Cardiology

A new scientific statement from the American Heart Association recommends that genetic testing for inherited cardiovascular disease should be reserved for four specific types of heart diseases – cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmias, and familial hypercholesterolemia – and should enlist skilled geneticists and genetic counselors in the care team.

The guidance comes in a scientific statement published online in the journal Circulation: Genomic and Precision Medicine.

Kiran Musunuru, MD, PhD, MPH, ML, chair of the writing group for the scientific statement, described in an interview the rationale for publishing the statement at this time. “There was no prior single statement that summarized best practices for the whole gamut of inherited cardiovascular diseases in adults, only statements for individual diseases,” he said in an interview. “With genetic testing seeing explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, we felt that cardiovascular practitioners would benefit from having a single document to serve as a general resource on genetic testing.”

The statement describes two types of patients who would be suitable for genetic testing for cardiovascular disease (CVD), Dr. Musunuru noted: “Patients who have been diagnosed with or are strongly suspected to have a cardiovascular disease that is often inherited and family members of patients who have been diagnosed with an inherited cardiovascular disease and found by genetic testing to have a mutation that is felt to be the cause of the disease.”

The statement also spells out two crucial elements for genetic testing: thorough disease-specific phenotyping – that is, using genetic information to identify the individual’s disease characteristics and a comprehensive family history that spans at least three generations. Testing should only proceed after patients has had genetic counseling and made a shared decision with their doctors.

“Genetic counseling is absolutely essential both before genetic testing to educate patients on what genetic testing entails and what potential results to expect, as well as the risks of testing; and after genetic testing, to review the results of the genetic testing and explain the potential consequences for the patient’s health and the health of family members, including children,” Dr. Musunuru said.

The process should involve board-certified geneticists or at least cardiovascular specialists well-versed in genetics and genetic counselors, the statement noted. The latter are “critical” in the care team, Dr. Musunuru said.

After the decision is made to do genetic testing, the next step is to decide the scope of the testing. That can range from targeted sequencing of a single gene or a few genes linked to the disease to large gene panels; the latter “may not increase the likelihood of clinically actionable results in adult patients,” Dr. Musunuru and colleagues wrote.

But genetic testing is no guarantee to identify a cause or confirm a diagnosis of CVD, the statement noted. “The yield for any genetic testing for any inherited cardiovascular disease remains <100%, usually much less than 100%,” the writing committee stated.

Dr. Musunuru explained that the results can sometimes be inconclusive. “In many cases, genetic testing reveals a mutation that is uninterpretable, what we call a variant of uncertain significance,” he said. “It is not clear whether the mutation increases the risk of disease or is entirely benign, which makes it very challenging to counsel patients as to whether anything should be done about the mutation.”

Even in a diagnosed patient the test results can be uncertain. “This makes it challenging to explain why the patient has the disease and whether any of the family members are at risk,” Dr. Musunuru said.

According to the statement, providers should encourage patients with a confirmed or likely pathogenic variant for CVD to share that information with “all of their at-risk relative,” the statement noted, suggesting “family letters” given to patients are a way to navigate HIPAA’s privacy limits.

The statement was written on behalf of the American Heart Association’s Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology.

Dr. Musunuru and writing group members have no relevant financial relationships to disclose.

SOURCE: Musunuru K et al. Circ Genom Precis Med. 2020 Jul 23. doi: 10.1161/HCG.0000000000000067.

A new scientific statement from the American Heart Association recommends that genetic testing for inherited cardiovascular disease should be reserved for four specific types of heart diseases – cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmias, and familial hypercholesterolemia – and should enlist skilled geneticists and genetic counselors in the care team.

The guidance comes in a scientific statement published online in the journal Circulation: Genomic and Precision Medicine.

Kiran Musunuru, MD, PhD, MPH, ML, chair of the writing group for the scientific statement, described in an interview the rationale for publishing the statement at this time. “There was no prior single statement that summarized best practices for the whole gamut of inherited cardiovascular diseases in adults, only statements for individual diseases,” he said in an interview. “With genetic testing seeing explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, we felt that cardiovascular practitioners would benefit from having a single document to serve as a general resource on genetic testing.”

The statement describes two types of patients who would be suitable for genetic testing for cardiovascular disease (CVD), Dr. Musunuru noted: “Patients who have been diagnosed with or are strongly suspected to have a cardiovascular disease that is often inherited and family members of patients who have been diagnosed with an inherited cardiovascular disease and found by genetic testing to have a mutation that is felt to be the cause of the disease.”

The statement also spells out two crucial elements for genetic testing: thorough disease-specific phenotyping – that is, using genetic information to identify the individual’s disease characteristics and a comprehensive family history that spans at least three generations. Testing should only proceed after patients has had genetic counseling and made a shared decision with their doctors.

“Genetic counseling is absolutely essential both before genetic testing to educate patients on what genetic testing entails and what potential results to expect, as well as the risks of testing; and after genetic testing, to review the results of the genetic testing and explain the potential consequences for the patient’s health and the health of family members, including children,” Dr. Musunuru said.

The process should involve board-certified geneticists or at least cardiovascular specialists well-versed in genetics and genetic counselors, the statement noted. The latter are “critical” in the care team, Dr. Musunuru said.

After the decision is made to do genetic testing, the next step is to decide the scope of the testing. That can range from targeted sequencing of a single gene or a few genes linked to the disease to large gene panels; the latter “may not increase the likelihood of clinically actionable results in adult patients,” Dr. Musunuru and colleagues wrote.

But genetic testing is no guarantee to identify a cause or confirm a diagnosis of CVD, the statement noted. “The yield for any genetic testing for any inherited cardiovascular disease remains <100%, usually much less than 100%,” the writing committee stated.

Dr. Musunuru explained that the results can sometimes be inconclusive. “In many cases, genetic testing reveals a mutation that is uninterpretable, what we call a variant of uncertain significance,” he said. “It is not clear whether the mutation increases the risk of disease or is entirely benign, which makes it very challenging to counsel patients as to whether anything should be done about the mutation.”

Even in a diagnosed patient the test results can be uncertain. “This makes it challenging to explain why the patient has the disease and whether any of the family members are at risk,” Dr. Musunuru said.

According to the statement, providers should encourage patients with a confirmed or likely pathogenic variant for CVD to share that information with “all of their at-risk relative,” the statement noted, suggesting “family letters” given to patients are a way to navigate HIPAA’s privacy limits.

The statement was written on behalf of the American Heart Association’s Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology.

Dr. Musunuru and writing group members have no relevant financial relationships to disclose.

SOURCE: Musunuru K et al. Circ Genom Precis Med. 2020 Jul 23. doi: 10.1161/HCG.0000000000000067.

A new scientific statement from the American Heart Association recommends that genetic testing for inherited cardiovascular disease should be reserved for four specific types of heart diseases – cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmias, and familial hypercholesterolemia – and should enlist skilled geneticists and genetic counselors in the care team.

The guidance comes in a scientific statement published online in the journal Circulation: Genomic and Precision Medicine.

Kiran Musunuru, MD, PhD, MPH, ML, chair of the writing group for the scientific statement, described in an interview the rationale for publishing the statement at this time. “There was no prior single statement that summarized best practices for the whole gamut of inherited cardiovascular diseases in adults, only statements for individual diseases,” he said in an interview. “With genetic testing seeing explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, we felt that cardiovascular practitioners would benefit from having a single document to serve as a general resource on genetic testing.”

The statement describes two types of patients who would be suitable for genetic testing for cardiovascular disease (CVD), Dr. Musunuru noted: “Patients who have been diagnosed with or are strongly suspected to have a cardiovascular disease that is often inherited and family members of patients who have been diagnosed with an inherited cardiovascular disease and found by genetic testing to have a mutation that is felt to be the cause of the disease.”

The statement also spells out two crucial elements for genetic testing: thorough disease-specific phenotyping – that is, using genetic information to identify the individual’s disease characteristics and a comprehensive family history that spans at least three generations. Testing should only proceed after patients has had genetic counseling and made a shared decision with their doctors.

“Genetic counseling is absolutely essential both before genetic testing to educate patients on what genetic testing entails and what potential results to expect, as well as the risks of testing; and after genetic testing, to review the results of the genetic testing and explain the potential consequences for the patient’s health and the health of family members, including children,” Dr. Musunuru said.

The process should involve board-certified geneticists or at least cardiovascular specialists well-versed in genetics and genetic counselors, the statement noted. The latter are “critical” in the care team, Dr. Musunuru said.

After the decision is made to do genetic testing, the next step is to decide the scope of the testing. That can range from targeted sequencing of a single gene or a few genes linked to the disease to large gene panels; the latter “may not increase the likelihood of clinically actionable results in adult patients,” Dr. Musunuru and colleagues wrote.

But genetic testing is no guarantee to identify a cause or confirm a diagnosis of CVD, the statement noted. “The yield for any genetic testing for any inherited cardiovascular disease remains <100%, usually much less than 100%,” the writing committee stated.

Dr. Musunuru explained that the results can sometimes be inconclusive. “In many cases, genetic testing reveals a mutation that is uninterpretable, what we call a variant of uncertain significance,” he said. “It is not clear whether the mutation increases the risk of disease or is entirely benign, which makes it very challenging to counsel patients as to whether anything should be done about the mutation.”

Even in a diagnosed patient the test results can be uncertain. “This makes it challenging to explain why the patient has the disease and whether any of the family members are at risk,” Dr. Musunuru said.

According to the statement, providers should encourage patients with a confirmed or likely pathogenic variant for CVD to share that information with “all of their at-risk relative,” the statement noted, suggesting “family letters” given to patients are a way to navigate HIPAA’s privacy limits.

The statement was written on behalf of the American Heart Association’s Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology.

Dr. Musunuru and writing group members have no relevant financial relationships to disclose.

SOURCE: Musunuru K et al. Circ Genom Precis Med. 2020 Jul 23. doi: 10.1161/HCG.0000000000000067.

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

 

 

Commentary

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

 

 

Commentary

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.

Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.

Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.

Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.

Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.

Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.

Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

 

 

Commentary

Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.¹ This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.^2,3

While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.

DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.

There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.

Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.

Applications for Clinical Practice

SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.

—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO

Study Overview

Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.

Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.

Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.

Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.

Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).

The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.

Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.

Commentary

Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.¹ Injection-site reactions remain an issue with this formulation.

Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.² While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.³ Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.⁴ The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.

Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.⁵ Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.³ These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.^6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.

In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.

Clinical Implications

The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.

–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS

Study Overview

Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.

Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.

Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.

Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.

Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).

The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.

Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.

Commentary

Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.¹ Injection-site reactions remain an issue with this formulation.

Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.² While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.³ Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.⁴ The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.

Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.⁵ Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.³ These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.^6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.

In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.

Clinical Implications

The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.

–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS

Study Overview

Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.

Design. Global, multicenter, randomized, open-label, phase 3 trial.

Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.

Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.

Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.

Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.

Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).

The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.

Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.

Commentary

Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.¹ Injection-site reactions remain an issue with this formulation.

Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.² While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.³ Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.⁴ The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.

Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.⁵ Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.³ These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.^6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.

In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.

Clinical Implications

The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.

–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS

One of the take-away messages from a review of multisystem inflammatory syndrome in children (MIS-C) is that clinicians treating this condition “need to be comfortable with uncertainty,” Melissa Hazen, MD, said at a synthesis of multiple published case series and personal experience summarized at the virtual Pediatric Hospital Medicine meeting.

She emphasized MIS-C patient care “requires flexibility,” and she advised clinicians managing these patients to open the lines of communication with the many specialists who often are required to deal with complications affecting an array of organ systems.

MIS-C might best be understood as the most serious manifestation of an immune-mediated response to COVID-19 infection that ranges from transient mild symptoms to the life-threatening multiple organ involvement that characterizes this newly recognized threat. Although “most children who encounter this pathogen only develop mild disease,” the spectrum of the disease can move in a subset of patients to a “Kawasaki-like illness” without hemodynamic instability and then to MIS-C “with highly elevated systemic inflammatory markers and multiple organ involvement,” explained Dr. Hazen, an attending physician in the rheumatology program at Boston Children’s Hospital.

A reliable profile of MIS-C is only beginning to emerge from the series of published case series, most of which have only recently reached publication, according to Dr. Hazen. In general, the description of the most common symptoms and their course has been relatively consistent.

In 186 cases of MIS-C collected in a study funded by the Centers for Disease Control and Prevention, 148 (80%) were admitted to intensive care, 90 patients (48%) received vasoactive support, 37 (20%) received mechanical ventilation, and 4 (2%) died.¹ The median age was 8 years (range, 3-13 years) in this study. The case definition was fever for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of COVID-19 infection. In this cohort of 186 children, 92% had gastrointestinal, 80% had cardiovascular, 76% had hematologic, and 70% had respiratory system involvement.

In a different series of 95 cases collected in New York State, 79 (80%) were admitted to intensive care, 61 (62%) received vasoactive support, 10 (10%) received mechanical ventilation, 4 (4%) received extracorporeal membrane oxygenation (ECMO), and 2 (2%) died. ² Thirty-one percent patients were aged 0-5 years, 42% were 6-12 years, and 26% were 13-20 years of age. In that series, for which the case definition was elevation of two or more inflammatory markers, virologic evidence of COVID-19 infection, 80% had gastrointestinal system involvement, and 53% had evidence of myocarditis.

In both of these series, as well as others published and unpublished, the peak in MIS-C cases has occurred about 3 to 4 weeks after peak COVID-19 activity, according to Diana Lee, MD, a pediatrician at Icahn School of Medicine at Mount Sinai, New York. This pattern, reported by others, was observed in New York State, where 230 cases of MIS-C were collected from the beginning of May until the end of June, which reflected this 3- to 4-week delay in peak incidence.

“This does seem to be a rare syndrome since this [group of] 230 cases is amongst the entire population of children in New York State. So, yes, we should be keeping this in mind in our differential, but we should not forget all the other reasons that children can have a fever,” she said.

Both Dr. Hazen and Dr. Lee cautioned that MIS-C, despite a general consistency among published studies, remains a moving target in regard to how it is being characterized. In a 2-day period in May, the CDC, the World Health Organization, and New York State all issued descriptions of MIS-C, employing compatible but slightly different terminology and diagnostic criteria. Many questions regarding optimal methods of diagnosis, treatment, and follow-up remain unanswered.

Questions regarding the risk to the cardiovascular system, one of the organs most commonly affected in MIS-C, are among the most urgent. It is not now clear how best to monitor cardiovascular involvement, how to intervene, and how to follow patients in the postinfection period, according to Kevin G. Friedman, MD, a pediatrician at Harvard Medical School, Boston, and an attending physician in the department of cardiology at Boston Children’s Hospital.

“The most frequent complication we have seen is ventricular dysfunction, which occurs in about half of these patients,” he reported. “Usually it is in the mild to moderate range, but occasionally patients have an ejection fraction of less than 40%.”

Coronary abnormalities, typically in the form of dilations or small aneurysms, occur in 10%-20% of children with MIS-C, according to Dr. Friedman. Giant aneurysms have been reported.

“Some of these findings can progress including in both the acute phase and, particularly for the coronary aneurysms, in the subacute phase. We recommend echocardiograms and EKGs at diagnosis and at 1-2 weeks to recheck coronary size or sooner if there are clinical indications,” Dr. Friedman advised.

Protocols like these are constantly under review as more information becomes available. There are as yet no guidelines, and practice differs across institutions, according to the investigators summarizing this information.

None of the speakers had any relevant financial disclosures.

References

1. Feldstein LR et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334-46.

2. Dufort EM et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med 2020;383:347-58.

One of the take-away messages from a review of multisystem inflammatory syndrome in children (MIS-C) is that clinicians treating this condition “need to be comfortable with uncertainty,” Melissa Hazen, MD, said at a synthesis of multiple published case series and personal experience summarized at the virtual Pediatric Hospital Medicine meeting.

She emphasized MIS-C patient care “requires flexibility,” and she advised clinicians managing these patients to open the lines of communication with the many specialists who often are required to deal with complications affecting an array of organ systems.

MIS-C might best be understood as the most serious manifestation of an immune-mediated response to COVID-19 infection that ranges from transient mild symptoms to the life-threatening multiple organ involvement that characterizes this newly recognized threat. Although “most children who encounter this pathogen only develop mild disease,” the spectrum of the disease can move in a subset of patients to a “Kawasaki-like illness” without hemodynamic instability and then to MIS-C “with highly elevated systemic inflammatory markers and multiple organ involvement,” explained Dr. Hazen, an attending physician in the rheumatology program at Boston Children’s Hospital.

A reliable profile of MIS-C is only beginning to emerge from the series of published case series, most of which have only recently reached publication, according to Dr. Hazen. In general, the description of the most common symptoms and their course has been relatively consistent.

In 186 cases of MIS-C collected in a study funded by the Centers for Disease Control and Prevention, 148 (80%) were admitted to intensive care, 90 patients (48%) received vasoactive support, 37 (20%) received mechanical ventilation, and 4 (2%) died.¹ The median age was 8 years (range, 3-13 years) in this study. The case definition was fever for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of COVID-19 infection. In this cohort of 186 children, 92% had gastrointestinal, 80% had cardiovascular, 76% had hematologic, and 70% had respiratory system involvement.

In a different series of 95 cases collected in New York State, 79 (80%) were admitted to intensive care, 61 (62%) received vasoactive support, 10 (10%) received mechanical ventilation, 4 (4%) received extracorporeal membrane oxygenation (ECMO), and 2 (2%) died. ² Thirty-one percent patients were aged 0-5 years, 42% were 6-12 years, and 26% were 13-20 years of age. In that series, for which the case definition was elevation of two or more inflammatory markers, virologic evidence of COVID-19 infection, 80% had gastrointestinal system involvement, and 53% had evidence of myocarditis.

In both of these series, as well as others published and unpublished, the peak in MIS-C cases has occurred about 3 to 4 weeks after peak COVID-19 activity, according to Diana Lee, MD, a pediatrician at Icahn School of Medicine at Mount Sinai, New York. This pattern, reported by others, was observed in New York State, where 230 cases of MIS-C were collected from the beginning of May until the end of June, which reflected this 3- to 4-week delay in peak incidence.

“This does seem to be a rare syndrome since this [group of] 230 cases is amongst the entire population of children in New York State. So, yes, we should be keeping this in mind in our differential, but we should not forget all the other reasons that children can have a fever,” she said.

Both Dr. Hazen and Dr. Lee cautioned that MIS-C, despite a general consistency among published studies, remains a moving target in regard to how it is being characterized. In a 2-day period in May, the CDC, the World Health Organization, and New York State all issued descriptions of MIS-C, employing compatible but slightly different terminology and diagnostic criteria. Many questions regarding optimal methods of diagnosis, treatment, and follow-up remain unanswered.

Questions regarding the risk to the cardiovascular system, one of the organs most commonly affected in MIS-C, are among the most urgent. It is not now clear how best to monitor cardiovascular involvement, how to intervene, and how to follow patients in the postinfection period, according to Kevin G. Friedman, MD, a pediatrician at Harvard Medical School, Boston, and an attending physician in the department of cardiology at Boston Children’s Hospital.

“The most frequent complication we have seen is ventricular dysfunction, which occurs in about half of these patients,” he reported. “Usually it is in the mild to moderate range, but occasionally patients have an ejection fraction of less than 40%.”

Coronary abnormalities, typically in the form of dilations or small aneurysms, occur in 10%-20% of children with MIS-C, according to Dr. Friedman. Giant aneurysms have been reported.

“Some of these findings can progress including in both the acute phase and, particularly for the coronary aneurysms, in the subacute phase. We recommend echocardiograms and EKGs at diagnosis and at 1-2 weeks to recheck coronary size or sooner if there are clinical indications,” Dr. Friedman advised.

Protocols like these are constantly under review as more information becomes available. There are as yet no guidelines, and practice differs across institutions, according to the investigators summarizing this information.

None of the speakers had any relevant financial disclosures.

References

1. Feldstein LR et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334-46.

2. Dufort EM et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med 2020;383:347-58.

One of the take-away messages from a review of multisystem inflammatory syndrome in children (MIS-C) is that clinicians treating this condition “need to be comfortable with uncertainty,” Melissa Hazen, MD, said at a synthesis of multiple published case series and personal experience summarized at the virtual Pediatric Hospital Medicine meeting.

She emphasized MIS-C patient care “requires flexibility,” and she advised clinicians managing these patients to open the lines of communication with the many specialists who often are required to deal with complications affecting an array of organ systems.

MIS-C might best be understood as the most serious manifestation of an immune-mediated response to COVID-19 infection that ranges from transient mild symptoms to the life-threatening multiple organ involvement that characterizes this newly recognized threat. Although “most children who encounter this pathogen only develop mild disease,” the spectrum of the disease can move in a subset of patients to a “Kawasaki-like illness” without hemodynamic instability and then to MIS-C “with highly elevated systemic inflammatory markers and multiple organ involvement,” explained Dr. Hazen, an attending physician in the rheumatology program at Boston Children’s Hospital.

A reliable profile of MIS-C is only beginning to emerge from the series of published case series, most of which have only recently reached publication, according to Dr. Hazen. In general, the description of the most common symptoms and their course has been relatively consistent.

In 186 cases of MIS-C collected in a study funded by the Centers for Disease Control and Prevention, 148 (80%) were admitted to intensive care, 90 patients (48%) received vasoactive support, 37 (20%) received mechanical ventilation, and 4 (2%) died.¹ The median age was 8 years (range, 3-13 years) in this study. The case definition was fever for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of COVID-19 infection. In this cohort of 186 children, 92% had gastrointestinal, 80% had cardiovascular, 76% had hematologic, and 70% had respiratory system involvement.

In a different series of 95 cases collected in New York State, 79 (80%) were admitted to intensive care, 61 (62%) received vasoactive support, 10 (10%) received mechanical ventilation, 4 (4%) received extracorporeal membrane oxygenation (ECMO), and 2 (2%) died. ² Thirty-one percent patients were aged 0-5 years, 42% were 6-12 years, and 26% were 13-20 years of age. In that series, for which the case definition was elevation of two or more inflammatory markers, virologic evidence of COVID-19 infection, 80% had gastrointestinal system involvement, and 53% had evidence of myocarditis.

In both of these series, as well as others published and unpublished, the peak in MIS-C cases has occurred about 3 to 4 weeks after peak COVID-19 activity, according to Diana Lee, MD, a pediatrician at Icahn School of Medicine at Mount Sinai, New York. This pattern, reported by others, was observed in New York State, where 230 cases of MIS-C were collected from the beginning of May until the end of June, which reflected this 3- to 4-week delay in peak incidence.

“This does seem to be a rare syndrome since this [group of] 230 cases is amongst the entire population of children in New York State. So, yes, we should be keeping this in mind in our differential, but we should not forget all the other reasons that children can have a fever,” she said.

Both Dr. Hazen and Dr. Lee cautioned that MIS-C, despite a general consistency among published studies, remains a moving target in regard to how it is being characterized. In a 2-day period in May, the CDC, the World Health Organization, and New York State all issued descriptions of MIS-C, employing compatible but slightly different terminology and diagnostic criteria. Many questions regarding optimal methods of diagnosis, treatment, and follow-up remain unanswered.

Questions regarding the risk to the cardiovascular system, one of the organs most commonly affected in MIS-C, are among the most urgent. It is not now clear how best to monitor cardiovascular involvement, how to intervene, and how to follow patients in the postinfection period, according to Kevin G. Friedman, MD, a pediatrician at Harvard Medical School, Boston, and an attending physician in the department of cardiology at Boston Children’s Hospital.

“The most frequent complication we have seen is ventricular dysfunction, which occurs in about half of these patients,” he reported. “Usually it is in the mild to moderate range, but occasionally patients have an ejection fraction of less than 40%.”

Coronary abnormalities, typically in the form of dilations or small aneurysms, occur in 10%-20% of children with MIS-C, according to Dr. Friedman. Giant aneurysms have been reported.

“Some of these findings can progress including in both the acute phase and, particularly for the coronary aneurysms, in the subacute phase. We recommend echocardiograms and EKGs at diagnosis and at 1-2 weeks to recheck coronary size or sooner if there are clinical indications,” Dr. Friedman advised.

Protocols like these are constantly under review as more information becomes available. There are as yet no guidelines, and practice differs across institutions, according to the investigators summarizing this information.

None of the speakers had any relevant financial disclosures.

References

1. Feldstein LR et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334-46.

2. Dufort EM et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med 2020;383:347-58.

A secondary analysis of a major study of polypill therapy for hypertension found that patients who don’t reach blood pressure targets are less likely to have their medications adjusted if they’re on fixed-dose combination therapy.

However, hypertension patients on low-dose, triple-pill combination therapy are more likely to achieve blood pressure control than are those on usual care.

The secondary analysis of Triple Pill vs. Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) was published online in JAMA Cardiology (2020 Jul 22. doi: 10.1001/jamacardio.2020.2739). The trial randomized 700 patients with hypertension in Sri Lanka to triple-pill fixed-dose combination (FDC) therapy or usual care during February 2016–May 2017, with follow-up ending in October 2017.

A greater proportion of FDC patients reached target BP by the end of the study compared with usual care, 70% vs. 55%. However, the study found that therapeutic inertia – the failure to intensify therapy in nonresponsive patients – was more common in the FDC group at 6- and 12-week follow-up: 87% vs. 64% and 90% vs. 65%, respectively; both differences were significant different at P < .001).

The once-daily FDC pill contained telmisartan 20 mg, amlodipine 2.5 mg; and chlorthalidone 12.5 mg.

“Using a triple low-dose combination blood-pressure pill reduced the need to uptitrate BP therapy as more patients are at target, but doctors were less likely to uptitrate with triple-pill therapy when it was needed,” lead author Nelson Wang, MD, a research fellow at the George Institute for Global Health in suburban Sydney, said in an interview.

“Overall, there were fewer treatment inertia episodes in the triple-pill group than in the usual care group, but this was driven by the fact that fewer triple-pill patients needed uptitration when coming to their follow-up visits,” Dr. Wang added.

The analysis found that clinicians who prescribed triple-pill FDC used 23 unique drug treatment regimens per 100 treated patients compared with 54 different regiments with usual care (P < .001). “There was a large simplification in care,” Dr. Wang said of the FDC approach.

Dr. Wang and colleagues called for greater efforts to address therapeutic inertia, particularly with FDC therapies, and suggested potential strategies consisting of patient education, incentives for appropriate treatment adjustments, and feedback mechanisms and reminders for physicians.

“There may also be a need for more dosage options with the FDC triple pill to allow physicians to intensify therapy without fear of overtreatment and adverse drug effects,” they wrote.

In an accompanying editorial (JAMA Cardiol. 2020 Jul 22. doi: 10.1001/jamacardio.2020.2693), Ann Marie Navar, MD, PhD, associate professor of cardiology at Duke Clinical Research Institute, Durham, N.C., noted that initiating treatment with FDC therapy doesn’t preclude a more personalized approach for patients who don’t achieve their BP target. “The real choice now is the choice of initial treatment,” she wrote, adding that future treatment guidelines should consider extending an FDC-first approach to patients with less severe levels of hypertension.

“The study showed there’s room for a both a population-based fixed-drug combination approach and a personalized approach to how we think about hypertension management with fixed-dose therapy,” she said in an interview. “It’s not a one-and-done situation.”

Dr. Wang has no financial relationships to disclose. Study coauthors received funding from the Australian National Health and Medical Research Council and the U.K. National Institute for Health Research. Dr. Navar has no relevant financial relationships to report.

SOURCE: Wang N et al. JAMA Cardiol. 2020. doi: 10.1001/jamacardio.2020.2739.

A secondary analysis of a major study of polypill therapy for hypertension found that patients who don’t reach blood pressure targets are less likely to have their medications adjusted if they’re on fixed-dose combination therapy.

However, hypertension patients on low-dose, triple-pill combination therapy are more likely to achieve blood pressure control than are those on usual care.

The secondary analysis of Triple Pill vs. Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) was published online in JAMA Cardiology (2020 Jul 22. doi: 10.1001/jamacardio.2020.2739). The trial randomized 700 patients with hypertension in Sri Lanka to triple-pill fixed-dose combination (FDC) therapy or usual care during February 2016–May 2017, with follow-up ending in October 2017.

A greater proportion of FDC patients reached target BP by the end of the study compared with usual care, 70% vs. 55%. However, the study found that therapeutic inertia – the failure to intensify therapy in nonresponsive patients – was more common in the FDC group at 6- and 12-week follow-up: 87% vs. 64% and 90% vs. 65%, respectively; both differences were significant different at P < .001).

The once-daily FDC pill contained telmisartan 20 mg, amlodipine 2.5 mg; and chlorthalidone 12.5 mg.

“Using a triple low-dose combination blood-pressure pill reduced the need to uptitrate BP therapy as more patients are at target, but doctors were less likely to uptitrate with triple-pill therapy when it was needed,” lead author Nelson Wang, MD, a research fellow at the George Institute for Global Health in suburban Sydney, said in an interview.

“Overall, there were fewer treatment inertia episodes in the triple-pill group than in the usual care group, but this was driven by the fact that fewer triple-pill patients needed uptitration when coming to their follow-up visits,” Dr. Wang added.

The analysis found that clinicians who prescribed triple-pill FDC used 23 unique drug treatment regimens per 100 treated patients compared with 54 different regiments with usual care (P < .001). “There was a large simplification in care,” Dr. Wang said of the FDC approach.

Dr. Wang and colleagues called for greater efforts to address therapeutic inertia, particularly with FDC therapies, and suggested potential strategies consisting of patient education, incentives for appropriate treatment adjustments, and feedback mechanisms and reminders for physicians.

“There may also be a need for more dosage options with the FDC triple pill to allow physicians to intensify therapy without fear of overtreatment and adverse drug effects,” they wrote.

In an accompanying editorial (JAMA Cardiol. 2020 Jul 22. doi: 10.1001/jamacardio.2020.2693), Ann Marie Navar, MD, PhD, associate professor of cardiology at Duke Clinical Research Institute, Durham, N.C., noted that initiating treatment with FDC therapy doesn’t preclude a more personalized approach for patients who don’t achieve their BP target. “The real choice now is the choice of initial treatment,” she wrote, adding that future treatment guidelines should consider extending an FDC-first approach to patients with less severe levels of hypertension.

“The study showed there’s room for a both a population-based fixed-drug combination approach and a personalized approach to how we think about hypertension management with fixed-dose therapy,” she said in an interview. “It’s not a one-and-done situation.”

Dr. Wang has no financial relationships to disclose. Study coauthors received funding from the Australian National Health and Medical Research Council and the U.K. National Institute for Health Research. Dr. Navar has no relevant financial relationships to report.

SOURCE: Wang N et al. JAMA Cardiol. 2020. doi: 10.1001/jamacardio.2020.2739.

A secondary analysis of a major study of polypill therapy for hypertension found that patients who don’t reach blood pressure targets are less likely to have their medications adjusted if they’re on fixed-dose combination therapy.

However, hypertension patients on low-dose, triple-pill combination therapy are more likely to achieve blood pressure control than are those on usual care.

The secondary analysis of Triple Pill vs. Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) was published online in JAMA Cardiology (2020 Jul 22. doi: 10.1001/jamacardio.2020.2739). The trial randomized 700 patients with hypertension in Sri Lanka to triple-pill fixed-dose combination (FDC) therapy or usual care during February 2016–May 2017, with follow-up ending in October 2017.

A greater proportion of FDC patients reached target BP by the end of the study compared with usual care, 70% vs. 55%. However, the study found that therapeutic inertia – the failure to intensify therapy in nonresponsive patients – was more common in the FDC group at 6- and 12-week follow-up: 87% vs. 64% and 90% vs. 65%, respectively; both differences were significant different at P < .001).

The once-daily FDC pill contained telmisartan 20 mg, amlodipine 2.5 mg; and chlorthalidone 12.5 mg.

“Using a triple low-dose combination blood-pressure pill reduced the need to uptitrate BP therapy as more patients are at target, but doctors were less likely to uptitrate with triple-pill therapy when it was needed,” lead author Nelson Wang, MD, a research fellow at the George Institute for Global Health in suburban Sydney, said in an interview.

“Overall, there were fewer treatment inertia episodes in the triple-pill group than in the usual care group, but this was driven by the fact that fewer triple-pill patients needed uptitration when coming to their follow-up visits,” Dr. Wang added.

The analysis found that clinicians who prescribed triple-pill FDC used 23 unique drug treatment regimens per 100 treated patients compared with 54 different regiments with usual care (P < .001). “There was a large simplification in care,” Dr. Wang said of the FDC approach.

Dr. Wang and colleagues called for greater efforts to address therapeutic inertia, particularly with FDC therapies, and suggested potential strategies consisting of patient education, incentives for appropriate treatment adjustments, and feedback mechanisms and reminders for physicians.

“There may also be a need for more dosage options with the FDC triple pill to allow physicians to intensify therapy without fear of overtreatment and adverse drug effects,” they wrote.

In an accompanying editorial (JAMA Cardiol. 2020 Jul 22. doi: 10.1001/jamacardio.2020.2693), Ann Marie Navar, MD, PhD, associate professor of cardiology at Duke Clinical Research Institute, Durham, N.C., noted that initiating treatment with FDC therapy doesn’t preclude a more personalized approach for patients who don’t achieve their BP target. “The real choice now is the choice of initial treatment,” she wrote, adding that future treatment guidelines should consider extending an FDC-first approach to patients with less severe levels of hypertension.

“The study showed there’s room for a both a population-based fixed-drug combination approach and a personalized approach to how we think about hypertension management with fixed-dose therapy,” she said in an interview. “It’s not a one-and-done situation.”

Dr. Wang has no financial relationships to disclose. Study coauthors received funding from the Australian National Health and Medical Research Council and the U.K. National Institute for Health Research. Dr. Navar has no relevant financial relationships to report.

SOURCE: Wang N et al. JAMA Cardiol. 2020. doi: 10.1001/jamacardio.2020.2739.

More than half of Hispanic adults would be afraid to go to a hospital for a possible heart attack or stroke because they might get infected with SARS-CoV-2, according to a new survey from the American Heart Association.

Compared with Hispanic respondents, 55% of whom said they feared COVID-19, significantly fewer Blacks (45%) and Whites (40%) would be scared to go to the hospital if they thought they were having a heart attack or stroke, the AHA said based on the survey of 2,050 adults, which was conducted May 29 to June 2, 2020, by the Harris Poll.

Hispanics also were significantly more likely to stay home if they thought they were experiencing a heart attack or stroke (41%), rather than risk getting infected at the hospital, than were Blacks (33%), who were significantly more likely than Whites (24%) to stay home, the AHA reported.

White respondents, on the other hand, were the most likely to believe (89%) that a hospital would give them the same quality of care provided to everyone else. Hispanics and Blacks had significantly lower rates, at 78% and 74%, respectively, the AHA noted.

These findings are “yet another challenge for Black and Hispanic communities, who are more likely to have underlying health conditions such as cardiovascular disease and diabetes and dying of COVID-19 at disproportionately high rates,” Rafael Ortiz, MD, American Heart Association volunteer medical expert and chief of neuro-endovascular surgery at Lenox Hill Hospital, New York, said in the AHA statement.

The survey was performed in conjunction with the AHA’s “Don’t Die of Doubt” campaign, which “reminds Americans, especially in Hispanic and Black communities, that the hospital remains the safest place to be if experiencing symptoms of a heart attack or a stroke.”

Among all the survey respondents, 57% said they would feel better if hospitals treated COVID-19 patients in a separate area. A number of other possible precautions ranked lower in helping them feel better:

• Screen all visitors, patients, and staff for COVID-19 symptoms when they enter the hospital: 39%.
• Require all patients, visitors, and staff to wear masks: 30%.
• Put increased cleaning protocols in place to disinfect multiple times per day: 23%.
• “Nothing would make me feel comfortable”: 6%.

Despite all the concerns about the risk of coronavirus infection, however, most Americans (77%) still believe that hospitals are the safest place to be in the event of a medical emergency, and 84% said that hospitals are prepared to safely treat emergencies that are not related to the pandemic, the AHA reported.

“Health care professionals know what to do even when things seem chaotic, and emergency departments have made plans behind the scenes to keep patients and healthcare workers safe even during a pandemic,” Dr. Ortiz pointed out.

rfranki@mdedge.com

More than half of Hispanic adults would be afraid to go to a hospital for a possible heart attack or stroke because they might get infected with SARS-CoV-2, according to a new survey from the American Heart Association.

Compared with Hispanic respondents, 55% of whom said they feared COVID-19, significantly fewer Blacks (45%) and Whites (40%) would be scared to go to the hospital if they thought they were having a heart attack or stroke, the AHA said based on the survey of 2,050 adults, which was conducted May 29 to June 2, 2020, by the Harris Poll.

Hispanics also were significantly more likely to stay home if they thought they were experiencing a heart attack or stroke (41%), rather than risk getting infected at the hospital, than were Blacks (33%), who were significantly more likely than Whites (24%) to stay home, the AHA reported.

White respondents, on the other hand, were the most likely to believe (89%) that a hospital would give them the same quality of care provided to everyone else. Hispanics and Blacks had significantly lower rates, at 78% and 74%, respectively, the AHA noted.

These findings are “yet another challenge for Black and Hispanic communities, who are more likely to have underlying health conditions such as cardiovascular disease and diabetes and dying of COVID-19 at disproportionately high rates,” Rafael Ortiz, MD, American Heart Association volunteer medical expert and chief of neuro-endovascular surgery at Lenox Hill Hospital, New York, said in the AHA statement.

The survey was performed in conjunction with the AHA’s “Don’t Die of Doubt” campaign, which “reminds Americans, especially in Hispanic and Black communities, that the hospital remains the safest place to be if experiencing symptoms of a heart attack or a stroke.”

Among all the survey respondents, 57% said they would feel better if hospitals treated COVID-19 patients in a separate area. A number of other possible precautions ranked lower in helping them feel better:

• Screen all visitors, patients, and staff for COVID-19 symptoms when they enter the hospital: 39%.
• Require all patients, visitors, and staff to wear masks: 30%.
• Put increased cleaning protocols in place to disinfect multiple times per day: 23%.
• “Nothing would make me feel comfortable”: 6%.

Despite all the concerns about the risk of coronavirus infection, however, most Americans (77%) still believe that hospitals are the safest place to be in the event of a medical emergency, and 84% said that hospitals are prepared to safely treat emergencies that are not related to the pandemic, the AHA reported.

“Health care professionals know what to do even when things seem chaotic, and emergency departments have made plans behind the scenes to keep patients and healthcare workers safe even during a pandemic,” Dr. Ortiz pointed out.

rfranki@mdedge.com

More than half of Hispanic adults would be afraid to go to a hospital for a possible heart attack or stroke because they might get infected with SARS-CoV-2, according to a new survey from the American Heart Association.

Compared with Hispanic respondents, 55% of whom said they feared COVID-19, significantly fewer Blacks (45%) and Whites (40%) would be scared to go to the hospital if they thought they were having a heart attack or stroke, the AHA said based on the survey of 2,050 adults, which was conducted May 29 to June 2, 2020, by the Harris Poll.

Hispanics also were significantly more likely to stay home if they thought they were experiencing a heart attack or stroke (41%), rather than risk getting infected at the hospital, than were Blacks (33%), who were significantly more likely than Whites (24%) to stay home, the AHA reported.

White respondents, on the other hand, were the most likely to believe (89%) that a hospital would give them the same quality of care provided to everyone else. Hispanics and Blacks had significantly lower rates, at 78% and 74%, respectively, the AHA noted.

These findings are “yet another challenge for Black and Hispanic communities, who are more likely to have underlying health conditions such as cardiovascular disease and diabetes and dying of COVID-19 at disproportionately high rates,” Rafael Ortiz, MD, American Heart Association volunteer medical expert and chief of neuro-endovascular surgery at Lenox Hill Hospital, New York, said in the AHA statement.

The survey was performed in conjunction with the AHA’s “Don’t Die of Doubt” campaign, which “reminds Americans, especially in Hispanic and Black communities, that the hospital remains the safest place to be if experiencing symptoms of a heart attack or a stroke.”

Among all the survey respondents, 57% said they would feel better if hospitals treated COVID-19 patients in a separate area. A number of other possible precautions ranked lower in helping them feel better:

• Screen all visitors, patients, and staff for COVID-19 symptoms when they enter the hospital: 39%.
• Require all patients, visitors, and staff to wear masks: 30%.
• Put increased cleaning protocols in place to disinfect multiple times per day: 23%.
• “Nothing would make me feel comfortable”: 6%.

Despite all the concerns about the risk of coronavirus infection, however, most Americans (77%) still believe that hospitals are the safest place to be in the event of a medical emergency, and 84% said that hospitals are prepared to safely treat emergencies that are not related to the pandemic, the AHA reported.

“Health care professionals know what to do even when things seem chaotic, and emergency departments have made plans behind the scenes to keep patients and healthcare workers safe even during a pandemic,” Dr. Ortiz pointed out.

rfranki@mdedge.com

Further refinement of data from patients hospitalized worldwide for COVID-19 disease showed a 12% prevalence rate of patients with diabetes in this population and a 17% prevalence rate for hypertension.

Irina Shatilova/Getty Images

These are lower rates than previously reported for COVID-19 patients with either of these two comorbidities, yet the findings still document important epidemiologic links between diabetes, hypertension, and COVID-19, said the study’s authors.

A meta-analysis of data from 15,794 patients hospitalized because of COVID-19 disease that was drawn from 65 carefully curated reports published from December 1, 2019, to April 6, 2020, also showed that, among the hospitalized COVID-19 patients with diabetes (either type 1 or type 2), the rate of patients who required ICU admission was 96% higher than among those without diabetes and mortality was 2.78-fold higher, both statistically significant differences.

The rate of ICU admissions among those hospitalized with COVID-19 who also had hypertension was 2.95-fold above those without hypertension, and mortality was 2.39-fold higher, also statistically significant differences, reported a team of researchers in the recently published report.

The new meta-analysis was notable for the extra effort investigators employed to eliminate duplicated patients from their database of COVID-19 patients included in various published reports, a potential source of bias that likely introduced errors into prior meta-analyses that used similar data. “We found an overwhelming proportion of studies at high risk of data repetition,” the report said. Virtually all of the included studies were retrospective case studies, nearly two-thirds had data from a single center, and 71% of the studies included only patients in China.

“We developed a method to identify reports that had a high risk for repetitions” of included patients, said Fady Hannah-Shmouni, MD, a senior author of the study. “We also used methods to minimize bias, we excluded certain patients populations, and we applied a uniform definition of COVID-19 disease severity,” specifically patients who died or needed ICU admission, because the definitions used originally by many of the reports were very heterogeneous, said Dr. Hannah-Shmouni, principal investigator for Endocrine, Genetics, and Hypertension at the National Institute of Child Health and Human Development.

Despite the effort to eliminate case duplications, the analysis remains subject to additional confounders, in part because of a lack of comprehensive patient information on factors such as smoking, body mass index, socioeconomic status, and the specific type of diabetes or hypertension a patient had. “Even with these limitations, we were able to show that the prevalence of hypertension and diabetes is elevated in patients with COVID-19, that patients with diabetes have increased risk for both death and ICU admissions, and that there is the potential for reverse causality in the reporting of hypertension as a risk factor for COVID-19,” Dr. Hannah-Shmouni said in an interview. “We believe the explosion of data that associated hypertension and COVID-19 may be partially the result of reverse causality.”

One possible example of this reverse causality is the overlap between hypertension and age as potential risk factors for COVID-19 disease or increased infection severity. People “older than 80 frequently develop severe disease if infected with the novel coronavirus, and 80% of people older than 80 have hypertension, so it’s not surprising that hypertension is highly prevalent among hospitalized COVID-19 patients,” but this “does not imply a causal relationship between hypertension and severe COVID-19; the risk of hypertension probably depends on older age,” noted Ernesto L. Schiffrin, MD, a coauthor of the study, as well as professor of medicine at McGill University and director of the Hypertension and Vascular Research Unit at the Lady Davis Institute for Medical Research, both in Montreal. “My current opinion, on the basis of the totality of data, is that hypertension does not worsen [COVID-19] outcomes, but patients who are elderly, obese, diabetic, or immunocompromised are susceptible to more severe COVID-19 and worse outcomes,” said Dr. Schiffrin in an interview.

The new findings show “there is certainly an interplay between the virus, diabetes, and hypertension and other risk factors,” and while still limited by biases, the new findings “get closer” to correctly estimating the COVID-19 risks associated with these comorbidities,” Dr. Hannah-Shmouni said.

The connections identified between COVID-19, diabetes, and hypertension mean that patients with these chronic diseases should receive education about their COVID-19 risks and should have adequate access to the drugs and supplies they need to control blood pressure and hyperglycemia. Patients with diabetes also need to be current on vaccinations to reduce their risk for pneumonia. And recognition of the heightened COVID-19 risk for people with these comorbidities is important among people who work in relevant government agencies, health care workers, and patient advocacy groups, he added.

The study received no commercial funding. Dr. Hannah-Shmouni and Dr. Schiffrin had no disclosures.

mzoler@mdedge.com

SOURCE: Barrera FJ et al. J Endocn Soc. 2020 July 21. doi: 10.1210/jendso/bvaa102.

Further refinement of data from patients hospitalized worldwide for COVID-19 disease showed a 12% prevalence rate of patients with diabetes in this population and a 17% prevalence rate for hypertension.

Irina Shatilova/Getty Images

These are lower rates than previously reported for COVID-19 patients with either of these two comorbidities, yet the findings still document important epidemiologic links between diabetes, hypertension, and COVID-19, said the study’s authors.

A meta-analysis of data from 15,794 patients hospitalized because of COVID-19 disease that was drawn from 65 carefully curated reports published from December 1, 2019, to April 6, 2020, also showed that, among the hospitalized COVID-19 patients with diabetes (either type 1 or type 2), the rate of patients who required ICU admission was 96% higher than among those without diabetes and mortality was 2.78-fold higher, both statistically significant differences.

The rate of ICU admissions among those hospitalized with COVID-19 who also had hypertension was 2.95-fold above those without hypertension, and mortality was 2.39-fold higher, also statistically significant differences, reported a team of researchers in the recently published report.

The new meta-analysis was notable for the extra effort investigators employed to eliminate duplicated patients from their database of COVID-19 patients included in various published reports, a potential source of bias that likely introduced errors into prior meta-analyses that used similar data. “We found an overwhelming proportion of studies at high risk of data repetition,” the report said. Virtually all of the included studies were retrospective case studies, nearly two-thirds had data from a single center, and 71% of the studies included only patients in China.

“We developed a method to identify reports that had a high risk for repetitions” of included patients, said Fady Hannah-Shmouni, MD, a senior author of the study. “We also used methods to minimize bias, we excluded certain patients populations, and we applied a uniform definition of COVID-19 disease severity,” specifically patients who died or needed ICU admission, because the definitions used originally by many of the reports were very heterogeneous, said Dr. Hannah-Shmouni, principal investigator for Endocrine, Genetics, and Hypertension at the National Institute of Child Health and Human Development.

Despite the effort to eliminate case duplications, the analysis remains subject to additional confounders, in part because of a lack of comprehensive patient information on factors such as smoking, body mass index, socioeconomic status, and the specific type of diabetes or hypertension a patient had. “Even with these limitations, we were able to show that the prevalence of hypertension and diabetes is elevated in patients with COVID-19, that patients with diabetes have increased risk for both death and ICU admissions, and that there is the potential for reverse causality in the reporting of hypertension as a risk factor for COVID-19,” Dr. Hannah-Shmouni said in an interview. “We believe the explosion of data that associated hypertension and COVID-19 may be partially the result of reverse causality.”

One possible example of this reverse causality is the overlap between hypertension and age as potential risk factors for COVID-19 disease or increased infection severity. People “older than 80 frequently develop severe disease if infected with the novel coronavirus, and 80% of people older than 80 have hypertension, so it’s not surprising that hypertension is highly prevalent among hospitalized COVID-19 patients,” but this “does not imply a causal relationship between hypertension and severe COVID-19; the risk of hypertension probably depends on older age,” noted Ernesto L. Schiffrin, MD, a coauthor of the study, as well as professor of medicine at McGill University and director of the Hypertension and Vascular Research Unit at the Lady Davis Institute for Medical Research, both in Montreal. “My current opinion, on the basis of the totality of data, is that hypertension does not worsen [COVID-19] outcomes, but patients who are elderly, obese, diabetic, or immunocompromised are susceptible to more severe COVID-19 and worse outcomes,” said Dr. Schiffrin in an interview.

The new findings show “there is certainly an interplay between the virus, diabetes, and hypertension and other risk factors,” and while still limited by biases, the new findings “get closer” to correctly estimating the COVID-19 risks associated with these comorbidities,” Dr. Hannah-Shmouni said.

The connections identified between COVID-19, diabetes, and hypertension mean that patients with these chronic diseases should receive education about their COVID-19 risks and should have adequate access to the drugs and supplies they need to control blood pressure and hyperglycemia. Patients with diabetes also need to be current on vaccinations to reduce their risk for pneumonia. And recognition of the heightened COVID-19 risk for people with these comorbidities is important among people who work in relevant government agencies, health care workers, and patient advocacy groups, he added.

The study received no commercial funding. Dr. Hannah-Shmouni and Dr. Schiffrin had no disclosures.

mzoler@mdedge.com

SOURCE: Barrera FJ et al. J Endocn Soc. 2020 July 21. doi: 10.1210/jendso/bvaa102.

Further refinement of data from patients hospitalized worldwide for COVID-19 disease showed a 12% prevalence rate of patients with diabetes in this population and a 17% prevalence rate for hypertension.

Irina Shatilova/Getty Images

These are lower rates than previously reported for COVID-19 patients with either of these two comorbidities, yet the findings still document important epidemiologic links between diabetes, hypertension, and COVID-19, said the study’s authors.

A meta-analysis of data from 15,794 patients hospitalized because of COVID-19 disease that was drawn from 65 carefully curated reports published from December 1, 2019, to April 6, 2020, also showed that, among the hospitalized COVID-19 patients with diabetes (either type 1 or type 2), the rate of patients who required ICU admission was 96% higher than among those without diabetes and mortality was 2.78-fold higher, both statistically significant differences.

The rate of ICU admissions among those hospitalized with COVID-19 who also had hypertension was 2.95-fold above those without hypertension, and mortality was 2.39-fold higher, also statistically significant differences, reported a team of researchers in the recently published report.

The new meta-analysis was notable for the extra effort investigators employed to eliminate duplicated patients from their database of COVID-19 patients included in various published reports, a potential source of bias that likely introduced errors into prior meta-analyses that used similar data. “We found an overwhelming proportion of studies at high risk of data repetition,” the report said. Virtually all of the included studies were retrospective case studies, nearly two-thirds had data from a single center, and 71% of the studies included only patients in China.

“We developed a method to identify reports that had a high risk for repetitions” of included patients, said Fady Hannah-Shmouni, MD, a senior author of the study. “We also used methods to minimize bias, we excluded certain patients populations, and we applied a uniform definition of COVID-19 disease severity,” specifically patients who died or needed ICU admission, because the definitions used originally by many of the reports were very heterogeneous, said Dr. Hannah-Shmouni, principal investigator for Endocrine, Genetics, and Hypertension at the National Institute of Child Health and Human Development.

Despite the effort to eliminate case duplications, the analysis remains subject to additional confounders, in part because of a lack of comprehensive patient information on factors such as smoking, body mass index, socioeconomic status, and the specific type of diabetes or hypertension a patient had. “Even with these limitations, we were able to show that the prevalence of hypertension and diabetes is elevated in patients with COVID-19, that patients with diabetes have increased risk for both death and ICU admissions, and that there is the potential for reverse causality in the reporting of hypertension as a risk factor for COVID-19,” Dr. Hannah-Shmouni said in an interview. “We believe the explosion of data that associated hypertension and COVID-19 may be partially the result of reverse causality.”

One possible example of this reverse causality is the overlap between hypertension and age as potential risk factors for COVID-19 disease or increased infection severity. People “older than 80 frequently develop severe disease if infected with the novel coronavirus, and 80% of people older than 80 have hypertension, so it’s not surprising that hypertension is highly prevalent among hospitalized COVID-19 patients,” but this “does not imply a causal relationship between hypertension and severe COVID-19; the risk of hypertension probably depends on older age,” noted Ernesto L. Schiffrin, MD, a coauthor of the study, as well as professor of medicine at McGill University and director of the Hypertension and Vascular Research Unit at the Lady Davis Institute for Medical Research, both in Montreal. “My current opinion, on the basis of the totality of data, is that hypertension does not worsen [COVID-19] outcomes, but patients who are elderly, obese, diabetic, or immunocompromised are susceptible to more severe COVID-19 and worse outcomes,” said Dr. Schiffrin in an interview.

The new findings show “there is certainly an interplay between the virus, diabetes, and hypertension and other risk factors,” and while still limited by biases, the new findings “get closer” to correctly estimating the COVID-19 risks associated with these comorbidities,” Dr. Hannah-Shmouni said.

The connections identified between COVID-19, diabetes, and hypertension mean that patients with these chronic diseases should receive education about their COVID-19 risks and should have adequate access to the drugs and supplies they need to control blood pressure and hyperglycemia. Patients with diabetes also need to be current on vaccinations to reduce their risk for pneumonia. And recognition of the heightened COVID-19 risk for people with these comorbidities is important among people who work in relevant government agencies, health care workers, and patient advocacy groups, he added.

The study received no commercial funding. Dr. Hannah-Shmouni and Dr. Schiffrin had no disclosures.

mzoler@mdedge.com

SOURCE: Barrera FJ et al. J Endocn Soc. 2020 July 21. doi: 10.1210/jendso/bvaa102.

For patients with acute myocardial infarction (MI) and mild subclinical hypothyroidism (SCH), treatment with levothyroxine does not improve left ventricular function, according to results of the Thyroid in Acute Myocardial Infarction (ThyrAMI-2) trial.

“SCH is common, affecting approximately 10% of the adult population, and has been associated with worse outcomes in patients with cardiovascular disease in observational studies,” Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, said in an interview.

This study shows that levothyroxine treatment for patients with SCH and acute MI is “unlikely to be of benefit,” he said.

“This study says that treating the thyroid failure does not help nor harm such patients,” Terry F. Davies, MD, director, division of endocrinology, diabetes, and bone diseases, Mount Sinai Beth Israel Medical Center, New York, said in an interview. He was not involved in the study, which was published online July 21 in JAMA.

Participants included 95 adults (mean age, 63.5 years; 72 men) with persistent mild SCH who presented with acute MI at six hospitals in the United Kingdom. Most (69%) had ST-segment elevation MI.

Inclusion criteria were age older than 18 years and serum thyrotropin level >4.0 mU/L with a normal free thyroxine level on two occasions 7-10 days apart and with one thyrotropin value <10 mU/L.

Forty-six participants were randomly allocated to receive levothyroxine starting at 25 mcg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L and 49 to matching placebo capsules taken once daily for 52 weeks.

The primary outcome was left ventricular ejection fraction (LVEF) at 52 weeks, assessed via MRI, with adjustment for age, sex, acute MI type, affected coronary artery territory, and baseline LVEF.

Secondary outcomes were LV volume, infarct size, adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

The median daily dose of levothyroxine at the end of the study was 50 mcg. Adherence to study medication was 94% during the course of the study.

At week 52, mean LVEF improved from 51.3% at baseline to 53.8% in the levothyroxine group and from 54.0% to 56.1% in the placebo group.

The difference was not significant between groups, with an adjusted between-group difference of 0.76% (95% confidence interval, –0.93% to 2.46%; P = .37).

There were also no significant differences in any of the secondary outcomes. There were 15 (33.3%) cardiovascular adverse events in the levothyroxine group and 18 (36.7%) in the placebo group.

Recent clinical practice guidelines have highlighted a lack of high-quality data to make recommendations regarding the management of mild SCH, particularly for patients with cardiovascular disease, Dr. Razvi and colleagues noted in their article.

“On the basis of these findings, screening for and subsequent treatment of subclinical hypothyroidism in patients with acute myocardial infarction to preserve LV function is not justified,” they concluded.

Important caveats

The investigators noted several important caveats and limitations. The trial recruited patients with mild SCH because this group constitutes the majority of patients with SCH and for whom there is the “greatest uncertainty” regarding treatment efficacy. It’s not known whether targeting treatment for individuals with more severe disease may be beneficial.

The therapeutic benefit of levothyroxine may have been blunted, owing to the delay between coronary occlusion and the start of levothyroxine (median delay, 17 days). It’s unclear whether earlier treatment or treatment for a longer period may be beneficial.

But Dr. Davies noted that “treatment is usually avoided in the emergency situation,” and therefore he doesn’t think the treatment delay is a limitation; rather, “it would appear prudent,” he said in the interview.

“The real issues with an otherwise very careful study is the small size of the population despite the statistical assessment that this was all that was needed and, secondly, the small dose of thyroxine used,” Dr. Davies said.

The authors agree that the low dose of levothyroxine is a limitation. The median dose at the end of the study – 50 mcg daily – is “lower than that used in other trials that have demonstrated a benefit of treatment on endothelial function and lipid profiles,” they pointed out.

Dr. Davies noted that thyroid tests are “usually routine” for patients with MI. “Mild subclinical thyroid failure has been associated with worse cardiac outcomes, [but] treating such patients with thyroid hormone is very controversial since thyroid hormone can induce arrhythmias,” he said.

The study was supported in part by the National Institute for Health Research (NIHR) at the University of Leeds. Dr. Razvi received grants from the NIHR and nonfinancial support from Amdipharm Pharmaceuticals UK during the conduct of the study and personal fees from Merck and Abbott Pharmaceuticals outside the submitted work. Dr. Davies has disclosed no relevant financial relationships.
 

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

For patients with acute myocardial infarction (MI) and mild subclinical hypothyroidism (SCH), treatment with levothyroxine does not improve left ventricular function, according to results of the Thyroid in Acute Myocardial Infarction (ThyrAMI-2) trial.

“SCH is common, affecting approximately 10% of the adult population, and has been associated with worse outcomes in patients with cardiovascular disease in observational studies,” Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, said in an interview.

This study shows that levothyroxine treatment for patients with SCH and acute MI is “unlikely to be of benefit,” he said.

“This study says that treating the thyroid failure does not help nor harm such patients,” Terry F. Davies, MD, director, division of endocrinology, diabetes, and bone diseases, Mount Sinai Beth Israel Medical Center, New York, said in an interview. He was not involved in the study, which was published online July 21 in JAMA.

Participants included 95 adults (mean age, 63.5 years; 72 men) with persistent mild SCH who presented with acute MI at six hospitals in the United Kingdom. Most (69%) had ST-segment elevation MI.

Inclusion criteria were age older than 18 years and serum thyrotropin level >4.0 mU/L with a normal free thyroxine level on two occasions 7-10 days apart and with one thyrotropin value <10 mU/L.

Forty-six participants were randomly allocated to receive levothyroxine starting at 25 mcg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L and 49 to matching placebo capsules taken once daily for 52 weeks.

The primary outcome was left ventricular ejection fraction (LVEF) at 52 weeks, assessed via MRI, with adjustment for age, sex, acute MI type, affected coronary artery territory, and baseline LVEF.

Secondary outcomes were LV volume, infarct size, adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

The median daily dose of levothyroxine at the end of the study was 50 mcg. Adherence to study medication was 94% during the course of the study.

At week 52, mean LVEF improved from 51.3% at baseline to 53.8% in the levothyroxine group and from 54.0% to 56.1% in the placebo group.

The difference was not significant between groups, with an adjusted between-group difference of 0.76% (95% confidence interval, –0.93% to 2.46%; P = .37).

There were also no significant differences in any of the secondary outcomes. There were 15 (33.3%) cardiovascular adverse events in the levothyroxine group and 18 (36.7%) in the placebo group.

Recent clinical practice guidelines have highlighted a lack of high-quality data to make recommendations regarding the management of mild SCH, particularly for patients with cardiovascular disease, Dr. Razvi and colleagues noted in their article.

“On the basis of these findings, screening for and subsequent treatment of subclinical hypothyroidism in patients with acute myocardial infarction to preserve LV function is not justified,” they concluded.

Important caveats

The investigators noted several important caveats and limitations. The trial recruited patients with mild SCH because this group constitutes the majority of patients with SCH and for whom there is the “greatest uncertainty” regarding treatment efficacy. It’s not known whether targeting treatment for individuals with more severe disease may be beneficial.

The therapeutic benefit of levothyroxine may have been blunted, owing to the delay between coronary occlusion and the start of levothyroxine (median delay, 17 days). It’s unclear whether earlier treatment or treatment for a longer period may be beneficial.

But Dr. Davies noted that “treatment is usually avoided in the emergency situation,” and therefore he doesn’t think the treatment delay is a limitation; rather, “it would appear prudent,” he said in the interview.

“The real issues with an otherwise very careful study is the small size of the population despite the statistical assessment that this was all that was needed and, secondly, the small dose of thyroxine used,” Dr. Davies said.

The authors agree that the low dose of levothyroxine is a limitation. The median dose at the end of the study – 50 mcg daily – is “lower than that used in other trials that have demonstrated a benefit of treatment on endothelial function and lipid profiles,” they pointed out.

Dr. Davies noted that thyroid tests are “usually routine” for patients with MI. “Mild subclinical thyroid failure has been associated with worse cardiac outcomes, [but] treating such patients with thyroid hormone is very controversial since thyroid hormone can induce arrhythmias,” he said.

The study was supported in part by the National Institute for Health Research (NIHR) at the University of Leeds. Dr. Razvi received grants from the NIHR and nonfinancial support from Amdipharm Pharmaceuticals UK during the conduct of the study and personal fees from Merck and Abbott Pharmaceuticals outside the submitted work. Dr. Davies has disclosed no relevant financial relationships.
 

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

For patients with acute myocardial infarction (MI) and mild subclinical hypothyroidism (SCH), treatment with levothyroxine does not improve left ventricular function, according to results of the Thyroid in Acute Myocardial Infarction (ThyrAMI-2) trial.

“SCH is common, affecting approximately 10% of the adult population, and has been associated with worse outcomes in patients with cardiovascular disease in observational studies,” Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, said in an interview.

This study shows that levothyroxine treatment for patients with SCH and acute MI is “unlikely to be of benefit,” he said.

“This study says that treating the thyroid failure does not help nor harm such patients,” Terry F. Davies, MD, director, division of endocrinology, diabetes, and bone diseases, Mount Sinai Beth Israel Medical Center, New York, said in an interview. He was not involved in the study, which was published online July 21 in JAMA.

Participants included 95 adults (mean age, 63.5 years; 72 men) with persistent mild SCH who presented with acute MI at six hospitals in the United Kingdom. Most (69%) had ST-segment elevation MI.

Inclusion criteria were age older than 18 years and serum thyrotropin level >4.0 mU/L with a normal free thyroxine level on two occasions 7-10 days apart and with one thyrotropin value <10 mU/L.

Forty-six participants were randomly allocated to receive levothyroxine starting at 25 mcg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L and 49 to matching placebo capsules taken once daily for 52 weeks.

The primary outcome was left ventricular ejection fraction (LVEF) at 52 weeks, assessed via MRI, with adjustment for age, sex, acute MI type, affected coronary artery territory, and baseline LVEF.

Secondary outcomes were LV volume, infarct size, adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

The median daily dose of levothyroxine at the end of the study was 50 mcg. Adherence to study medication was 94% during the course of the study.

At week 52, mean LVEF improved from 51.3% at baseline to 53.8% in the levothyroxine group and from 54.0% to 56.1% in the placebo group.

The difference was not significant between groups, with an adjusted between-group difference of 0.76% (95% confidence interval, –0.93% to 2.46%; P = .37).

There were also no significant differences in any of the secondary outcomes. There were 15 (33.3%) cardiovascular adverse events in the levothyroxine group and 18 (36.7%) in the placebo group.

Recent clinical practice guidelines have highlighted a lack of high-quality data to make recommendations regarding the management of mild SCH, particularly for patients with cardiovascular disease, Dr. Razvi and colleagues noted in their article.

“On the basis of these findings, screening for and subsequent treatment of subclinical hypothyroidism in patients with acute myocardial infarction to preserve LV function is not justified,” they concluded.

Important caveats

The investigators noted several important caveats and limitations. The trial recruited patients with mild SCH because this group constitutes the majority of patients with SCH and for whom there is the “greatest uncertainty” regarding treatment efficacy. It’s not known whether targeting treatment for individuals with more severe disease may be beneficial.

The therapeutic benefit of levothyroxine may have been blunted, owing to the delay between coronary occlusion and the start of levothyroxine (median delay, 17 days). It’s unclear whether earlier treatment or treatment for a longer period may be beneficial.

But Dr. Davies noted that “treatment is usually avoided in the emergency situation,” and therefore he doesn’t think the treatment delay is a limitation; rather, “it would appear prudent,” he said in the interview.

“The real issues with an otherwise very careful study is the small size of the population despite the statistical assessment that this was all that was needed and, secondly, the small dose of thyroxine used,” Dr. Davies said.

The authors agree that the low dose of levothyroxine is a limitation. The median dose at the end of the study – 50 mcg daily – is “lower than that used in other trials that have demonstrated a benefit of treatment on endothelial function and lipid profiles,” they pointed out.

Dr. Davies noted that thyroid tests are “usually routine” for patients with MI. “Mild subclinical thyroid failure has been associated with worse cardiac outcomes, [but] treating such patients with thyroid hormone is very controversial since thyroid hormone can induce arrhythmias,” he said.

The study was supported in part by the National Institute for Health Research (NIHR) at the University of Leeds. Dr. Razvi received grants from the NIHR and nonfinancial support from Amdipharm Pharmaceuticals UK during the conduct of the study and personal fees from Merck and Abbott Pharmaceuticals outside the submitted work. Dr. Davies has disclosed no relevant financial relationships.
 

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

As if the management of patients with severe COVID-19 infections is not complicated enough, an estimated 50%-60% of patients admitted to an ICU with the disease will have some form of cardiovascular involvement, which further increases their already high risk for morbidity and mortality.

Multimodality cardiovascular imaging, chosen wisely, can both help to direct management of cardiovascular complications associated with COVID-19 and lessen risk of exposure of health care workers to SARS-CoV-2, said members of an expert panel from the American College of Cardiology Cardiovascular Imaging Leadership Council.

“When we face a patient with known or suspected COVID-19, it’s not like any other disease because we face potential exposure risk to personnel doing imaging studies and also to other patients,” corresponding author Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital Boston said in an interview.

“Any imaging study that is being considered should be performed only if we think it will help us make a change in the way that we’re going to treat that particular patient. This is true for imaging in any disease – why would you do an imaging study that will make no difference in treatment? – but the stakes are even higher in COVID-19,” he said.

The panel’s recommendations for cardiovascular imaging in patients with COVID-19 are outlined in a guidance document published online in the Journal of the American College of Cardiology.
 

Testing and biomarkers

The guidance begins by highlighting the importance of diagnostic testing for COVID-19 infection and the use of universal precautions for health care personnel performing imaging studies, as well as disinfection of imaging equipment and rooms after each use.

Circulating biomarkers that measure end-organ stress or injury, inflammation, hypoperfusion, and activation of thrombosis/hemostasis pathways may be prognostically useful, but “almost none of the widely measured biomarkers represent a specific trigger for imaging outside of that supported by clinical judgment,” the guidance states.

In contrast, low to moderate, nonrising concentrations of markers for myocardial stress, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), or of myocardial injury, such as cardiac troponins (cTn), may be helpful for excluding the need for imaging.

“Importantly, clinicians should be aware that most patients with abnormal BNP/NT-proBNP or cTn do not have acute heart failure or myocardial infarction; and rise in concentration of either class of biomarker presumably reflects complex processes including direct myocardial stress/injury related to systemic illness,” the panel members wrote.
 

Oldies but goodies

“One thing that we found out in our review of the literature and in our experiences in our own work settings is that cardiac ultrasound plays a huge role in this disease – like in any disease – but this one in particular,” Dr. Di Carli said. “One of the most feared complications in COVID-19 leads to inflammation of the heart muscle, which then leads to heart dysfunction. And of course cardiac ultrasound, because of its portability, can be performed at bedside to help clinicians ascertain an abnormality in the heart.”

Cardiac CT is also extremely helpful for determining whether patients with ECG findings suggestive of infarction have suffered an actual thrombotic event.

“These patients may best be served by a noninvasive study as compared to an invasive coronary angiogram,” he said.
 

Clinical scenarios

Cardiologists may be called in to consult on the evaluation of possible cardiogenic components of pulmonary abnormalities in patients who present with dyspnea and chest x-rays showing airspace or interstitial infiltrates suggestive of pneumonia, the authors noted.

“Clinicians will rely on history, physical exam, ECG [electrocardiogram] and biomarkers, and recent cardiac imaging tests if available. Underlying cardiac history including [coronary artery disease], cardiomyopathy, heart failure, and arrhythmia should be sought, and frequent contributors to decompensation should be eliminated,” they wrote.

For patients with suspected cardiac injury, either point-of-care ultrasound or limited echocardiography can be used for the initial evaluation, with additional, more advanced technologies called into play for specific clinical scenarios outlined in the guidance.

For example, the guidance recommends that patients with chest pain and abnormal ECG readings with clinical concern for ST-elevation acute coronary syndrome or high clinical risk for in-hospital mortality from conditions such as cardiogenic shock, dynamic ST-segment changes, or left ventricular ejection fraction less than 40% thought to be caused by non–ST-elevation myocardial infarction be referred for emergent coronary angiography and reperfusion.

In contrast, in patients with chest pain and abnormal ECG but equivocal symptoms, atypical or equivocal ECG abnormalities, or late presentations, point-of-care ultrasound or limited echocardiogram could be used to look for regional wall motion abnormalities and left ventricular ejection fraction, whereas in patients with chest pain and ST-elevation without clear evidence of ST-elevation myocardial infarction, coronary CT angiography can help to rule out ACS and point to alternate diagnoses, the authors said.

The guidance also offers recommendations for imaging in patients with hemodynamic instability (shock or hypotension), patients with new left ventricular dysfunction in the absence of shock or hypotension, and patients with subacute and chronic-phase disease.

Development of the guidance document was supported by the ACC. Dr. Di Carli disclosed institutional grant support from Gilead Sciences and Spectrum Dynamics, and consulting income from Janssen and Bayer.

SOURCE: Rudski L et al. J Am Coll Cardiol. 2020 Jul 22. doi: 10.1016/j.jacc.2020.06.080.

As if the management of patients with severe COVID-19 infections is not complicated enough, an estimated 50%-60% of patients admitted to an ICU with the disease will have some form of cardiovascular involvement, which further increases their already high risk for morbidity and mortality.

Multimodality cardiovascular imaging, chosen wisely, can both help to direct management of cardiovascular complications associated with COVID-19 and lessen risk of exposure of health care workers to SARS-CoV-2, said members of an expert panel from the American College of Cardiology Cardiovascular Imaging Leadership Council.

“When we face a patient with known or suspected COVID-19, it’s not like any other disease because we face potential exposure risk to personnel doing imaging studies and also to other patients,” corresponding author Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital Boston said in an interview.

“Any imaging study that is being considered should be performed only if we think it will help us make a change in the way that we’re going to treat that particular patient. This is true for imaging in any disease – why would you do an imaging study that will make no difference in treatment? – but the stakes are even higher in COVID-19,” he said.

The panel’s recommendations for cardiovascular imaging in patients with COVID-19 are outlined in a guidance document published online in the Journal of the American College of Cardiology.
 

Testing and biomarkers

The guidance begins by highlighting the importance of diagnostic testing for COVID-19 infection and the use of universal precautions for health care personnel performing imaging studies, as well as disinfection of imaging equipment and rooms after each use.

Circulating biomarkers that measure end-organ stress or injury, inflammation, hypoperfusion, and activation of thrombosis/hemostasis pathways may be prognostically useful, but “almost none of the widely measured biomarkers represent a specific trigger for imaging outside of that supported by clinical judgment,” the guidance states.

In contrast, low to moderate, nonrising concentrations of markers for myocardial stress, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), or of myocardial injury, such as cardiac troponins (cTn), may be helpful for excluding the need for imaging.

“Importantly, clinicians should be aware that most patients with abnormal BNP/NT-proBNP or cTn do not have acute heart failure or myocardial infarction; and rise in concentration of either class of biomarker presumably reflects complex processes including direct myocardial stress/injury related to systemic illness,” the panel members wrote.
 

Oldies but goodies

“One thing that we found out in our review of the literature and in our experiences in our own work settings is that cardiac ultrasound plays a huge role in this disease – like in any disease – but this one in particular,” Dr. Di Carli said. “One of the most feared complications in COVID-19 leads to inflammation of the heart muscle, which then leads to heart dysfunction. And of course cardiac ultrasound, because of its portability, can be performed at bedside to help clinicians ascertain an abnormality in the heart.”

Cardiac CT is also extremely helpful for determining whether patients with ECG findings suggestive of infarction have suffered an actual thrombotic event.

“These patients may best be served by a noninvasive study as compared to an invasive coronary angiogram,” he said.
 

Clinical scenarios

Cardiologists may be called in to consult on the evaluation of possible cardiogenic components of pulmonary abnormalities in patients who present with dyspnea and chest x-rays showing airspace or interstitial infiltrates suggestive of pneumonia, the authors noted.

“Clinicians will rely on history, physical exam, ECG [electrocardiogram] and biomarkers, and recent cardiac imaging tests if available. Underlying cardiac history including [coronary artery disease], cardiomyopathy, heart failure, and arrhythmia should be sought, and frequent contributors to decompensation should be eliminated,” they wrote.

For patients with suspected cardiac injury, either point-of-care ultrasound or limited echocardiography can be used for the initial evaluation, with additional, more advanced technologies called into play for specific clinical scenarios outlined in the guidance.

For example, the guidance recommends that patients with chest pain and abnormal ECG readings with clinical concern for ST-elevation acute coronary syndrome or high clinical risk for in-hospital mortality from conditions such as cardiogenic shock, dynamic ST-segment changes, or left ventricular ejection fraction less than 40% thought to be caused by non–ST-elevation myocardial infarction be referred for emergent coronary angiography and reperfusion.

In contrast, in patients with chest pain and abnormal ECG but equivocal symptoms, atypical or equivocal ECG abnormalities, or late presentations, point-of-care ultrasound or limited echocardiogram could be used to look for regional wall motion abnormalities and left ventricular ejection fraction, whereas in patients with chest pain and ST-elevation without clear evidence of ST-elevation myocardial infarction, coronary CT angiography can help to rule out ACS and point to alternate diagnoses, the authors said.

The guidance also offers recommendations for imaging in patients with hemodynamic instability (shock or hypotension), patients with new left ventricular dysfunction in the absence of shock or hypotension, and patients with subacute and chronic-phase disease.

Development of the guidance document was supported by the ACC. Dr. Di Carli disclosed institutional grant support from Gilead Sciences and Spectrum Dynamics, and consulting income from Janssen and Bayer.

SOURCE: Rudski L et al. J Am Coll Cardiol. 2020 Jul 22. doi: 10.1016/j.jacc.2020.06.080.

As if the management of patients with severe COVID-19 infections is not complicated enough, an estimated 50%-60% of patients admitted to an ICU with the disease will have some form of cardiovascular involvement, which further increases their already high risk for morbidity and mortality.

Multimodality cardiovascular imaging, chosen wisely, can both help to direct management of cardiovascular complications associated with COVID-19 and lessen risk of exposure of health care workers to SARS-CoV-2, said members of an expert panel from the American College of Cardiology Cardiovascular Imaging Leadership Council.

“When we face a patient with known or suspected COVID-19, it’s not like any other disease because we face potential exposure risk to personnel doing imaging studies and also to other patients,” corresponding author Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital Boston said in an interview.

“Any imaging study that is being considered should be performed only if we think it will help us make a change in the way that we’re going to treat that particular patient. This is true for imaging in any disease – why would you do an imaging study that will make no difference in treatment? – but the stakes are even higher in COVID-19,” he said.

The panel’s recommendations for cardiovascular imaging in patients with COVID-19 are outlined in a guidance document published online in the Journal of the American College of Cardiology.
 

Testing and biomarkers

The guidance begins by highlighting the importance of diagnostic testing for COVID-19 infection and the use of universal precautions for health care personnel performing imaging studies, as well as disinfection of imaging equipment and rooms after each use.

Circulating biomarkers that measure end-organ stress or injury, inflammation, hypoperfusion, and activation of thrombosis/hemostasis pathways may be prognostically useful, but “almost none of the widely measured biomarkers represent a specific trigger for imaging outside of that supported by clinical judgment,” the guidance states.

In contrast, low to moderate, nonrising concentrations of markers for myocardial stress, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), or of myocardial injury, such as cardiac troponins (cTn), may be helpful for excluding the need for imaging.

“Importantly, clinicians should be aware that most patients with abnormal BNP/NT-proBNP or cTn do not have acute heart failure or myocardial infarction; and rise in concentration of either class of biomarker presumably reflects complex processes including direct myocardial stress/injury related to systemic illness,” the panel members wrote.
 

Oldies but goodies

“One thing that we found out in our review of the literature and in our experiences in our own work settings is that cardiac ultrasound plays a huge role in this disease – like in any disease – but this one in particular,” Dr. Di Carli said. “One of the most feared complications in COVID-19 leads to inflammation of the heart muscle, which then leads to heart dysfunction. And of course cardiac ultrasound, because of its portability, can be performed at bedside to help clinicians ascertain an abnormality in the heart.”

Cardiac CT is also extremely helpful for determining whether patients with ECG findings suggestive of infarction have suffered an actual thrombotic event.

“These patients may best be served by a noninvasive study as compared to an invasive coronary angiogram,” he said.
 

Clinical scenarios

Cardiologists may be called in to consult on the evaluation of possible cardiogenic components of pulmonary abnormalities in patients who present with dyspnea and chest x-rays showing airspace or interstitial infiltrates suggestive of pneumonia, the authors noted.

“Clinicians will rely on history, physical exam, ECG [electrocardiogram] and biomarkers, and recent cardiac imaging tests if available. Underlying cardiac history including [coronary artery disease], cardiomyopathy, heart failure, and arrhythmia should be sought, and frequent contributors to decompensation should be eliminated,” they wrote.

For patients with suspected cardiac injury, either point-of-care ultrasound or limited echocardiography can be used for the initial evaluation, with additional, more advanced technologies called into play for specific clinical scenarios outlined in the guidance.

For example, the guidance recommends that patients with chest pain and abnormal ECG readings with clinical concern for ST-elevation acute coronary syndrome or high clinical risk for in-hospital mortality from conditions such as cardiogenic shock, dynamic ST-segment changes, or left ventricular ejection fraction less than 40% thought to be caused by non–ST-elevation myocardial infarction be referred for emergent coronary angiography and reperfusion.

In contrast, in patients with chest pain and abnormal ECG but equivocal symptoms, atypical or equivocal ECG abnormalities, or late presentations, point-of-care ultrasound or limited echocardiogram could be used to look for regional wall motion abnormalities and left ventricular ejection fraction, whereas in patients with chest pain and ST-elevation without clear evidence of ST-elevation myocardial infarction, coronary CT angiography can help to rule out ACS and point to alternate diagnoses, the authors said.

The guidance also offers recommendations for imaging in patients with hemodynamic instability (shock or hypotension), patients with new left ventricular dysfunction in the absence of shock or hypotension, and patients with subacute and chronic-phase disease.

Development of the guidance document was supported by the ACC. Dr. Di Carli disclosed institutional grant support from Gilead Sciences and Spectrum Dynamics, and consulting income from Janssen and Bayer.

SOURCE: Rudski L et al. J Am Coll Cardiol. 2020 Jul 22. doi: 10.1016/j.jacc.2020.06.080.

Adults who ate chocolate more than once a week or more than 3.5 times a month were significantly less likely to develop coronary artery disease than were those who ate less chocolate, according to data from a meta-analysis of more than 300,000 individuals.

Howard Shooter/Thinkstock

Consumption of chocolate has shown beneficial effects on blood pressure and endothelial function, wrote Chayakrit Krittanawong, MD, of Baylor College of Medicine, Houston, and colleagues in the European Journal of Preventive Cardiology. “However, the potential benefit of increased chocolate consumption reducing coronary artery disease (CAD) risk is not known,” they said.

The investigators reviewed data from 5 decades of research, including six studies with a total of 336,289 individuals who reported chocolate consumption. The study participants experienced 14,043 cases of CAD, 4,667 myocardial infarctions, 2,735 cerebrovascular accidents, and 332 cases of heart failure over an average follow-up period of 8.78 years.

Overall, higher chocolate consumption (defined as more than once a week or more than 3.5 times a month) was significantly associated with a decreased CAD risk (pooled risk ratio, 0.94; P < .001) compared to eating no chocolate or eating chocolate less than once a week.

The cardioprotective effects of chocolate may be linked to several nutrients, the researchers noted. Chocolate’s flavenols (epicatechin, catechin, and procyanidins) have demonstrated an ability to reduce myocardial infarct size in an animal study and to reduce platelet aggregation and improve endothelial function in humans with and without CAD. In addition, methylxanthines have demonstrated beneficial effects on cardiovascular function, polyphenols have been shown to facilitate nitric oxide synthesis, and stearic acid has been associated with reduced mean platelet volume, they wrote.

“The benefits of nutrients in chocolate appear promising and chocolate consumption at least once a week may be beneficial for CAD prevention,” the researchers suggested, although they cautioned that the effects of supplemental calories and the impact of fats, milk, and sugar in commercial chocolate must be taken into account.

The study findings were limited by several factors, including the potential dietary confounders such as total energy intake and the type of chocolate consumed (milk, dark, or white) and the relatively homogeneous study population, which included mainly individuals from Europe and the United States.

Additional long-term, double-blind, randomized trials are needed to identify the cardioprotective effects of chocolate, and “studies to determine the role of genetic potential and the beneficial effects of chocolate on CAD may be needed,” the researchers noted.

However, the current study results suggest that “consumption of chocolates at least once a week is associated with a reduction in the risk of CAD,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Krittanawong C et al. Eur J Prev Cardiol. 2020 Jul 23. doi: 10.1177/2047487320936787.

Adults who ate chocolate more than once a week or more than 3.5 times a month were significantly less likely to develop coronary artery disease than were those who ate less chocolate, according to data from a meta-analysis of more than 300,000 individuals.

Howard Shooter/Thinkstock

Consumption of chocolate has shown beneficial effects on blood pressure and endothelial function, wrote Chayakrit Krittanawong, MD, of Baylor College of Medicine, Houston, and colleagues in the European Journal of Preventive Cardiology. “However, the potential benefit of increased chocolate consumption reducing coronary artery disease (CAD) risk is not known,” they said.

The investigators reviewed data from 5 decades of research, including six studies with a total of 336,289 individuals who reported chocolate consumption. The study participants experienced 14,043 cases of CAD, 4,667 myocardial infarctions, 2,735 cerebrovascular accidents, and 332 cases of heart failure over an average follow-up period of 8.78 years.

Overall, higher chocolate consumption (defined as more than once a week or more than 3.5 times a month) was significantly associated with a decreased CAD risk (pooled risk ratio, 0.94; P < .001) compared to eating no chocolate or eating chocolate less than once a week.

The cardioprotective effects of chocolate may be linked to several nutrients, the researchers noted. Chocolate’s flavenols (epicatechin, catechin, and procyanidins) have demonstrated an ability to reduce myocardial infarct size in an animal study and to reduce platelet aggregation and improve endothelial function in humans with and without CAD. In addition, methylxanthines have demonstrated beneficial effects on cardiovascular function, polyphenols have been shown to facilitate nitric oxide synthesis, and stearic acid has been associated with reduced mean platelet volume, they wrote.

“The benefits of nutrients in chocolate appear promising and chocolate consumption at least once a week may be beneficial for CAD prevention,” the researchers suggested, although they cautioned that the effects of supplemental calories and the impact of fats, milk, and sugar in commercial chocolate must be taken into account.

The study findings were limited by several factors, including the potential dietary confounders such as total energy intake and the type of chocolate consumed (milk, dark, or white) and the relatively homogeneous study population, which included mainly individuals from Europe and the United States.

Additional long-term, double-blind, randomized trials are needed to identify the cardioprotective effects of chocolate, and “studies to determine the role of genetic potential and the beneficial effects of chocolate on CAD may be needed,” the researchers noted.

However, the current study results suggest that “consumption of chocolates at least once a week is associated with a reduction in the risk of CAD,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Krittanawong C et al. Eur J Prev Cardiol. 2020 Jul 23. doi: 10.1177/2047487320936787.

Adults who ate chocolate more than once a week or more than 3.5 times a month were significantly less likely to develop coronary artery disease than were those who ate less chocolate, according to data from a meta-analysis of more than 300,000 individuals.

Howard Shooter/Thinkstock

Consumption of chocolate has shown beneficial effects on blood pressure and endothelial function, wrote Chayakrit Krittanawong, MD, of Baylor College of Medicine, Houston, and colleagues in the European Journal of Preventive Cardiology. “However, the potential benefit of increased chocolate consumption reducing coronary artery disease (CAD) risk is not known,” they said.

The investigators reviewed data from 5 decades of research, including six studies with a total of 336,289 individuals who reported chocolate consumption. The study participants experienced 14,043 cases of CAD, 4,667 myocardial infarctions, 2,735 cerebrovascular accidents, and 332 cases of heart failure over an average follow-up period of 8.78 years.

Overall, higher chocolate consumption (defined as more than once a week or more than 3.5 times a month) was significantly associated with a decreased CAD risk (pooled risk ratio, 0.94; P < .001) compared to eating no chocolate or eating chocolate less than once a week.

The cardioprotective effects of chocolate may be linked to several nutrients, the researchers noted. Chocolate’s flavenols (epicatechin, catechin, and procyanidins) have demonstrated an ability to reduce myocardial infarct size in an animal study and to reduce platelet aggregation and improve endothelial function in humans with and without CAD. In addition, methylxanthines have demonstrated beneficial effects on cardiovascular function, polyphenols have been shown to facilitate nitric oxide synthesis, and stearic acid has been associated with reduced mean platelet volume, they wrote.

“The benefits of nutrients in chocolate appear promising and chocolate consumption at least once a week may be beneficial for CAD prevention,” the researchers suggested, although they cautioned that the effects of supplemental calories and the impact of fats, milk, and sugar in commercial chocolate must be taken into account.

The study findings were limited by several factors, including the potential dietary confounders such as total energy intake and the type of chocolate consumed (milk, dark, or white) and the relatively homogeneous study population, which included mainly individuals from Europe and the United States.

Additional long-term, double-blind, randomized trials are needed to identify the cardioprotective effects of chocolate, and “studies to determine the role of genetic potential and the beneficial effects of chocolate on CAD may be needed,” the researchers noted.

However, the current study results suggest that “consumption of chocolates at least once a week is associated with a reduction in the risk of CAD,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Krittanawong C et al. Eur J Prev Cardiol. 2020 Jul 23. doi: 10.1177/2047487320936787.