Cardiology

Study Overview

Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.

Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.

Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).

Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.

Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).

Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.

Commentary

Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.¹ Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.² This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes³; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.

A particular challenge in determining when to initiate palliative care lies in predicting outcomes,⁴ particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.⁵ These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.

Applications for Clinical Practice

Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.

Study Overview

Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.

Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.

Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).

Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.

Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).

Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.

Commentary

Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.¹ Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.² This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes³; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.

A particular challenge in determining when to initiate palliative care lies in predicting outcomes,⁴ particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.⁵ These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.

Applications for Clinical Practice

Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.

Study Overview

Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.

Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.

Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).

Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.

Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).

Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.

Commentary

Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.¹ Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.² This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes³; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.

A particular challenge in determining when to initiate palliative care lies in predicting outcomes,⁴ particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.⁵ These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.

Applications for Clinical Practice

Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

mzoler@mdedge.com

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

mzoler@mdedge.com

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

mzoler@mdedge.com

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Some nonsleepy patients with coronary artery disease and obstructive sleep apnea (OSA) may receive cardiovascular benefit from continuous positive airway pressure (CPAP) therapy, according to a post hoc analysis of the RICCADSA clinical trial. That study found no benefit among patients overall, but the new analysis found that patients whose heart rate increases (delta heart rate, or dHR) more than average during apnea or hypopnea experienced fewer cardiovascular or cerebrovascular events during apnea or hypopnea when treated with CPAP.

Although RICCADSA showed no benefit, an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS) cohorts found that elevated pulse rate response to respiratory events was associated with greater risk of cardiovascular disease (CVD) morbidity and mortality. But the effect was seen only in nonsleepy patients. “We hypothesized that pulse rate response to apneas would predict which patients with OSA may most benefit from CPAP treatment. Now, our study suggests that there is, in fact, a subgroup of nonsleepy patients with OSA for whom CPAP could provide a reduction in risk, specifically those with a higher pulse rate response to their respiratory events,” Ali Azarbarzin, PhD, said in an interview.

Dr. Azarbarzin presented the study at the American Thoracic Society’s virtual international conference (Abstract A1103). He is in the division of sleep and circadian disorders at Brigham and Women’s Hospital, and is assistant professor of medicine at Harvard Medical School, both in Boston.

The study is in line with recent efforts to subgroup OSA patients to determine which are at higher risk of cardiovascular events and other complications, and which are most likely to respond to treatment, according to Esra Tasali, MD, of the University of Chicago, who moderated the session where the study was presented. “The field is really urgently in need of coming up with new methods, and I think this study is getting a handle on that,” said Dr. Tasali in an interview.

“I think that this is really pointing toward a new area that the whole (sleep field) is moving toward, which is better phenotyping of sleep apnea so that we can come up with more personalized treatments,” said Dr. Tasali.

The patients who appeared to gain a cardiovascular benefit from CPAP represented about 16% of trial participants. Dr. Azarbarzin refrained from making clinical recommendations, citing the need for more data. The team next plans to reproduce the findings in additional, larger trials such as the SAVE and ISAACC trials. “Ultimately, our goal is to confirm our findings in a future randomized controlled trial of CPAP by enrolling participants based on their pulse rate response,” said Dr. Azarbarzin.

The RICCADSA study was a single center randomized, controlled trial with 226 patients with coronary artery disease and OSA who were randomized to CPAP or no CPAP treatment. In the overall population, CPAP treatment was not associated with a statistically significant change in repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality (hazard ratio [HR], 0.79; P = .435). That study assumed that the effect of OSA on CVD is similar across all subgroups of dHR.

The mean increase in heart rate was 7.1 beats per minute (BPM; standard deviation, 3.7). Each standard deviation increase in dHR was linked to greater CVD risk (HR, 1.45; P = .029). For each standard deviation decrease in dHR, treatment with CPAP decreased the CVD risk (HR, 0.54; P = .043).

For patients with a low dHR of 4 BPM, the hazard ratio for CVD was 0.8 with no CPAP treatment and 1.2 for CPAP treatment. For those at the mean value of 7 BPM, the HRs were 1.1 and 0.9 respectively. For those with a high dHR, (10 BPM), the hazard ratio was 1.6 without treatment and 0.7 with CPAP.

“We modeled delta heart rate interaction with CPAP, which was significant. What this means is that for someone with a mean delta heart rate of 7 beats per minute, the risk reduction (with CPAP) is similar to what RICCADSA reported. But if you look at those with high delta heart rate, the risk reduction was significantly larger. It was actually a more than 50% reduction of risk with CPAP treatment,” said Dr. Azarbarzin.

Dr. Azarbarzin has consulted for Somnifix and Apnimed and has received grants from Somnifix. Dr. Tasali has no relevant financial disclosures.

Some nonsleepy patients with coronary artery disease and obstructive sleep apnea (OSA) may receive cardiovascular benefit from continuous positive airway pressure (CPAP) therapy, according to a post hoc analysis of the RICCADSA clinical trial. That study found no benefit among patients overall, but the new analysis found that patients whose heart rate increases (delta heart rate, or dHR) more than average during apnea or hypopnea experienced fewer cardiovascular or cerebrovascular events during apnea or hypopnea when treated with CPAP.

Although RICCADSA showed no benefit, an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS) cohorts found that elevated pulse rate response to respiratory events was associated with greater risk of cardiovascular disease (CVD) morbidity and mortality. But the effect was seen only in nonsleepy patients. “We hypothesized that pulse rate response to apneas would predict which patients with OSA may most benefit from CPAP treatment. Now, our study suggests that there is, in fact, a subgroup of nonsleepy patients with OSA for whom CPAP could provide a reduction in risk, specifically those with a higher pulse rate response to their respiratory events,” Ali Azarbarzin, PhD, said in an interview.

Dr. Azarbarzin presented the study at the American Thoracic Society’s virtual international conference (Abstract A1103). He is in the division of sleep and circadian disorders at Brigham and Women’s Hospital, and is assistant professor of medicine at Harvard Medical School, both in Boston.

The study is in line with recent efforts to subgroup OSA patients to determine which are at higher risk of cardiovascular events and other complications, and which are most likely to respond to treatment, according to Esra Tasali, MD, of the University of Chicago, who moderated the session where the study was presented. “The field is really urgently in need of coming up with new methods, and I think this study is getting a handle on that,” said Dr. Tasali in an interview.

“I think that this is really pointing toward a new area that the whole (sleep field) is moving toward, which is better phenotyping of sleep apnea so that we can come up with more personalized treatments,” said Dr. Tasali.

The patients who appeared to gain a cardiovascular benefit from CPAP represented about 16% of trial participants. Dr. Azarbarzin refrained from making clinical recommendations, citing the need for more data. The team next plans to reproduce the findings in additional, larger trials such as the SAVE and ISAACC trials. “Ultimately, our goal is to confirm our findings in a future randomized controlled trial of CPAP by enrolling participants based on their pulse rate response,” said Dr. Azarbarzin.

The RICCADSA study was a single center randomized, controlled trial with 226 patients with coronary artery disease and OSA who were randomized to CPAP or no CPAP treatment. In the overall population, CPAP treatment was not associated with a statistically significant change in repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality (hazard ratio [HR], 0.79; P = .435). That study assumed that the effect of OSA on CVD is similar across all subgroups of dHR.

The mean increase in heart rate was 7.1 beats per minute (BPM; standard deviation, 3.7). Each standard deviation increase in dHR was linked to greater CVD risk (HR, 1.45; P = .029). For each standard deviation decrease in dHR, treatment with CPAP decreased the CVD risk (HR, 0.54; P = .043).

For patients with a low dHR of 4 BPM, the hazard ratio for CVD was 0.8 with no CPAP treatment and 1.2 for CPAP treatment. For those at the mean value of 7 BPM, the HRs were 1.1 and 0.9 respectively. For those with a high dHR, (10 BPM), the hazard ratio was 1.6 without treatment and 0.7 with CPAP.

“We modeled delta heart rate interaction with CPAP, which was significant. What this means is that for someone with a mean delta heart rate of 7 beats per minute, the risk reduction (with CPAP) is similar to what RICCADSA reported. But if you look at those with high delta heart rate, the risk reduction was significantly larger. It was actually a more than 50% reduction of risk with CPAP treatment,” said Dr. Azarbarzin.

Dr. Azarbarzin has consulted for Somnifix and Apnimed and has received grants from Somnifix. Dr. Tasali has no relevant financial disclosures.

Some nonsleepy patients with coronary artery disease and obstructive sleep apnea (OSA) may receive cardiovascular benefit from continuous positive airway pressure (CPAP) therapy, according to a post hoc analysis of the RICCADSA clinical trial. That study found no benefit among patients overall, but the new analysis found that patients whose heart rate increases (delta heart rate, or dHR) more than average during apnea or hypopnea experienced fewer cardiovascular or cerebrovascular events during apnea or hypopnea when treated with CPAP.

Although RICCADSA showed no benefit, an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS) cohorts found that elevated pulse rate response to respiratory events was associated with greater risk of cardiovascular disease (CVD) morbidity and mortality. But the effect was seen only in nonsleepy patients. “We hypothesized that pulse rate response to apneas would predict which patients with OSA may most benefit from CPAP treatment. Now, our study suggests that there is, in fact, a subgroup of nonsleepy patients with OSA for whom CPAP could provide a reduction in risk, specifically those with a higher pulse rate response to their respiratory events,” Ali Azarbarzin, PhD, said in an interview.

Dr. Azarbarzin presented the study at the American Thoracic Society’s virtual international conference (Abstract A1103). He is in the division of sleep and circadian disorders at Brigham and Women’s Hospital, and is assistant professor of medicine at Harvard Medical School, both in Boston.

The study is in line with recent efforts to subgroup OSA patients to determine which are at higher risk of cardiovascular events and other complications, and which are most likely to respond to treatment, according to Esra Tasali, MD, of the University of Chicago, who moderated the session where the study was presented. “The field is really urgently in need of coming up with new methods, and I think this study is getting a handle on that,” said Dr. Tasali in an interview.

“I think that this is really pointing toward a new area that the whole (sleep field) is moving toward, which is better phenotyping of sleep apnea so that we can come up with more personalized treatments,” said Dr. Tasali.

The patients who appeared to gain a cardiovascular benefit from CPAP represented about 16% of trial participants. Dr. Azarbarzin refrained from making clinical recommendations, citing the need for more data. The team next plans to reproduce the findings in additional, larger trials such as the SAVE and ISAACC trials. “Ultimately, our goal is to confirm our findings in a future randomized controlled trial of CPAP by enrolling participants based on their pulse rate response,” said Dr. Azarbarzin.

The RICCADSA study was a single center randomized, controlled trial with 226 patients with coronary artery disease and OSA who were randomized to CPAP or no CPAP treatment. In the overall population, CPAP treatment was not associated with a statistically significant change in repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality (hazard ratio [HR], 0.79; P = .435). That study assumed that the effect of OSA on CVD is similar across all subgroups of dHR.

The mean increase in heart rate was 7.1 beats per minute (BPM; standard deviation, 3.7). Each standard deviation increase in dHR was linked to greater CVD risk (HR, 1.45; P = .029). For each standard deviation decrease in dHR, treatment with CPAP decreased the CVD risk (HR, 0.54; P = .043).

For patients with a low dHR of 4 BPM, the hazard ratio for CVD was 0.8 with no CPAP treatment and 1.2 for CPAP treatment. For those at the mean value of 7 BPM, the HRs were 1.1 and 0.9 respectively. For those with a high dHR, (10 BPM), the hazard ratio was 1.6 without treatment and 0.7 with CPAP.

“We modeled delta heart rate interaction with CPAP, which was significant. What this means is that for someone with a mean delta heart rate of 7 beats per minute, the risk reduction (with CPAP) is similar to what RICCADSA reported. But if you look at those with high delta heart rate, the risk reduction was significantly larger. It was actually a more than 50% reduction of risk with CPAP treatment,” said Dr. Azarbarzin.

Dr. Azarbarzin has consulted for Somnifix and Apnimed and has received grants from Somnifix. Dr. Tasali has no relevant financial disclosures.

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

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

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

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

Extremely low birth weight associated with faster aging in men

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In his editorial, Dr. Notterman emphasized this point.

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

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

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

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

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

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

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

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

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

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

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

Extremely low birth weight associated with faster aging in men

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In his editorial, Dr. Notterman emphasized this point.

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

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

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

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

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

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

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

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

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

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

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

Extremely low birth weight associated with faster aging in men

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In his editorial, Dr. Notterman emphasized this point.

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

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

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

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

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

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

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

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

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

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

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

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

31° C and 34° C are equivalent

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

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

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

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

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

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

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

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

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

More trials like CAPITAL-CHILL needed

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

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

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

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

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

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

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

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

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

31° C and 34° C are equivalent

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

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

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

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

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

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

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

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

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

More trials like CAPITAL-CHILL needed

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

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

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

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

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

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

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

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

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

31° C and 34° C are equivalent

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

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

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

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

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

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

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

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

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

More trials like CAPITAL-CHILL needed

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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