cardiovascular complications and sequelae, such as higher risk for stroke and CVD mortality. Therefore, we thought that understanding sex differences in risk and modifiable risk factors for AF that could reduce the burden of disease would be important.
It’s known that greater height is a risk factor for AF, but the extent to which it explains the differences in AF risk between men and women isn’t really known. So we looked at these questions in the VITAL cohort. VITAL has more than 25,000 participants. It’s a large, diverse, nationwide cohort. About 51% are women, and all are aged 50 years or older, with a mean age of 67. All were free of known clinical cardiovascular disease at the start of the study.
AF reports were confirmed by medical records and also supplemented by Medicare CMS linkage for fuller ascertainment of outcomes. We had 900 incident cases of AF in the study, and we did see that women were less likely to be diagnosed with AF. They had a 32% lower risk – strongly statistically significant compared with men, with a P < .001. Women were also more likely to be symptomatic: About 77% of women vs. 63% of men had symptoms prior to or at diagnosis.
It was very interesting that adjustment for height eliminated the lower risk for AF in women compared with men. After accounting for height, there was not only no reduction in risk for AF among the women, there was actually a reversal of the association so that there was a slightly higher risk for AF in the women. Other risk factors for AF in the cohort included older age, higher body mass index, hypertension, and higher consumption of alcohol. We did not see an association between diabetes and higher risk for AF. We also saw no clear association with physical activity, although very strenuous physical activity has been linked to AF in some other studies.
We looked at the interventions of vitamin D (2,000 IU/day) and omega-3 fatty acids (460 mg/day of EPA and 380 mg/day of DHA) and found no association with AF, although some other studies have seen increased risk for AF with higher doses of the marine omega-3s > 1 g/day and certainly at doses of 4 g/day. So overall, the findings highlight the fact that many of the risk factors for AF do seem to be modifiable, and it is really important to identify and try to reduce these risk factors in order to reduce the burden of AF. This may be particularly important in women because women are more likely to have stroke and cardiovascular mortality in these adverse cardiovascular outcomes.
A version of this article first appeared on Medscape.com.
Little-used fitness measure could be key to exercise results
A new study out of Brigham Young University, Provo, Utah, suggests doctors could take that initiative to the next level, prescribing exercise plans that result in a specific health outcome; say, lowering your blood pressure or losing weight.
“The findings of this study, and others, suggest that we should be able to more consistently and accurately prescribe exercise like medicine,” says senior study author Jayson Gifford, PhD, an exercise sciences professor at BYU.
These exercise prescriptions would be tailored to patients based on a largely ignored fitness measure called critical power, or maximum steady state – the fastest you can go while maintaining a pace you can sustain for a long time.
By crafting workouts around critical power instead of the more frequently used VO2 max (maximum effort), we could more accurately predict health outcomes, just as we can with medicine, the researchers wrote in the Journal of Applied Physiology.
“We’ve known for centuries that exercise is part of the way to develop a healthy and long life,” says Jordan Metzl, MD, a sports medicine doctor at the Hospital for Special Surgery in New York and author of The Exercise Cure. “But it’s only in the past 70 years that we’ve recognized the medicinal value of exercise.”
Dr. Metzl, who was not involved in the study, helped develop an annual seminar at Cornell Medical School teaching medical students ways to prescribe exercise that go beyond the “30 minutes per day” cookie-cutter advice. Still, doctors and other health care professionals often struggle to prescribe exercise to prevent or treat disease. And a recent study from Oxford found that when doctors do give weight loss advice, it’s often vague and hard for patients to use.
“The drug of movement is one of the safest and most effective forms of preventive health,” says Dr. Metzl. “We need to get the medical community fully engaged in prescribing exercise for their patients.”
This study suggests that a focus on critical power could be key in making that happen.
What the research found
In the study, 22 adults completed 8 weeks of either moderate-intensity training or high-intensity interval training (HIIT). The intensity levels specified in both plans were based on VO2 max. So, the people in the study trained at given percentages of their VO2 max.
Both groups saw improvements in endurance, but results varied greatly from person to person. Those mixed results could be explained by individual differences in critical power.
“Improvement was much more correlated with the percentage of critical powers the individuals worked at rather than the percentage of their VO2max, like exercise physiologists have thought for years,” says lead study author Jessica Collins, a researcher at Brigham Young University.
Not only that but several subjects who did not improve their VO2 max did see an increase in critical power and endurance.
“People tend to only focus on VO2 max,” Dr. Gifford says. “Many might see the lack of increase in VO2 max for some people and conclude that the training was ineffective. I personally believe that a lot of potentially useful therapies have been ruled out because of an almost exclusive focus on VO2 max.”
Turns out, critical power varies a lot from person to person, even among those with similar VO2 maxes.
“Let’s say you and Jessica had the same VO2 max,” explains Dr. Gifford. “If we had you both going at 70% of [your VO2 max], it could be above your maximum steady state, which would make it really hard for you. And it could be below her maximum steady state, which would make it easy for her.”
This means you are each stressing your body differently, and that stress is what triggers improvements in fitness and endurance.
“Below critical power, the metabolic stressors are well-managed and maintained at elevated-but-steady levels,” Dr. Gifford says. “Above critical power, the metabolic stressors are produced so fast that they cannot be controlled, and consistently accrue until reaching very high levels that cause failure.”
Knowing your critical power means you can predict how those stressors will build up, and you can tailor an exercise program that provides just the right stressor “dose” for you, Dr. Gifford says.
Such programs could be used for rehab patients recovering from a heart attack or from lung disease, Dr. Gifford suggests. Or they could help older adults improve endurance and physical function, Ms. Collins notes.
But first, researchers must confirm these results by programming workouts based on people’s critical power and seeing how much different measures improve.
How to find your critical power
Critical power is not new, but exercise physiologists and medical professionals have largely ignored it because it’s not easy to measure.
“People generally train off VO2 max or maximum heart rate, which is even less precise,” Dr. Gifford says.
Finding people’s critical power in the study involved multiple timed trials and calculating the relationship between speed/power and time, Dr. Gifford explains.
But for a rough measure of your critical power, you could use an app that measures functional threshold power (FTP), something Dr. Gifford refers to as the “Walmart version” of critical power. “It’s not exactly the same, but it’s close,” he says. (The app Strava features FTP as well as a pretty sophisticated power analysis.)
Or skip the tech and go by feel. If you’re below your critical power, “it’s going to be challenging, but you’ll feel under control,” Dr. Gifford says. Above your critical power, “your breathing and heart rate will continuously climb until you fail in about 2 to 15 minutes, depending on how far above you are.” Still, you don’t need to know your critical power to start exercising, Ms. Collins notes.
“The beauty of exercise is that it is such a powerful drug that you can see benefits without fine-tuning the workout this way,” Dr. Gifford explains. “I would hate for this to become a barrier to exercising. The important thing is to do something.”
A version of this article first appeared on WebMD.com.
A new study out of Brigham Young University, Provo, Utah, suggests doctors could take that initiative to the next level, prescribing exercise plans that result in a specific health outcome; say, lowering your blood pressure or losing weight.
“The findings of this study, and others, suggest that we should be able to more consistently and accurately prescribe exercise like medicine,” says senior study author Jayson Gifford, PhD, an exercise sciences professor at BYU.
These exercise prescriptions would be tailored to patients based on a largely ignored fitness measure called critical power, or maximum steady state – the fastest you can go while maintaining a pace you can sustain for a long time.
By crafting workouts around critical power instead of the more frequently used VO2 max (maximum effort), we could more accurately predict health outcomes, just as we can with medicine, the researchers wrote in the Journal of Applied Physiology.
“We’ve known for centuries that exercise is part of the way to develop a healthy and long life,” says Jordan Metzl, MD, a sports medicine doctor at the Hospital for Special Surgery in New York and author of The Exercise Cure. “But it’s only in the past 70 years that we’ve recognized the medicinal value of exercise.”
Dr. Metzl, who was not involved in the study, helped develop an annual seminar at Cornell Medical School teaching medical students ways to prescribe exercise that go beyond the “30 minutes per day” cookie-cutter advice. Still, doctors and other health care professionals often struggle to prescribe exercise to prevent or treat disease. And a recent study from Oxford found that when doctors do give weight loss advice, it’s often vague and hard for patients to use.
“The drug of movement is one of the safest and most effective forms of preventive health,” says Dr. Metzl. “We need to get the medical community fully engaged in prescribing exercise for their patients.”
This study suggests that a focus on critical power could be key in making that happen.
What the research found
In the study, 22 adults completed 8 weeks of either moderate-intensity training or high-intensity interval training (HIIT). The intensity levels specified in both plans were based on VO2 max. So, the people in the study trained at given percentages of their VO2 max.
Both groups saw improvements in endurance, but results varied greatly from person to person. Those mixed results could be explained by individual differences in critical power.
“Improvement was much more correlated with the percentage of critical powers the individuals worked at rather than the percentage of their VO2max, like exercise physiologists have thought for years,” says lead study author Jessica Collins, a researcher at Brigham Young University.
Not only that but several subjects who did not improve their VO2 max did see an increase in critical power and endurance.
“People tend to only focus on VO2 max,” Dr. Gifford says. “Many might see the lack of increase in VO2 max for some people and conclude that the training was ineffective. I personally believe that a lot of potentially useful therapies have been ruled out because of an almost exclusive focus on VO2 max.”
Turns out, critical power varies a lot from person to person, even among those with similar VO2 maxes.
“Let’s say you and Jessica had the same VO2 max,” explains Dr. Gifford. “If we had you both going at 70% of [your VO2 max], it could be above your maximum steady state, which would make it really hard for you. And it could be below her maximum steady state, which would make it easy for her.”
This means you are each stressing your body differently, and that stress is what triggers improvements in fitness and endurance.
“Below critical power, the metabolic stressors are well-managed and maintained at elevated-but-steady levels,” Dr. Gifford says. “Above critical power, the metabolic stressors are produced so fast that they cannot be controlled, and consistently accrue until reaching very high levels that cause failure.”
Knowing your critical power means you can predict how those stressors will build up, and you can tailor an exercise program that provides just the right stressor “dose” for you, Dr. Gifford says.
Such programs could be used for rehab patients recovering from a heart attack or from lung disease, Dr. Gifford suggests. Or they could help older adults improve endurance and physical function, Ms. Collins notes.
But first, researchers must confirm these results by programming workouts based on people’s critical power and seeing how much different measures improve.
How to find your critical power
Critical power is not new, but exercise physiologists and medical professionals have largely ignored it because it’s not easy to measure.
“People generally train off VO2 max or maximum heart rate, which is even less precise,” Dr. Gifford says.
Finding people’s critical power in the study involved multiple timed trials and calculating the relationship between speed/power and time, Dr. Gifford explains.
But for a rough measure of your critical power, you could use an app that measures functional threshold power (FTP), something Dr. Gifford refers to as the “Walmart version” of critical power. “It’s not exactly the same, but it’s close,” he says. (The app Strava features FTP as well as a pretty sophisticated power analysis.)
Or skip the tech and go by feel. If you’re below your critical power, “it’s going to be challenging, but you’ll feel under control,” Dr. Gifford says. Above your critical power, “your breathing and heart rate will continuously climb until you fail in about 2 to 15 minutes, depending on how far above you are.” Still, you don’t need to know your critical power to start exercising, Ms. Collins notes.
“The beauty of exercise is that it is such a powerful drug that you can see benefits without fine-tuning the workout this way,” Dr. Gifford explains. “I would hate for this to become a barrier to exercising. The important thing is to do something.”
A version of this article first appeared on WebMD.com.
A new study out of Brigham Young University, Provo, Utah, suggests doctors could take that initiative to the next level, prescribing exercise plans that result in a specific health outcome; say, lowering your blood pressure or losing weight.
“The findings of this study, and others, suggest that we should be able to more consistently and accurately prescribe exercise like medicine,” says senior study author Jayson Gifford, PhD, an exercise sciences professor at BYU.
These exercise prescriptions would be tailored to patients based on a largely ignored fitness measure called critical power, or maximum steady state – the fastest you can go while maintaining a pace you can sustain for a long time.
By crafting workouts around critical power instead of the more frequently used VO2 max (maximum effort), we could more accurately predict health outcomes, just as we can with medicine, the researchers wrote in the Journal of Applied Physiology.
“We’ve known for centuries that exercise is part of the way to develop a healthy and long life,” says Jordan Metzl, MD, a sports medicine doctor at the Hospital for Special Surgery in New York and author of The Exercise Cure. “But it’s only in the past 70 years that we’ve recognized the medicinal value of exercise.”
Dr. Metzl, who was not involved in the study, helped develop an annual seminar at Cornell Medical School teaching medical students ways to prescribe exercise that go beyond the “30 minutes per day” cookie-cutter advice. Still, doctors and other health care professionals often struggle to prescribe exercise to prevent or treat disease. And a recent study from Oxford found that when doctors do give weight loss advice, it’s often vague and hard for patients to use.
“The drug of movement is one of the safest and most effective forms of preventive health,” says Dr. Metzl. “We need to get the medical community fully engaged in prescribing exercise for their patients.”
This study suggests that a focus on critical power could be key in making that happen.
What the research found
In the study, 22 adults completed 8 weeks of either moderate-intensity training or high-intensity interval training (HIIT). The intensity levels specified in both plans were based on VO2 max. So, the people in the study trained at given percentages of their VO2 max.
Both groups saw improvements in endurance, but results varied greatly from person to person. Those mixed results could be explained by individual differences in critical power.
“Improvement was much more correlated with the percentage of critical powers the individuals worked at rather than the percentage of their VO2max, like exercise physiologists have thought for years,” says lead study author Jessica Collins, a researcher at Brigham Young University.
Not only that but several subjects who did not improve their VO2 max did see an increase in critical power and endurance.
“People tend to only focus on VO2 max,” Dr. Gifford says. “Many might see the lack of increase in VO2 max for some people and conclude that the training was ineffective. I personally believe that a lot of potentially useful therapies have been ruled out because of an almost exclusive focus on VO2 max.”
Turns out, critical power varies a lot from person to person, even among those with similar VO2 maxes.
“Let’s say you and Jessica had the same VO2 max,” explains Dr. Gifford. “If we had you both going at 70% of [your VO2 max], it could be above your maximum steady state, which would make it really hard for you. And it could be below her maximum steady state, which would make it easy for her.”
This means you are each stressing your body differently, and that stress is what triggers improvements in fitness and endurance.
“Below critical power, the metabolic stressors are well-managed and maintained at elevated-but-steady levels,” Dr. Gifford says. “Above critical power, the metabolic stressors are produced so fast that they cannot be controlled, and consistently accrue until reaching very high levels that cause failure.”
Knowing your critical power means you can predict how those stressors will build up, and you can tailor an exercise program that provides just the right stressor “dose” for you, Dr. Gifford says.
Such programs could be used for rehab patients recovering from a heart attack or from lung disease, Dr. Gifford suggests. Or they could help older adults improve endurance and physical function, Ms. Collins notes.
But first, researchers must confirm these results by programming workouts based on people’s critical power and seeing how much different measures improve.
How to find your critical power
Critical power is not new, but exercise physiologists and medical professionals have largely ignored it because it’s not easy to measure.
“People generally train off VO2 max or maximum heart rate, which is even less precise,” Dr. Gifford says.
Finding people’s critical power in the study involved multiple timed trials and calculating the relationship between speed/power and time, Dr. Gifford explains.
But for a rough measure of your critical power, you could use an app that measures functional threshold power (FTP), something Dr. Gifford refers to as the “Walmart version” of critical power. “It’s not exactly the same, but it’s close,” he says. (The app Strava features FTP as well as a pretty sophisticated power analysis.)
Or skip the tech and go by feel. If you’re below your critical power, “it’s going to be challenging, but you’ll feel under control,” Dr. Gifford says. Above your critical power, “your breathing and heart rate will continuously climb until you fail in about 2 to 15 minutes, depending on how far above you are.” Still, you don’t need to know your critical power to start exercising, Ms. Collins notes.
“The beauty of exercise is that it is such a powerful drug that you can see benefits without fine-tuning the workout this way,” Dr. Gifford explains. “I would hate for this to become a barrier to exercising. The important thing is to do something.”
A version of this article first appeared on WebMD.com.
FROM THE JOURNAL OF APPLIED PHYSIOLOGY
Recount of FOURIER data finds higher mortality with evolocumab; trialists push back
Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.
“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”
Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”
Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
Evaluating hard outcomes
The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.
As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.
The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).
Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).
For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.
The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
An ‘obvious disconnect’
Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.
Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.
At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.
“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.
Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”
Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
The ‘full picture’
Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”
In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.
Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.
When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.
“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.
“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.
Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.
“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”
Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.
Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
Open access
Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.
“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.
“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”
Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”
Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”
The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.
“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”
Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”
Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
Evaluating hard outcomes
The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.
As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.
The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).
Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).
For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.
The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
An ‘obvious disconnect’
Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.
Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.
At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.
“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.
Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”
Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
The ‘full picture’
Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”
In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.
Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.
When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.
“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.
“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.
Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.
“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”
Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.
Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
Open access
Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.
“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.
“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”
Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”
Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”
The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.
“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”
Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”
Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
Evaluating hard outcomes
The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.
As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.
The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).
Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).
For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.
The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
An ‘obvious disconnect’
Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.
Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.
At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.
“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.
Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”
Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
The ‘full picture’
Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”
In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.
Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.
When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.
“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.
“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.
Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.
“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”
Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.
Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
Open access
Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.
“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.
“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”
Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”
Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”
The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
Five thoughts on the Damar Hamlin collapse
The obvious first statement is that it’s neither wise nor appropriate to speculate on the specifics of Damar Hamlin’s cardiac event during a football game on Jan. 2 (including the possibility of commotio cordis) or his ongoing care. The public nature of his collapse induces intense curiosity but people with illness deserve privacy. Privacy in health care is in short supply. I disagree strongly with those who say his doctors ought to be giving public updates. That’s up to the family.
But there are important general concepts to consider about this incident. These include ...
Cardiac arrest can happen to anyone
People with structural heart disease or other chronic illnesses have a higher risk of arrhythmia, but the notion that athletes are immune from cardiac arrest is wrong. This sentence almost seems too obvious to write, but to this day, I hear clinicians express surprise that an athletic person has heart disease.
Survival turns on rapid and effective intervention
In the old days of electrophysiology, we used to test implantable cardioverter-defibrillators during an implant procedure by inducing ventricular fibrillation (VF) and watching the device convert it. Thankfully, trials have shown that this is no longer necessary for most implants.
When you induce VF In the EP lab, you learn quickly that a) it causes loss of consciousness in a matter of seconds, b) rapid defibrillation restores consciousness, often without the patients knowing or remembering they passed out, and c) the failure of the shock to terminate VF results in deterioration in a matter of 1-2 minutes. Even 1 minute in VF feels so long.
Need is an appropriate word in VF treatment
Clinicians often use the verb need. As in, this patient needs this pill or this procedure. It’s rarely appropriate.
But in the case of treating VF, patients truly need rapid defibrillation. Survival of out-of-hospital cardiac arrest is low because there just aren’t enough automated external defibrillators (AEDs) or people trained to use them. A study of patients who had out-of-hospital cardiac arrest in Denmark found that 30-day survival almost doubled (28.8% vs. 16.4%), when the nearest AED was accessible.
Bystanders must act
The public messages are simple: If a person loses consciousness in front of you, and is not breathing normally, assume it is a cardiac arrest, call 911 to get professional help, and start hands-only chest compressions. Don’t spend time checking for a pulse or trying to wake the person. If this is not a cardiac arrest, they will soon tell you to stop compressing their chest. Seconds matter.
Chest compressions are important but what is really needed is defibrillation. A crucial step in CPR is to send someone to get an AED and get the pads attached. If this is a shockable rhythm, deliver the shock. Hamlin’s collapse emphasizes the importance of the AED; without it, his survival to the hospital would have been unlikely.
Widespread preparticipation screening of young athletes remains a bad idea
Whenever cardiac arrest occurs in an athlete, in such a public way, people think about prevention. Surely it is better to prevent such an event than react to it, goes the thinking. The argument against this idea has four prongs:
The incidence of cardiac disease in a young athlete is extremely low, which sets up a situation where most “positive” tests are false positive. A false positive screening ECG or echocardiogram can create harm in multiple ways. One is the risk from downstream procedures, but worse is the inappropriate disqualification from sport. Healthwise, few harms could be greater than creating long-term fear of exercise in someone.
There is also the problem of false-negative screening tests. An ECG may be normal in the setting of hypertrophic cardiomyopathy. And a normal echocardiogram does not exclude arrhythmogenic right ventricular cardiomyopathy or other genetic causes of cardiac arrest. In a 2018 study from a major sports cardiology center in London, 6 of the 8 sudden cardiac deaths in their series were in athletes who had no detectable abnormalities on screening.
Even when disease is found, it’s not clear that prohibiting participation in sports prevents sudden death. Many previous class III recommendations against participation in sport now carry class II – may be considered – designations.
Finally, screening for any disease loses value as treatments improve. Public education regarding rapid intervention with CPR and AED use is the best treatment option. A great example is the case of Christian Erikson, a Danish soccer player who suffered cardiac arrest during a match at the European Championships in 2021 and was rapidly defibrillated on the field. Therapy was so effective that he was conscious and able to wave to fans on his way out of the stadium. He has now returned to elite competition.
Proponents of screening might oppose my take by saying that National Football League players are intensely screened. But this is different from widespread screening of high school and college athletes. It might sound harsh to say, but professional teams have dualities of interests in the health of their athletes given the million-dollar contracts.
What’s more, professional teams can afford to hire expert cardiologists to perform the testing. This would likely reduce the rate of false-positive findings, compared with screening in the community setting. I often have young people referred to me because of asymptomatic bradycardia found during athletic screening – an obviously normal finding.
Conclusions
As long as there are sports, there will be athletes who suffer cardiac arrest.
We can both hope for Hamlin’s full recovery and learn lessons to help reduce the rate of death from out-of-hospital cardiac arrest. This mostly involves education on how to help fellow humans and a public health commitment to access to AEDs.
John Mandrola, MD, practices cardiac electrophysiology in Louisville, Ky. and is a writer and podcaster for Medscape. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.
The obvious first statement is that it’s neither wise nor appropriate to speculate on the specifics of Damar Hamlin’s cardiac event during a football game on Jan. 2 (including the possibility of commotio cordis) or his ongoing care. The public nature of his collapse induces intense curiosity but people with illness deserve privacy. Privacy in health care is in short supply. I disagree strongly with those who say his doctors ought to be giving public updates. That’s up to the family.
But there are important general concepts to consider about this incident. These include ...
Cardiac arrest can happen to anyone
People with structural heart disease or other chronic illnesses have a higher risk of arrhythmia, but the notion that athletes are immune from cardiac arrest is wrong. This sentence almost seems too obvious to write, but to this day, I hear clinicians express surprise that an athletic person has heart disease.
Survival turns on rapid and effective intervention
In the old days of electrophysiology, we used to test implantable cardioverter-defibrillators during an implant procedure by inducing ventricular fibrillation (VF) and watching the device convert it. Thankfully, trials have shown that this is no longer necessary for most implants.
When you induce VF In the EP lab, you learn quickly that a) it causes loss of consciousness in a matter of seconds, b) rapid defibrillation restores consciousness, often without the patients knowing or remembering they passed out, and c) the failure of the shock to terminate VF results in deterioration in a matter of 1-2 minutes. Even 1 minute in VF feels so long.
Need is an appropriate word in VF treatment
Clinicians often use the verb need. As in, this patient needs this pill or this procedure. It’s rarely appropriate.
But in the case of treating VF, patients truly need rapid defibrillation. Survival of out-of-hospital cardiac arrest is low because there just aren’t enough automated external defibrillators (AEDs) or people trained to use them. A study of patients who had out-of-hospital cardiac arrest in Denmark found that 30-day survival almost doubled (28.8% vs. 16.4%), when the nearest AED was accessible.
Bystanders must act
The public messages are simple: If a person loses consciousness in front of you, and is not breathing normally, assume it is a cardiac arrest, call 911 to get professional help, and start hands-only chest compressions. Don’t spend time checking for a pulse or trying to wake the person. If this is not a cardiac arrest, they will soon tell you to stop compressing their chest. Seconds matter.
Chest compressions are important but what is really needed is defibrillation. A crucial step in CPR is to send someone to get an AED and get the pads attached. If this is a shockable rhythm, deliver the shock. Hamlin’s collapse emphasizes the importance of the AED; without it, his survival to the hospital would have been unlikely.
Widespread preparticipation screening of young athletes remains a bad idea
Whenever cardiac arrest occurs in an athlete, in such a public way, people think about prevention. Surely it is better to prevent such an event than react to it, goes the thinking. The argument against this idea has four prongs:
The incidence of cardiac disease in a young athlete is extremely low, which sets up a situation where most “positive” tests are false positive. A false positive screening ECG or echocardiogram can create harm in multiple ways. One is the risk from downstream procedures, but worse is the inappropriate disqualification from sport. Healthwise, few harms could be greater than creating long-term fear of exercise in someone.
There is also the problem of false-negative screening tests. An ECG may be normal in the setting of hypertrophic cardiomyopathy. And a normal echocardiogram does not exclude arrhythmogenic right ventricular cardiomyopathy or other genetic causes of cardiac arrest. In a 2018 study from a major sports cardiology center in London, 6 of the 8 sudden cardiac deaths in their series were in athletes who had no detectable abnormalities on screening.
Even when disease is found, it’s not clear that prohibiting participation in sports prevents sudden death. Many previous class III recommendations against participation in sport now carry class II – may be considered – designations.
Finally, screening for any disease loses value as treatments improve. Public education regarding rapid intervention with CPR and AED use is the best treatment option. A great example is the case of Christian Erikson, a Danish soccer player who suffered cardiac arrest during a match at the European Championships in 2021 and was rapidly defibrillated on the field. Therapy was so effective that he was conscious and able to wave to fans on his way out of the stadium. He has now returned to elite competition.
Proponents of screening might oppose my take by saying that National Football League players are intensely screened. But this is different from widespread screening of high school and college athletes. It might sound harsh to say, but professional teams have dualities of interests in the health of their athletes given the million-dollar contracts.
What’s more, professional teams can afford to hire expert cardiologists to perform the testing. This would likely reduce the rate of false-positive findings, compared with screening in the community setting. I often have young people referred to me because of asymptomatic bradycardia found during athletic screening – an obviously normal finding.
Conclusions
As long as there are sports, there will be athletes who suffer cardiac arrest.
We can both hope for Hamlin’s full recovery and learn lessons to help reduce the rate of death from out-of-hospital cardiac arrest. This mostly involves education on how to help fellow humans and a public health commitment to access to AEDs.
John Mandrola, MD, practices cardiac electrophysiology in Louisville, Ky. and is a writer and podcaster for Medscape. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.
The obvious first statement is that it’s neither wise nor appropriate to speculate on the specifics of Damar Hamlin’s cardiac event during a football game on Jan. 2 (including the possibility of commotio cordis) or his ongoing care. The public nature of his collapse induces intense curiosity but people with illness deserve privacy. Privacy in health care is in short supply. I disagree strongly with those who say his doctors ought to be giving public updates. That’s up to the family.
But there are important general concepts to consider about this incident. These include ...
Cardiac arrest can happen to anyone
People with structural heart disease or other chronic illnesses have a higher risk of arrhythmia, but the notion that athletes are immune from cardiac arrest is wrong. This sentence almost seems too obvious to write, but to this day, I hear clinicians express surprise that an athletic person has heart disease.
Survival turns on rapid and effective intervention
In the old days of electrophysiology, we used to test implantable cardioverter-defibrillators during an implant procedure by inducing ventricular fibrillation (VF) and watching the device convert it. Thankfully, trials have shown that this is no longer necessary for most implants.
When you induce VF In the EP lab, you learn quickly that a) it causes loss of consciousness in a matter of seconds, b) rapid defibrillation restores consciousness, often without the patients knowing or remembering they passed out, and c) the failure of the shock to terminate VF results in deterioration in a matter of 1-2 minutes. Even 1 minute in VF feels so long.
Need is an appropriate word in VF treatment
Clinicians often use the verb need. As in, this patient needs this pill or this procedure. It’s rarely appropriate.
But in the case of treating VF, patients truly need rapid defibrillation. Survival of out-of-hospital cardiac arrest is low because there just aren’t enough automated external defibrillators (AEDs) or people trained to use them. A study of patients who had out-of-hospital cardiac arrest in Denmark found that 30-day survival almost doubled (28.8% vs. 16.4%), when the nearest AED was accessible.
Bystanders must act
The public messages are simple: If a person loses consciousness in front of you, and is not breathing normally, assume it is a cardiac arrest, call 911 to get professional help, and start hands-only chest compressions. Don’t spend time checking for a pulse or trying to wake the person. If this is not a cardiac arrest, they will soon tell you to stop compressing their chest. Seconds matter.
Chest compressions are important but what is really needed is defibrillation. A crucial step in CPR is to send someone to get an AED and get the pads attached. If this is a shockable rhythm, deliver the shock. Hamlin’s collapse emphasizes the importance of the AED; without it, his survival to the hospital would have been unlikely.
Widespread preparticipation screening of young athletes remains a bad idea
Whenever cardiac arrest occurs in an athlete, in such a public way, people think about prevention. Surely it is better to prevent such an event than react to it, goes the thinking. The argument against this idea has four prongs:
The incidence of cardiac disease in a young athlete is extremely low, which sets up a situation where most “positive” tests are false positive. A false positive screening ECG or echocardiogram can create harm in multiple ways. One is the risk from downstream procedures, but worse is the inappropriate disqualification from sport. Healthwise, few harms could be greater than creating long-term fear of exercise in someone.
There is also the problem of false-negative screening tests. An ECG may be normal in the setting of hypertrophic cardiomyopathy. And a normal echocardiogram does not exclude arrhythmogenic right ventricular cardiomyopathy or other genetic causes of cardiac arrest. In a 2018 study from a major sports cardiology center in London, 6 of the 8 sudden cardiac deaths in their series were in athletes who had no detectable abnormalities on screening.
Even when disease is found, it’s not clear that prohibiting participation in sports prevents sudden death. Many previous class III recommendations against participation in sport now carry class II – may be considered – designations.
Finally, screening for any disease loses value as treatments improve. Public education regarding rapid intervention with CPR and AED use is the best treatment option. A great example is the case of Christian Erikson, a Danish soccer player who suffered cardiac arrest during a match at the European Championships in 2021 and was rapidly defibrillated on the field. Therapy was so effective that he was conscious and able to wave to fans on his way out of the stadium. He has now returned to elite competition.
Proponents of screening might oppose my take by saying that National Football League players are intensely screened. But this is different from widespread screening of high school and college athletes. It might sound harsh to say, but professional teams have dualities of interests in the health of their athletes given the million-dollar contracts.
What’s more, professional teams can afford to hire expert cardiologists to perform the testing. This would likely reduce the rate of false-positive findings, compared with screening in the community setting. I often have young people referred to me because of asymptomatic bradycardia found during athletic screening – an obviously normal finding.
Conclusions
As long as there are sports, there will be athletes who suffer cardiac arrest.
We can both hope for Hamlin’s full recovery and learn lessons to help reduce the rate of death from out-of-hospital cardiac arrest. This mostly involves education on how to help fellow humans and a public health commitment to access to AEDs.
John Mandrola, MD, practices cardiac electrophysiology in Louisville, Ky. and is a writer and podcaster for Medscape. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.
One in four cardiologists worldwide report mental health issues
ranging from anxiety or anger issues to major depression or other psychiatric disorders.
Such conditions varied in prevalence by cardiology subspecialty and years in the field, were more common in women than in men, and were closely linked to enduring hostile work environments and other strains of professional life.
The survey, conducted only months before the COVID-19 pandemic and with its share of limitations, still paints a picture that’s not pretty.
For example, mental health concerns were reported by about 42% of respondents who cited a hostile work environment, defined as workplace experience of discrimination based on age, sex, religion, race or ethnicity, or emotional or sexual harassment. Conversely, the prevalence of these concerns reached only 17% among those without such workplace conditions.
The study shows substantial overlap between cardiologists reporting hostility at work and those with mental health concerns, “and that was a significant finding,” Garima Sharma, MD, Johns Hopkins University, Baltimore, said in an interview.
Still, only 31% of male and 42% of female cardiologists (P < .001) reporting mental health concerns also said they had sought professional help either within or outside their own institutions.
That means “there is a lot of silent suffering” in the field, said Dr. Sharma, who is lead author on the study, published in the Journal of the American College of Cardiology.
Bringing back the conversation
The survey findings, she added, point to at least two potential ways the cardiology community can strive to diminish what may be a major underlying cause of the mental health concerns and their consequences.
“If you work towards reducing hostility at work and making mental health a priority for your workforce, then those experiencing these types of egregious conditions based on age, gender, race, ethnicity, or sexual orientation are less likely to be harmed.”
Mental health concerns among cardiologists are seldom openly discussed, so the current study can be “a way to bring them back into the conversation,” Dr. Sharma said. Clinician mental health “is extremely important because it directly impacts patient care and productivity.”
The survey’s reported mental health conditions “are an issue across the board in medicine, and amongst our medical students as well,” senior author Laxmi S. Mehta, MD, professor of internal medicine at Ohio State University, Columbus, said in an interview. The current study provides new details about their prevalence and predictors in cardiology and, she hopes, may improve the field’s awareness of and efforts to address the problem.
“We need to support those who have underlying mental health conditions, as well as improve the work environment to reduce contributory factors to mental illnesses. And we also need to work on reducing the stigma associated with seeking treatment and on reducing the barriers to receiving treatment,” said Dr. Mehta, who chairs the Workgroup on Clinician Well-Being of the ACC, which conducted the survey in 2019.
A global perspective
Cardiologists in Africa, the Americas, Asia, Europe, the Middle East, and Oceania – 5,890 in all – responded to mental health questions on the survey, which was novel for its global reach and insights across continents and cultures.
Respondents in South America and Central America reported the highest prevalences of mental health concerns, outliers at about 39% and 33%, respectively. Rates for most other geographic regions ranged narrowly from about 20% to 26%, the lowest reported in Asia and the Middle East.
Dr. Sharma acknowledged that the countries probably varied widely in social and cultural factors likely to influence survey responses, such as interpretation of the questionnaire’s mental health terminology or the degree to which the disorders are stigmatized.
“I think it’s hard to say how people may or may not respond culturally to a certain word or metric,” she said. But on the survey results, “whether you’re practicing in rural America, in rural India, or in the United Arab Emirates, Oceania, or Eastern Europe, there is a level of consistency, across the board, in what people are recognizing as mental health conditions.”
Junior vs. senior physicians
The global perspective “is a nice positive of the study, and the high rates in Central America and South America I think were something the field was not aware of and are an important contribution,” Srijan Sen, MD, PhD, said in an interview.
The psychological toll of hostile work environments is an issue throughout medicine, “but it seems greater in certain specialties, and cardiology may be one where it’s more of a problem,” observed Dr. Sen, who studies physician mental health at the University of Michigan, Ann Arbor, and wasn’t associated with the survey.
Mental health concerns in the survey were significantly more common among women than men (33.7% vs 26.3%), and for younger cardiologists, compared with older cardiologists (32.2% for those < 40 vs. 22.1% and 16.8% for those 55-69 and 70 or older, respectively).
Those findings seem to make sense, Dr. Sen observed. “Generally, cardiology and medicine broadly are hierarchical, so being more junior can be stressful.” And if there’s more hostility in the workplace, “it might fall on junior people.”
In other studies, moreover, “a high level of work-family conflict has been a real driver of depression and burnout, and that likely is affecting younger physicians, particularly young women physicians,” who may have smaller children and a greater burden of childcare than their seniors.
He pointed to the survey’s low response rate as an important limitation of the study. Of the 71,022 cardiologists invited to participate, only 5,890 (8.3%) responded and answered the queries on mental health.
With a response rate that low, a survey “can be biased in ways that we can’t predict,” Dr. Sen noted. Also, anyone concerned about the toxicity of their own workplace might be “more likely to respond to the survey than if they worked in a more pleasant place. That would provide a skewed sense of the overall experience of cardiologists.”
Those issues might not be a concern with the current survey, however, “because the results are consistent with other studies with higher response rates.”
‘Sobering report’
An accompanying editorial said Dr. Sharm and colleagues have provided “a sobering report on the global prevalence and potential contributors to mental health concerns” in the surveyed population.
Based on its lessons, Andrew J. Sauer, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., proposed several potential “interventions” the field could enact.
It could “selectively promote leaders who strive to mitigate implicit bias, discrimination, and harassment while advancing diversity, equity, and inclusion within the broad ranks of cardiologists.”
Also, he continued, “we must eliminate the stigmatization of mental illness among physicians. We need to handle mental health concerns with compassion and without blaming, like how we strive to treat our veterans who suffer from posttraumatic stress disorder.”
Lastly, Dr. Sauer wrote, “mentorship programs should be formalized to assist the cardiologist in transition zones from early to mid-career, with particular attention to women and those experiencing a simultaneously increased load of family burdens that compound existing workplace contributors to burnout and psychological distress.”
Years in practice
Of the cardiologists who responded to the survey’s mental health questions, 28% reported they have experienced mental health issues that could include alcohol/drug use disorder, suicidal tendencies, psychological distress (including anxiety, irritability, or anger), “other psychiatric disorders” (such as panic disorder, posttraumatic stress, or eating disorders) or major psychiatric disorders such as major depression, bipolar disorder, or schizophrenia.
Cardiologists with 5-10 years of practice post-training were more likely than cardiologists practicing for at least 20 years to have mental health concerns (31.9% vs. 22.6%, P < .001).
Mental health concerns were cited by 42% of respondents who cited “any type of discrimination” based on age, sex, race or ethnicity, or sexual orientation, the report noted.
Among those reporting any mental health concern, 2.7% considered suicide within the past year and 2.9% considered suicide more than 12 months previously. Women were more likely than men to consider suicide within the past year (3.8% vs. 2.3%) but were also more likely to seek help (42.3% vs. 31.1%; P < .001 for both differences), the authors wrote.
In multivariate analysis, predictors of mental health concerns included emotional harassment, 2.81 (odds ratio, 2.81; 95% confidence interval, 2.46-3.20), any discrimination (OR, 1.85; 95% CI, 1.61-2.12), being divorced (OR, 1.73; 95% CI, 1.26-2.36, age less than 55 years (OR, 1.43; 95% CI, 1.24-1.66), and being mid-career versus late (OR, 1.36; 95% CI, 1.14-1.62).
Because the survey was conducted from September to October 2019, before the pandemic’s traumatic effects unfolded on health care nearly everywhere, “I think there needs to be a follow-up at some point when everything has leveled out,” Dr. Sharma said. The current study is “a baseline, and not a healthy baseline,” for the field’s state of mental health that has likely grown worse during the pandemic.
But even without such a follow-up, the current study “is actionable enough that it forces us to do something about it right now.”
Dr. Sharma, Dr. Mehta, their coauthors, Dr. Sen, and Dr. Sauer reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
ranging from anxiety or anger issues to major depression or other psychiatric disorders.
Such conditions varied in prevalence by cardiology subspecialty and years in the field, were more common in women than in men, and were closely linked to enduring hostile work environments and other strains of professional life.
The survey, conducted only months before the COVID-19 pandemic and with its share of limitations, still paints a picture that’s not pretty.
For example, mental health concerns were reported by about 42% of respondents who cited a hostile work environment, defined as workplace experience of discrimination based on age, sex, religion, race or ethnicity, or emotional or sexual harassment. Conversely, the prevalence of these concerns reached only 17% among those without such workplace conditions.
The study shows substantial overlap between cardiologists reporting hostility at work and those with mental health concerns, “and that was a significant finding,” Garima Sharma, MD, Johns Hopkins University, Baltimore, said in an interview.
Still, only 31% of male and 42% of female cardiologists (P < .001) reporting mental health concerns also said they had sought professional help either within or outside their own institutions.
That means “there is a lot of silent suffering” in the field, said Dr. Sharma, who is lead author on the study, published in the Journal of the American College of Cardiology.
Bringing back the conversation
The survey findings, she added, point to at least two potential ways the cardiology community can strive to diminish what may be a major underlying cause of the mental health concerns and their consequences.
“If you work towards reducing hostility at work and making mental health a priority for your workforce, then those experiencing these types of egregious conditions based on age, gender, race, ethnicity, or sexual orientation are less likely to be harmed.”
Mental health concerns among cardiologists are seldom openly discussed, so the current study can be “a way to bring them back into the conversation,” Dr. Sharma said. Clinician mental health “is extremely important because it directly impacts patient care and productivity.”
The survey’s reported mental health conditions “are an issue across the board in medicine, and amongst our medical students as well,” senior author Laxmi S. Mehta, MD, professor of internal medicine at Ohio State University, Columbus, said in an interview. The current study provides new details about their prevalence and predictors in cardiology and, she hopes, may improve the field’s awareness of and efforts to address the problem.
“We need to support those who have underlying mental health conditions, as well as improve the work environment to reduce contributory factors to mental illnesses. And we also need to work on reducing the stigma associated with seeking treatment and on reducing the barriers to receiving treatment,” said Dr. Mehta, who chairs the Workgroup on Clinician Well-Being of the ACC, which conducted the survey in 2019.
A global perspective
Cardiologists in Africa, the Americas, Asia, Europe, the Middle East, and Oceania – 5,890 in all – responded to mental health questions on the survey, which was novel for its global reach and insights across continents and cultures.
Respondents in South America and Central America reported the highest prevalences of mental health concerns, outliers at about 39% and 33%, respectively. Rates for most other geographic regions ranged narrowly from about 20% to 26%, the lowest reported in Asia and the Middle East.
Dr. Sharma acknowledged that the countries probably varied widely in social and cultural factors likely to influence survey responses, such as interpretation of the questionnaire’s mental health terminology or the degree to which the disorders are stigmatized.
“I think it’s hard to say how people may or may not respond culturally to a certain word or metric,” she said. But on the survey results, “whether you’re practicing in rural America, in rural India, or in the United Arab Emirates, Oceania, or Eastern Europe, there is a level of consistency, across the board, in what people are recognizing as mental health conditions.”
Junior vs. senior physicians
The global perspective “is a nice positive of the study, and the high rates in Central America and South America I think were something the field was not aware of and are an important contribution,” Srijan Sen, MD, PhD, said in an interview.
The psychological toll of hostile work environments is an issue throughout medicine, “but it seems greater in certain specialties, and cardiology may be one where it’s more of a problem,” observed Dr. Sen, who studies physician mental health at the University of Michigan, Ann Arbor, and wasn’t associated with the survey.
Mental health concerns in the survey were significantly more common among women than men (33.7% vs 26.3%), and for younger cardiologists, compared with older cardiologists (32.2% for those < 40 vs. 22.1% and 16.8% for those 55-69 and 70 or older, respectively).
Those findings seem to make sense, Dr. Sen observed. “Generally, cardiology and medicine broadly are hierarchical, so being more junior can be stressful.” And if there’s more hostility in the workplace, “it might fall on junior people.”
In other studies, moreover, “a high level of work-family conflict has been a real driver of depression and burnout, and that likely is affecting younger physicians, particularly young women physicians,” who may have smaller children and a greater burden of childcare than their seniors.
He pointed to the survey’s low response rate as an important limitation of the study. Of the 71,022 cardiologists invited to participate, only 5,890 (8.3%) responded and answered the queries on mental health.
With a response rate that low, a survey “can be biased in ways that we can’t predict,” Dr. Sen noted. Also, anyone concerned about the toxicity of their own workplace might be “more likely to respond to the survey than if they worked in a more pleasant place. That would provide a skewed sense of the overall experience of cardiologists.”
Those issues might not be a concern with the current survey, however, “because the results are consistent with other studies with higher response rates.”
‘Sobering report’
An accompanying editorial said Dr. Sharm and colleagues have provided “a sobering report on the global prevalence and potential contributors to mental health concerns” in the surveyed population.
Based on its lessons, Andrew J. Sauer, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., proposed several potential “interventions” the field could enact.
It could “selectively promote leaders who strive to mitigate implicit bias, discrimination, and harassment while advancing diversity, equity, and inclusion within the broad ranks of cardiologists.”
Also, he continued, “we must eliminate the stigmatization of mental illness among physicians. We need to handle mental health concerns with compassion and without blaming, like how we strive to treat our veterans who suffer from posttraumatic stress disorder.”
Lastly, Dr. Sauer wrote, “mentorship programs should be formalized to assist the cardiologist in transition zones from early to mid-career, with particular attention to women and those experiencing a simultaneously increased load of family burdens that compound existing workplace contributors to burnout and psychological distress.”
Years in practice
Of the cardiologists who responded to the survey’s mental health questions, 28% reported they have experienced mental health issues that could include alcohol/drug use disorder, suicidal tendencies, psychological distress (including anxiety, irritability, or anger), “other psychiatric disorders” (such as panic disorder, posttraumatic stress, or eating disorders) or major psychiatric disorders such as major depression, bipolar disorder, or schizophrenia.
Cardiologists with 5-10 years of practice post-training were more likely than cardiologists practicing for at least 20 years to have mental health concerns (31.9% vs. 22.6%, P < .001).
Mental health concerns were cited by 42% of respondents who cited “any type of discrimination” based on age, sex, race or ethnicity, or sexual orientation, the report noted.
Among those reporting any mental health concern, 2.7% considered suicide within the past year and 2.9% considered suicide more than 12 months previously. Women were more likely than men to consider suicide within the past year (3.8% vs. 2.3%) but were also more likely to seek help (42.3% vs. 31.1%; P < .001 for both differences), the authors wrote.
In multivariate analysis, predictors of mental health concerns included emotional harassment, 2.81 (odds ratio, 2.81; 95% confidence interval, 2.46-3.20), any discrimination (OR, 1.85; 95% CI, 1.61-2.12), being divorced (OR, 1.73; 95% CI, 1.26-2.36, age less than 55 years (OR, 1.43; 95% CI, 1.24-1.66), and being mid-career versus late (OR, 1.36; 95% CI, 1.14-1.62).
Because the survey was conducted from September to October 2019, before the pandemic’s traumatic effects unfolded on health care nearly everywhere, “I think there needs to be a follow-up at some point when everything has leveled out,” Dr. Sharma said. The current study is “a baseline, and not a healthy baseline,” for the field’s state of mental health that has likely grown worse during the pandemic.
But even without such a follow-up, the current study “is actionable enough that it forces us to do something about it right now.”
Dr. Sharma, Dr. Mehta, their coauthors, Dr. Sen, and Dr. Sauer reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
ranging from anxiety or anger issues to major depression or other psychiatric disorders.
Such conditions varied in prevalence by cardiology subspecialty and years in the field, were more common in women than in men, and were closely linked to enduring hostile work environments and other strains of professional life.
The survey, conducted only months before the COVID-19 pandemic and with its share of limitations, still paints a picture that’s not pretty.
For example, mental health concerns were reported by about 42% of respondents who cited a hostile work environment, defined as workplace experience of discrimination based on age, sex, religion, race or ethnicity, or emotional or sexual harassment. Conversely, the prevalence of these concerns reached only 17% among those without such workplace conditions.
The study shows substantial overlap between cardiologists reporting hostility at work and those with mental health concerns, “and that was a significant finding,” Garima Sharma, MD, Johns Hopkins University, Baltimore, said in an interview.
Still, only 31% of male and 42% of female cardiologists (P < .001) reporting mental health concerns also said they had sought professional help either within or outside their own institutions.
That means “there is a lot of silent suffering” in the field, said Dr. Sharma, who is lead author on the study, published in the Journal of the American College of Cardiology.
Bringing back the conversation
The survey findings, she added, point to at least two potential ways the cardiology community can strive to diminish what may be a major underlying cause of the mental health concerns and their consequences.
“If you work towards reducing hostility at work and making mental health a priority for your workforce, then those experiencing these types of egregious conditions based on age, gender, race, ethnicity, or sexual orientation are less likely to be harmed.”
Mental health concerns among cardiologists are seldom openly discussed, so the current study can be “a way to bring them back into the conversation,” Dr. Sharma said. Clinician mental health “is extremely important because it directly impacts patient care and productivity.”
The survey’s reported mental health conditions “are an issue across the board in medicine, and amongst our medical students as well,” senior author Laxmi S. Mehta, MD, professor of internal medicine at Ohio State University, Columbus, said in an interview. The current study provides new details about their prevalence and predictors in cardiology and, she hopes, may improve the field’s awareness of and efforts to address the problem.
“We need to support those who have underlying mental health conditions, as well as improve the work environment to reduce contributory factors to mental illnesses. And we also need to work on reducing the stigma associated with seeking treatment and on reducing the barriers to receiving treatment,” said Dr. Mehta, who chairs the Workgroup on Clinician Well-Being of the ACC, which conducted the survey in 2019.
A global perspective
Cardiologists in Africa, the Americas, Asia, Europe, the Middle East, and Oceania – 5,890 in all – responded to mental health questions on the survey, which was novel for its global reach and insights across continents and cultures.
Respondents in South America and Central America reported the highest prevalences of mental health concerns, outliers at about 39% and 33%, respectively. Rates for most other geographic regions ranged narrowly from about 20% to 26%, the lowest reported in Asia and the Middle East.
Dr. Sharma acknowledged that the countries probably varied widely in social and cultural factors likely to influence survey responses, such as interpretation of the questionnaire’s mental health terminology or the degree to which the disorders are stigmatized.
“I think it’s hard to say how people may or may not respond culturally to a certain word or metric,” she said. But on the survey results, “whether you’re practicing in rural America, in rural India, or in the United Arab Emirates, Oceania, or Eastern Europe, there is a level of consistency, across the board, in what people are recognizing as mental health conditions.”
Junior vs. senior physicians
The global perspective “is a nice positive of the study, and the high rates in Central America and South America I think were something the field was not aware of and are an important contribution,” Srijan Sen, MD, PhD, said in an interview.
The psychological toll of hostile work environments is an issue throughout medicine, “but it seems greater in certain specialties, and cardiology may be one where it’s more of a problem,” observed Dr. Sen, who studies physician mental health at the University of Michigan, Ann Arbor, and wasn’t associated with the survey.
Mental health concerns in the survey were significantly more common among women than men (33.7% vs 26.3%), and for younger cardiologists, compared with older cardiologists (32.2% for those < 40 vs. 22.1% and 16.8% for those 55-69 and 70 or older, respectively).
Those findings seem to make sense, Dr. Sen observed. “Generally, cardiology and medicine broadly are hierarchical, so being more junior can be stressful.” And if there’s more hostility in the workplace, “it might fall on junior people.”
In other studies, moreover, “a high level of work-family conflict has been a real driver of depression and burnout, and that likely is affecting younger physicians, particularly young women physicians,” who may have smaller children and a greater burden of childcare than their seniors.
He pointed to the survey’s low response rate as an important limitation of the study. Of the 71,022 cardiologists invited to participate, only 5,890 (8.3%) responded and answered the queries on mental health.
With a response rate that low, a survey “can be biased in ways that we can’t predict,” Dr. Sen noted. Also, anyone concerned about the toxicity of their own workplace might be “more likely to respond to the survey than if they worked in a more pleasant place. That would provide a skewed sense of the overall experience of cardiologists.”
Those issues might not be a concern with the current survey, however, “because the results are consistent with other studies with higher response rates.”
‘Sobering report’
An accompanying editorial said Dr. Sharm and colleagues have provided “a sobering report on the global prevalence and potential contributors to mental health concerns” in the surveyed population.
Based on its lessons, Andrew J. Sauer, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., proposed several potential “interventions” the field could enact.
It could “selectively promote leaders who strive to mitigate implicit bias, discrimination, and harassment while advancing diversity, equity, and inclusion within the broad ranks of cardiologists.”
Also, he continued, “we must eliminate the stigmatization of mental illness among physicians. We need to handle mental health concerns with compassion and without blaming, like how we strive to treat our veterans who suffer from posttraumatic stress disorder.”
Lastly, Dr. Sauer wrote, “mentorship programs should be formalized to assist the cardiologist in transition zones from early to mid-career, with particular attention to women and those experiencing a simultaneously increased load of family burdens that compound existing workplace contributors to burnout and psychological distress.”
Years in practice
Of the cardiologists who responded to the survey’s mental health questions, 28% reported they have experienced mental health issues that could include alcohol/drug use disorder, suicidal tendencies, psychological distress (including anxiety, irritability, or anger), “other psychiatric disorders” (such as panic disorder, posttraumatic stress, or eating disorders) or major psychiatric disorders such as major depression, bipolar disorder, or schizophrenia.
Cardiologists with 5-10 years of practice post-training were more likely than cardiologists practicing for at least 20 years to have mental health concerns (31.9% vs. 22.6%, P < .001).
Mental health concerns were cited by 42% of respondents who cited “any type of discrimination” based on age, sex, race or ethnicity, or sexual orientation, the report noted.
Among those reporting any mental health concern, 2.7% considered suicide within the past year and 2.9% considered suicide more than 12 months previously. Women were more likely than men to consider suicide within the past year (3.8% vs. 2.3%) but were also more likely to seek help (42.3% vs. 31.1%; P < .001 for both differences), the authors wrote.
In multivariate analysis, predictors of mental health concerns included emotional harassment, 2.81 (odds ratio, 2.81; 95% confidence interval, 2.46-3.20), any discrimination (OR, 1.85; 95% CI, 1.61-2.12), being divorced (OR, 1.73; 95% CI, 1.26-2.36, age less than 55 years (OR, 1.43; 95% CI, 1.24-1.66), and being mid-career versus late (OR, 1.36; 95% CI, 1.14-1.62).
Because the survey was conducted from September to October 2019, before the pandemic’s traumatic effects unfolded on health care nearly everywhere, “I think there needs to be a follow-up at some point when everything has leveled out,” Dr. Sharma said. The current study is “a baseline, and not a healthy baseline,” for the field’s state of mental health that has likely grown worse during the pandemic.
But even without such a follow-up, the current study “is actionable enough that it forces us to do something about it right now.”
Dr. Sharma, Dr. Mehta, their coauthors, Dr. Sen, and Dr. Sauer reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
STEMI times to treatment usually miss established goals
Therapy initiated within national treatment-time goals set a decade ago for patients with ST-segment elevation myocardial infarction (STEMI) remains associated with improved survival in recent years. But for many such patients, time from first symptoms to initiation of reperfusion therapy still fails to meet those goals, suggests a cross-sectional registry analysis.
For example, patients initially transported to centers with percutaneous coronary intervention (PCI) capability had a median treatment time of 148 minutes, in the analysis spanning the second quarter (Q2) of 2018 to the third quarter (Q3) of 2021. But the goal for centers called for treatment initiation within 90 minutes for at least 75% of such STEMI patients.
Moreover, overall STEMI treatment times and in-hospital mortality rose in tandem significantly from Q2 2018 through the first quarter (Q1) of 2021, which included the first year of the COVID-19 pandemic. Median time to treatment went from 86 minutes to 91 minutes during that period. Meanwhile, in-hospital mortality went from 5.6% to 8.7%, report the study authors led by James G. Jollis, MD, Duke University, Durham, N.C.
Their report, based on 114,871 STEMI patients at 601 US hospitals contributing to the Get With The Guidelines – Coronary Artery Disease registry, was published online in JAMA.
Of those patients, 25,085 had been transferred from non-PCI hospitals, 32,483 were walk-ins, and 57,303 arrived via emergency medical services (EMS). Their median times from symptom onset to PCI were 240, 195, and 148 minutes, respectively.
In-hospital mortality was significantly reduced in an adjusted analysis for patients treated within target times, compared with those whose treatment missed the time goals, regardless of whether they were transported by EMS, walked into a hospital with on-site PCI, or were transferred from a non-PCI center (Table 1).
Regardless of mode of patient presentation, treatment time goals were not met most of the time, the group reports. Patients who required interhospital transfer experienced the longest system delays; only 17% were treated within 120 minutes.
Among patients who received primary PCI, 20% had a registry-defined hospital-specified reason for delay, including cardiac arrest and/or need for intubation in 6.8%, “difficulty crossing the culprit lesion” in 3.8%, and “other reasons” in 5.8%, the group reports.
“In 2020, a new reason for delay was added to the registry, ‘need for additional personal protective equipment for suspected/confirmed infectious disease.’ This reason was most commonly used in the second quarter of 2020 (6%) and then declined over time to 1% in the final 2 quarters,” they write.
“Thus, active SARS-CoV-2 infection appeared to have a smaller direct role in longer treatment times or worse outcomes.” Rather, they continue, “the pandemic potentially had a significant indirect role as hospitals were overwhelmed with patients, EMS and hospitals were challenged in maintaining paramedic and nurse staffing and intensive care bed availability, and patients experienced delayed care due to barriers to access or perceived fear of becoming entangled in an overwhelmed medical system.”
Still an important quality metric
STEMI treatment times remain an important quality metric to which hospitals should continue to pay attention because shorter times improve patient care, Deepak Bhatt, MD, MPH, told this news organization.
“Having said that, as with all metrics, one needs to be thoughtful and realize that a difference of a couple of minutes is probably not a crucial thing,” said Dr. Bhatt, Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved with the current study.
Interhospital transfers indeed involve longer delays, he observed, suggesting that regional integrated health systems should develop methods for optimizing STEMI care – even, for example, if they involve bypassing non-PCI centers or stopping patients briefly for stabilization followed by rapid transport to a PCI-capable facility.
“That, of course, requires cooperation among hospitals. Sometimes that requires hospitals putting aside economic considerations and just focusing on doing the right thing for that individual patient,” Dr. Bhatt said.
Transfer delays are common for patients presenting with STEMI at hospitals without PCI capability, he noted. “Having clear protocols in place that expedite that type of transfer, I think, could go a long way in reducing the time to treatment in patients that are presenting to the hospital without cath labs. That’s an important message that these data provide.”
The onset of COVID-19 led to widespread delays in STEMI time to treatment early in the pandemic. There were concerns about exposing cath lab personnel to SARS-CoV-2 and potential adverse consequences of sick personnel being unable to provide patient care in the subsequent weeks and months, Dr. Bhatt observed.
However, “All of that seems to have quieted down, and I don’t think COVID is impacting time to treatment right now.”
‘Suboptimal compliance’ with standards
The current findings of “suboptimal compliance with national targets underscore why reassessing quality metrics, in light of changing practice patterns and other secular trends, is critical,” write Andrew S. Oseran, MD, MBA, and Robert W. Yeh, MD, both of Harvard Medical School, in an accompanying editorial.
“While the importance of coordinated and expeditious care for this high-risk patient population is undeniable, the specific actions that hospitals can – or should – take to further improve overall STEMI outcomes are less clear,” they say.
“As physicians contemplate the optimal path forward in managing the care of STEMI patients, they must recognize the clinical and operational nuance that exists in caring for this diverse population and acknowledge the trade-offs associated with uniform quality metrics,” write the editorialists.
“Global reductions in time to treatment for STEMI patients has been one of health care’s great success stories. As we move forward, it may be time to consider whether efforts to achieve additional improvement in target treatment times will result in substantive benefits, or whether we have reached the point of diminishing returns.”
A version of this article first appeared on Medscape.com.
Therapy initiated within national treatment-time goals set a decade ago for patients with ST-segment elevation myocardial infarction (STEMI) remains associated with improved survival in recent years. But for many such patients, time from first symptoms to initiation of reperfusion therapy still fails to meet those goals, suggests a cross-sectional registry analysis.
For example, patients initially transported to centers with percutaneous coronary intervention (PCI) capability had a median treatment time of 148 minutes, in the analysis spanning the second quarter (Q2) of 2018 to the third quarter (Q3) of 2021. But the goal for centers called for treatment initiation within 90 minutes for at least 75% of such STEMI patients.
Moreover, overall STEMI treatment times and in-hospital mortality rose in tandem significantly from Q2 2018 through the first quarter (Q1) of 2021, which included the first year of the COVID-19 pandemic. Median time to treatment went from 86 minutes to 91 minutes during that period. Meanwhile, in-hospital mortality went from 5.6% to 8.7%, report the study authors led by James G. Jollis, MD, Duke University, Durham, N.C.
Their report, based on 114,871 STEMI patients at 601 US hospitals contributing to the Get With The Guidelines – Coronary Artery Disease registry, was published online in JAMA.
Of those patients, 25,085 had been transferred from non-PCI hospitals, 32,483 were walk-ins, and 57,303 arrived via emergency medical services (EMS). Their median times from symptom onset to PCI were 240, 195, and 148 minutes, respectively.
In-hospital mortality was significantly reduced in an adjusted analysis for patients treated within target times, compared with those whose treatment missed the time goals, regardless of whether they were transported by EMS, walked into a hospital with on-site PCI, or were transferred from a non-PCI center (Table 1).
Regardless of mode of patient presentation, treatment time goals were not met most of the time, the group reports. Patients who required interhospital transfer experienced the longest system delays; only 17% were treated within 120 minutes.
Among patients who received primary PCI, 20% had a registry-defined hospital-specified reason for delay, including cardiac arrest and/or need for intubation in 6.8%, “difficulty crossing the culprit lesion” in 3.8%, and “other reasons” in 5.8%, the group reports.
“In 2020, a new reason for delay was added to the registry, ‘need for additional personal protective equipment for suspected/confirmed infectious disease.’ This reason was most commonly used in the second quarter of 2020 (6%) and then declined over time to 1% in the final 2 quarters,” they write.
“Thus, active SARS-CoV-2 infection appeared to have a smaller direct role in longer treatment times or worse outcomes.” Rather, they continue, “the pandemic potentially had a significant indirect role as hospitals were overwhelmed with patients, EMS and hospitals were challenged in maintaining paramedic and nurse staffing and intensive care bed availability, and patients experienced delayed care due to barriers to access or perceived fear of becoming entangled in an overwhelmed medical system.”
Still an important quality metric
STEMI treatment times remain an important quality metric to which hospitals should continue to pay attention because shorter times improve patient care, Deepak Bhatt, MD, MPH, told this news organization.
“Having said that, as with all metrics, one needs to be thoughtful and realize that a difference of a couple of minutes is probably not a crucial thing,” said Dr. Bhatt, Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved with the current study.
Interhospital transfers indeed involve longer delays, he observed, suggesting that regional integrated health systems should develop methods for optimizing STEMI care – even, for example, if they involve bypassing non-PCI centers or stopping patients briefly for stabilization followed by rapid transport to a PCI-capable facility.
“That, of course, requires cooperation among hospitals. Sometimes that requires hospitals putting aside economic considerations and just focusing on doing the right thing for that individual patient,” Dr. Bhatt said.
Transfer delays are common for patients presenting with STEMI at hospitals without PCI capability, he noted. “Having clear protocols in place that expedite that type of transfer, I think, could go a long way in reducing the time to treatment in patients that are presenting to the hospital without cath labs. That’s an important message that these data provide.”
The onset of COVID-19 led to widespread delays in STEMI time to treatment early in the pandemic. There were concerns about exposing cath lab personnel to SARS-CoV-2 and potential adverse consequences of sick personnel being unable to provide patient care in the subsequent weeks and months, Dr. Bhatt observed.
However, “All of that seems to have quieted down, and I don’t think COVID is impacting time to treatment right now.”
‘Suboptimal compliance’ with standards
The current findings of “suboptimal compliance with national targets underscore why reassessing quality metrics, in light of changing practice patterns and other secular trends, is critical,” write Andrew S. Oseran, MD, MBA, and Robert W. Yeh, MD, both of Harvard Medical School, in an accompanying editorial.
“While the importance of coordinated and expeditious care for this high-risk patient population is undeniable, the specific actions that hospitals can – or should – take to further improve overall STEMI outcomes are less clear,” they say.
“As physicians contemplate the optimal path forward in managing the care of STEMI patients, they must recognize the clinical and operational nuance that exists in caring for this diverse population and acknowledge the trade-offs associated with uniform quality metrics,” write the editorialists.
“Global reductions in time to treatment for STEMI patients has been one of health care’s great success stories. As we move forward, it may be time to consider whether efforts to achieve additional improvement in target treatment times will result in substantive benefits, or whether we have reached the point of diminishing returns.”
A version of this article first appeared on Medscape.com.
Therapy initiated within national treatment-time goals set a decade ago for patients with ST-segment elevation myocardial infarction (STEMI) remains associated with improved survival in recent years. But for many such patients, time from first symptoms to initiation of reperfusion therapy still fails to meet those goals, suggests a cross-sectional registry analysis.
For example, patients initially transported to centers with percutaneous coronary intervention (PCI) capability had a median treatment time of 148 minutes, in the analysis spanning the second quarter (Q2) of 2018 to the third quarter (Q3) of 2021. But the goal for centers called for treatment initiation within 90 minutes for at least 75% of such STEMI patients.
Moreover, overall STEMI treatment times and in-hospital mortality rose in tandem significantly from Q2 2018 through the first quarter (Q1) of 2021, which included the first year of the COVID-19 pandemic. Median time to treatment went from 86 minutes to 91 minutes during that period. Meanwhile, in-hospital mortality went from 5.6% to 8.7%, report the study authors led by James G. Jollis, MD, Duke University, Durham, N.C.
Their report, based on 114,871 STEMI patients at 601 US hospitals contributing to the Get With The Guidelines – Coronary Artery Disease registry, was published online in JAMA.
Of those patients, 25,085 had been transferred from non-PCI hospitals, 32,483 were walk-ins, and 57,303 arrived via emergency medical services (EMS). Their median times from symptom onset to PCI were 240, 195, and 148 minutes, respectively.
In-hospital mortality was significantly reduced in an adjusted analysis for patients treated within target times, compared with those whose treatment missed the time goals, regardless of whether they were transported by EMS, walked into a hospital with on-site PCI, or were transferred from a non-PCI center (Table 1).
Regardless of mode of patient presentation, treatment time goals were not met most of the time, the group reports. Patients who required interhospital transfer experienced the longest system delays; only 17% were treated within 120 minutes.
Among patients who received primary PCI, 20% had a registry-defined hospital-specified reason for delay, including cardiac arrest and/or need for intubation in 6.8%, “difficulty crossing the culprit lesion” in 3.8%, and “other reasons” in 5.8%, the group reports.
“In 2020, a new reason for delay was added to the registry, ‘need for additional personal protective equipment for suspected/confirmed infectious disease.’ This reason was most commonly used in the second quarter of 2020 (6%) and then declined over time to 1% in the final 2 quarters,” they write.
“Thus, active SARS-CoV-2 infection appeared to have a smaller direct role in longer treatment times or worse outcomes.” Rather, they continue, “the pandemic potentially had a significant indirect role as hospitals were overwhelmed with patients, EMS and hospitals were challenged in maintaining paramedic and nurse staffing and intensive care bed availability, and patients experienced delayed care due to barriers to access or perceived fear of becoming entangled in an overwhelmed medical system.”
Still an important quality metric
STEMI treatment times remain an important quality metric to which hospitals should continue to pay attention because shorter times improve patient care, Deepak Bhatt, MD, MPH, told this news organization.
“Having said that, as with all metrics, one needs to be thoughtful and realize that a difference of a couple of minutes is probably not a crucial thing,” said Dr. Bhatt, Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved with the current study.
Interhospital transfers indeed involve longer delays, he observed, suggesting that regional integrated health systems should develop methods for optimizing STEMI care – even, for example, if they involve bypassing non-PCI centers or stopping patients briefly for stabilization followed by rapid transport to a PCI-capable facility.
“That, of course, requires cooperation among hospitals. Sometimes that requires hospitals putting aside economic considerations and just focusing on doing the right thing for that individual patient,” Dr. Bhatt said.
Transfer delays are common for patients presenting with STEMI at hospitals without PCI capability, he noted. “Having clear protocols in place that expedite that type of transfer, I think, could go a long way in reducing the time to treatment in patients that are presenting to the hospital without cath labs. That’s an important message that these data provide.”
The onset of COVID-19 led to widespread delays in STEMI time to treatment early in the pandemic. There were concerns about exposing cath lab personnel to SARS-CoV-2 and potential adverse consequences of sick personnel being unable to provide patient care in the subsequent weeks and months, Dr. Bhatt observed.
However, “All of that seems to have quieted down, and I don’t think COVID is impacting time to treatment right now.”
‘Suboptimal compliance’ with standards
The current findings of “suboptimal compliance with national targets underscore why reassessing quality metrics, in light of changing practice patterns and other secular trends, is critical,” write Andrew S. Oseran, MD, MBA, and Robert W. Yeh, MD, both of Harvard Medical School, in an accompanying editorial.
“While the importance of coordinated and expeditious care for this high-risk patient population is undeniable, the specific actions that hospitals can – or should – take to further improve overall STEMI outcomes are less clear,” they say.
“As physicians contemplate the optimal path forward in managing the care of STEMI patients, they must recognize the clinical and operational nuance that exists in caring for this diverse population and acknowledge the trade-offs associated with uniform quality metrics,” write the editorialists.
“Global reductions in time to treatment for STEMI patients has been one of health care’s great success stories. As we move forward, it may be time to consider whether efforts to achieve additional improvement in target treatment times will result in substantive benefits, or whether we have reached the point of diminishing returns.”
A version of this article first appeared on Medscape.com.
FROM JAMA