Cardiology

Screening for atrial fibrillation with wearable devices is cost effective, when compared with either no screening or screening using traditional methods, a new study concludes.

“Undiagnosed atrial fibrillation (AFib) is an important cause of stroke. Screening for AFib using wrist-worn wearable devices may prevent strokes, but their cost effectiveness is unknown,” write Wanyi Chen, PhD, from Massachusetts General Hospital, Boston, and colleagues, in JAMA Health Forum.

The investigators used a microsimulation decision-analytic model to evaluate the cost effectiveness of these devices to screen for undiagnosed AFib.

The model comprised 30 million simulated individuals with an age, sex, and comorbidity profile matching the United States population aged 65 years or older.

The model looked at eight AFib screening strategies: six using wrist-worn wearable devices (either watch or band photoplethysmography with or without watch or band electrocardiography) and two using traditional modalities (that is, pulse palpation and 12-lead electrocardiogram) versus no screening.

The primary outcome was the incremental cost effectiveness ratio, defined as U.S. dollars per quality-adjusted life-year (QALY). Secondary outcomes included rates of stroke and major bleeding.

In the model, the mean age was 72.5 years and 50% were women.

All 6 screening strategies using wrist-worn wearable devices were estimated to be more cost effective than no screening. The model showed that the range of QALYs gained, compared with no screening, was 226 to 957 per 100,000 individuals.

The wrist-worn devices were also associated with greater relative benefit than screening using traditional modalities, as the range of QALYs gained, compared with no screening, was –116 to 93 per 100,000 individuals.

Compared with no screening, screening with wrist-worn wearable devices was associated with a reduction in stroke incidence by 20 to 23 per 100,000 person-years but an increase in major bleeding by 20 to 44 per 100,000 person years.

Overall, the preferred strategy for screening was wearable photoplethysmography, followed by wearable electrocardiography with patch monitor confirmation. This strategy had an incremental cost effectiveness ratio of $57,894 per QALY, “meeting the acceptability threshold of $100,000 per QALY,” the authors write.

The cost effectiveness of screening was consistent across multiple clinically relevant scenarios, including screening a general population aged 50 years or older with risk factors for stroke, the authors report.

“When deployed within specific AFib screening pathways, wearable devices are likely to be an important component of cost-effective AFib screening,” the investigators conclude.

Study based on modeled data

“This study is the first simulation of various screening strategies for atrial fibrillation using wearable devices and suggests that wearable devices, in particular wrist-worn wearables, in an elderly population, [are] estimated to be cost-effective,” Emma Svennberg, MD, PhD, from the Karolinska University Hospital, Stockholm, told this news organization.

“I find this study interesting, as the adoption of wearables amongst individuals is high and increasing, hence many wearers will screen themselves for arrhythmias (even if health care recommendations are discordant), and the potential costs for society have been unknown,” said Dr. Svennberg, who was not part of this study.

“Of course, no study is without its flaws, and here one must note that the study is based on modeled data alone and not RCTs of the wearable screening strategies ... hence true clinical outcome data is missing,” Dr. Svennberg added.

The large STROKESTOP study, on which she was the lead investigator, “presented data based on true clinical outcomes at ESC 2021 (European Society of Cardiology) and showed cost effectiveness,” Dr. Svennberg said.

The study authors report financial relationships with Bristol Myers Squibb, Fitbit, Medtronic, Pfizer, UpToDate, American Heart Association, IBM, Bayer AG, Novartis, MyoKardia, Boehringer Ingelheim, Heart Rhythm Society, Avania Consulting, Apple, Premier, the National Institutes of Health, Invitae, Blackstone Life Sciences, Flatiron, and Value Analytics Labs. Dr. Svennberg reports no relevant financial relationships.

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

Screening for atrial fibrillation with wearable devices is cost effective, when compared with either no screening or screening using traditional methods, a new study concludes.

“Undiagnosed atrial fibrillation (AFib) is an important cause of stroke. Screening for AFib using wrist-worn wearable devices may prevent strokes, but their cost effectiveness is unknown,” write Wanyi Chen, PhD, from Massachusetts General Hospital, Boston, and colleagues, in JAMA Health Forum.

The investigators used a microsimulation decision-analytic model to evaluate the cost effectiveness of these devices to screen for undiagnosed AFib.

The model comprised 30 million simulated individuals with an age, sex, and comorbidity profile matching the United States population aged 65 years or older.

The model looked at eight AFib screening strategies: six using wrist-worn wearable devices (either watch or band photoplethysmography with or without watch or band electrocardiography) and two using traditional modalities (that is, pulse palpation and 12-lead electrocardiogram) versus no screening.

The primary outcome was the incremental cost effectiveness ratio, defined as U.S. dollars per quality-adjusted life-year (QALY). Secondary outcomes included rates of stroke and major bleeding.

In the model, the mean age was 72.5 years and 50% were women.

All 6 screening strategies using wrist-worn wearable devices were estimated to be more cost effective than no screening. The model showed that the range of QALYs gained, compared with no screening, was 226 to 957 per 100,000 individuals.

The wrist-worn devices were also associated with greater relative benefit than screening using traditional modalities, as the range of QALYs gained, compared with no screening, was –116 to 93 per 100,000 individuals.

Compared with no screening, screening with wrist-worn wearable devices was associated with a reduction in stroke incidence by 20 to 23 per 100,000 person-years but an increase in major bleeding by 20 to 44 per 100,000 person years.

Overall, the preferred strategy for screening was wearable photoplethysmography, followed by wearable electrocardiography with patch monitor confirmation. This strategy had an incremental cost effectiveness ratio of $57,894 per QALY, “meeting the acceptability threshold of $100,000 per QALY,” the authors write.

The cost effectiveness of screening was consistent across multiple clinically relevant scenarios, including screening a general population aged 50 years or older with risk factors for stroke, the authors report.

“When deployed within specific AFib screening pathways, wearable devices are likely to be an important component of cost-effective AFib screening,” the investigators conclude.

Study based on modeled data

“This study is the first simulation of various screening strategies for atrial fibrillation using wearable devices and suggests that wearable devices, in particular wrist-worn wearables, in an elderly population, [are] estimated to be cost-effective,” Emma Svennberg, MD, PhD, from the Karolinska University Hospital, Stockholm, told this news organization.

“I find this study interesting, as the adoption of wearables amongst individuals is high and increasing, hence many wearers will screen themselves for arrhythmias (even if health care recommendations are discordant), and the potential costs for society have been unknown,” said Dr. Svennberg, who was not part of this study.

“Of course, no study is without its flaws, and here one must note that the study is based on modeled data alone and not RCTs of the wearable screening strategies ... hence true clinical outcome data is missing,” Dr. Svennberg added.

The large STROKESTOP study, on which she was the lead investigator, “presented data based on true clinical outcomes at ESC 2021 (European Society of Cardiology) and showed cost effectiveness,” Dr. Svennberg said.

The study authors report financial relationships with Bristol Myers Squibb, Fitbit, Medtronic, Pfizer, UpToDate, American Heart Association, IBM, Bayer AG, Novartis, MyoKardia, Boehringer Ingelheim, Heart Rhythm Society, Avania Consulting, Apple, Premier, the National Institutes of Health, Invitae, Blackstone Life Sciences, Flatiron, and Value Analytics Labs. Dr. Svennberg reports no relevant financial relationships.

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

Screening for atrial fibrillation with wearable devices is cost effective, when compared with either no screening or screening using traditional methods, a new study concludes.

“Undiagnosed atrial fibrillation (AFib) is an important cause of stroke. Screening for AFib using wrist-worn wearable devices may prevent strokes, but their cost effectiveness is unknown,” write Wanyi Chen, PhD, from Massachusetts General Hospital, Boston, and colleagues, in JAMA Health Forum.

The investigators used a microsimulation decision-analytic model to evaluate the cost effectiveness of these devices to screen for undiagnosed AFib.

The model comprised 30 million simulated individuals with an age, sex, and comorbidity profile matching the United States population aged 65 years or older.

The model looked at eight AFib screening strategies: six using wrist-worn wearable devices (either watch or band photoplethysmography with or without watch or band electrocardiography) and two using traditional modalities (that is, pulse palpation and 12-lead electrocardiogram) versus no screening.

The primary outcome was the incremental cost effectiveness ratio, defined as U.S. dollars per quality-adjusted life-year (QALY). Secondary outcomes included rates of stroke and major bleeding.

In the model, the mean age was 72.5 years and 50% were women.

All 6 screening strategies using wrist-worn wearable devices were estimated to be more cost effective than no screening. The model showed that the range of QALYs gained, compared with no screening, was 226 to 957 per 100,000 individuals.

The wrist-worn devices were also associated with greater relative benefit than screening using traditional modalities, as the range of QALYs gained, compared with no screening, was –116 to 93 per 100,000 individuals.

Compared with no screening, screening with wrist-worn wearable devices was associated with a reduction in stroke incidence by 20 to 23 per 100,000 person-years but an increase in major bleeding by 20 to 44 per 100,000 person years.

Overall, the preferred strategy for screening was wearable photoplethysmography, followed by wearable electrocardiography with patch monitor confirmation. This strategy had an incremental cost effectiveness ratio of $57,894 per QALY, “meeting the acceptability threshold of $100,000 per QALY,” the authors write.

The cost effectiveness of screening was consistent across multiple clinically relevant scenarios, including screening a general population aged 50 years or older with risk factors for stroke, the authors report.

“When deployed within specific AFib screening pathways, wearable devices are likely to be an important component of cost-effective AFib screening,” the investigators conclude.

Study based on modeled data

“This study is the first simulation of various screening strategies for atrial fibrillation using wearable devices and suggests that wearable devices, in particular wrist-worn wearables, in an elderly population, [are] estimated to be cost-effective,” Emma Svennberg, MD, PhD, from the Karolinska University Hospital, Stockholm, told this news organization.

“I find this study interesting, as the adoption of wearables amongst individuals is high and increasing, hence many wearers will screen themselves for arrhythmias (even if health care recommendations are discordant), and the potential costs for society have been unknown,” said Dr. Svennberg, who was not part of this study.

“Of course, no study is without its flaws, and here one must note that the study is based on modeled data alone and not RCTs of the wearable screening strategies ... hence true clinical outcome data is missing,” Dr. Svennberg added.

The large STROKESTOP study, on which she was the lead investigator, “presented data based on true clinical outcomes at ESC 2021 (European Society of Cardiology) and showed cost effectiveness,” Dr. Svennberg said.

The study authors report financial relationships with Bristol Myers Squibb, Fitbit, Medtronic, Pfizer, UpToDate, American Heart Association, IBM, Bayer AG, Novartis, MyoKardia, Boehringer Ingelheim, Heart Rhythm Society, Avania Consulting, Apple, Premier, the National Institutes of Health, Invitae, Blackstone Life Sciences, Flatiron, and Value Analytics Labs. Dr. Svennberg reports no relevant financial relationships.

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

Dietary salt substitutes not only lower blood pressure but also have a clear impact on hard clinical endpoints, lowering the risk of myocardial infarction (MI), stroke, and death from all causes and cardiovascular disease (CVD), a meta-analysis shows.

jirkaejc/Getty Images

The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.

“These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure, and prevent major cardiovascular events,” they write.

The study was published online  in Heart.
 

Strong support for landmark study

In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. They are known to help lower blood pressure, but less is known about their impact on hard clinical endpoints, Maoyi Tian, PhD, with Harbin Medical University, China, and the George Institute for Global Health, Sydney, and colleagues note in their article.

In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk of MI, stroke, and early death, as reported previously by this news organization.

But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.

To investigate, Dr. Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.

A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% confidence interval, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).

The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.

Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P = .045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P = .025) greater reduction in DBP.

Reductions in blood pressure appeared consistent, irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.

Clear benefit on hard outcomes

Pooled data on clinical outcomes from five trials that included 24,306 participants, mostly from the SSaSS, showed clear protective effects of salt substitutes on total mortality (risk ratio, 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).

Dr. Tian and colleagues say that “broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalemia in this review.”

They note, however, that all of the trials took “pragmatic steps to exclude participants at elevated risk of hyperkalemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium.”

Offering perspective on the study, Harlan Krumholz, MD, with Yale New Haven Hospital and Yale School of Medicine, both in New Haven, Conn., said it provides “useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context.”

Dr. Krumholz said that at this point, he thinks salt substitutes “could be included in recommendations to patients.”

“SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement,” Dr. Krumholz told this news organization.

Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, agrees that in the absence of contraindications, salt substitutes should be recommended.

“Americans put salt on everything and don’t even think about it. The salt substitutes are very helpful,” Dr. Contreras said in an interview.

“People who don’t have high blood pressure should limit salt intake, because what we have seen is that if you have high blood pressure in your family – even if you don’t have high blood pressure in your 20s or 30s – you’re likely to develop high blood pressure,” Dr. Contreras said.

“Therefore, it’s wise early on to start protecting yourself and using low salt and salt substitutes,” she added.

The study had no specific funding. Dr. Tian, Dr. Krumholz, and Dr. Contreras have disclosed no relevant financial relationships.

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

Dietary salt substitutes not only lower blood pressure but also have a clear impact on hard clinical endpoints, lowering the risk of myocardial infarction (MI), stroke, and death from all causes and cardiovascular disease (CVD), a meta-analysis shows.

jirkaejc/Getty Images

The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.

“These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure, and prevent major cardiovascular events,” they write.

The study was published online  in Heart.
 

Strong support for landmark study

In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. They are known to help lower blood pressure, but less is known about their impact on hard clinical endpoints, Maoyi Tian, PhD, with Harbin Medical University, China, and the George Institute for Global Health, Sydney, and colleagues note in their article.

In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk of MI, stroke, and early death, as reported previously by this news organization.

But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.

To investigate, Dr. Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.

A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% confidence interval, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).

The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.

Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P = .045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P = .025) greater reduction in DBP.

Reductions in blood pressure appeared consistent, irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.

Clear benefit on hard outcomes

Pooled data on clinical outcomes from five trials that included 24,306 participants, mostly from the SSaSS, showed clear protective effects of salt substitutes on total mortality (risk ratio, 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).

Dr. Tian and colleagues say that “broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalemia in this review.”

They note, however, that all of the trials took “pragmatic steps to exclude participants at elevated risk of hyperkalemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium.”

Offering perspective on the study, Harlan Krumholz, MD, with Yale New Haven Hospital and Yale School of Medicine, both in New Haven, Conn., said it provides “useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context.”

Dr. Krumholz said that at this point, he thinks salt substitutes “could be included in recommendations to patients.”

“SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement,” Dr. Krumholz told this news organization.

Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, agrees that in the absence of contraindications, salt substitutes should be recommended.

“Americans put salt on everything and don’t even think about it. The salt substitutes are very helpful,” Dr. Contreras said in an interview.

“People who don’t have high blood pressure should limit salt intake, because what we have seen is that if you have high blood pressure in your family – even if you don’t have high blood pressure in your 20s or 30s – you’re likely to develop high blood pressure,” Dr. Contreras said.

“Therefore, it’s wise early on to start protecting yourself and using low salt and salt substitutes,” she added.

The study had no specific funding. Dr. Tian, Dr. Krumholz, and Dr. Contreras have disclosed no relevant financial relationships.

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

Dietary salt substitutes not only lower blood pressure but also have a clear impact on hard clinical endpoints, lowering the risk of myocardial infarction (MI), stroke, and death from all causes and cardiovascular disease (CVD), a meta-analysis shows.

jirkaejc/Getty Images

The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.

“These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure, and prevent major cardiovascular events,” they write.

The study was published online  in Heart.
 

Strong support for landmark study

In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. They are known to help lower blood pressure, but less is known about their impact on hard clinical endpoints, Maoyi Tian, PhD, with Harbin Medical University, China, and the George Institute for Global Health, Sydney, and colleagues note in their article.

In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk of MI, stroke, and early death, as reported previously by this news organization.

But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.

To investigate, Dr. Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.

A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% confidence interval, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).

The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.

Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P = .045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P = .025) greater reduction in DBP.

Reductions in blood pressure appeared consistent, irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.

Clear benefit on hard outcomes

Pooled data on clinical outcomes from five trials that included 24,306 participants, mostly from the SSaSS, showed clear protective effects of salt substitutes on total mortality (risk ratio, 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).

Dr. Tian and colleagues say that “broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalemia in this review.”

They note, however, that all of the trials took “pragmatic steps to exclude participants at elevated risk of hyperkalemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium.”

Offering perspective on the study, Harlan Krumholz, MD, with Yale New Haven Hospital and Yale School of Medicine, both in New Haven, Conn., said it provides “useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context.”

Dr. Krumholz said that at this point, he thinks salt substitutes “could be included in recommendations to patients.”

“SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement,” Dr. Krumholz told this news organization.

Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, agrees that in the absence of contraindications, salt substitutes should be recommended.

“Americans put salt on everything and don’t even think about it. The salt substitutes are very helpful,” Dr. Contreras said in an interview.

“People who don’t have high blood pressure should limit salt intake, because what we have seen is that if you have high blood pressure in your family – even if you don’t have high blood pressure in your 20s or 30s – you’re likely to develop high blood pressure,” Dr. Contreras said.

“Therefore, it’s wise early on to start protecting yourself and using low salt and salt substitutes,” she added.

The study had no specific funding. Dr. Tian, Dr. Krumholz, and Dr. Contreras have disclosed no relevant financial relationships.

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

Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations. 

In this issue:

• Vaccinations
• Mental Health and Related Disorders
• LGBTQ+ Veterans
• Military Sexual Trauma
• Sleep Disorders
• Respiratory Illnesses
• HIV Care in the VA
• Rheumatologic Diseases
• The Cancer-Obesity Connection
• Skin Health for Active-Duty Personnel
• Contraception
• Chronic Kidney Disease
• Cardiovascular Diseases
• Neurologic Disorders
• Hearing, Vision, and Balance

Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue: 

Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN

Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations. 

In this issue:

• Vaccinations
• Mental Health and Related Disorders
• LGBTQ+ Veterans
• Military Sexual Trauma
• Sleep Disorders
• Respiratory Illnesses
• HIV Care in the VA
• Rheumatologic Diseases
• The Cancer-Obesity Connection
• Skin Health for Active-Duty Personnel
• Contraception
• Chronic Kidney Disease
• Cardiovascular Diseases
• Neurologic Disorders
• Hearing, Vision, and Balance

Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue: 

Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN

Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations. 

In this issue:

• Vaccinations
• Mental Health and Related Disorders
• LGBTQ+ Veterans
• Military Sexual Trauma
• Sleep Disorders
• Respiratory Illnesses
• HIV Care in the VA
• Rheumatologic Diseases
• The Cancer-Obesity Connection
• Skin Health for Active-Duty Personnel
• Contraception
• Chronic Kidney Disease
• Cardiovascular Diseases
• Neurologic Disorders
• Hearing, Vision, and Balance

Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue: 

Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN

Cardiorespiratory fitness emerged as a stronger predictor of all-cause mortality than did any traditional risk factor across the spectrum of age, sex, and race in a modeling study that included more than 750,000 U.S. veterans.

In addition, mortality risk was cut in half if individuals achieved a moderate cardiorespiratory fitness (CRF) level – that is, by meeting the current U.S. physical activity recommendations of 150 minutes per week, the authors note.

Furthermore, contrary to some previous research, “extremely high” fitness was not associated with an increased risk for mortality in the study, published online in the Journal of the American College of Cardiology.

“This study has been 15 years in the making,” lead author Peter Kokkinos, PhD, Rutgers University, New Brunswick, N.J., and the VA Medical Center, Washington, told this news organization. “We waited until we had the computer power and the right people to really assess this. We wanted to be very liberal in excluding patients we thought might contaminate the results, such as those with cardiovascular disease in the 6 months prior to a stress test.”

Figuring the time was right, the team analyzed data from the VA’s Exercise Testing and Health Outcomes Study (ETHOS) on individuals aged 30-95 years who underwent exercise treadmill tests between 1999 and 2020.

After exclusions, 750,302 individuals (from among 822,995) were included: 6.5% were women; 73.7% were White individuals; 19% were African American individuals; 4.7% were Hispanic individuals; and 2.1% were Native American, Asian, or Hawaiian individuals. Septuagenarians made up 14.7% of the cohort, and octogenarians made up 3.6%.

CRF categories for age and sex were determined by the peak metabolic equivalent of task (MET) achieved during the treadmill test. One MET is the energy spent at rest – that is the basal metabolic rate.

Although some physicians may resist putting patients through a stress test, “the amount of information we get from it is incredible,” Dr. Kokkinos noted. “We get blood pressure, we get heart rate, we get a response if you’re not doing exercise. This tells us a lot more than having you sit around so we can measure resting heart rate and blood pressure.”

Lowest mortality at 14.0 METs

During a median follow-up of 10.2 years (7,803,861 person-years), 23% of participants died, for an average of 22.4 events per 1,000 person-years.

Higher exercise capacity was inversely related to mortality risk across the cohort and within each age category. Specifically, every 1 MET increase in exercise capacity yielded an adjusted hazard ratio for mortality of 0.86 (95% confidence interval, 0.85-0.87; P < .001) for the entire cohort and similar HRs by sex and race.

The mortality risk for the least-fit individuals (20th percentile) was fourfold higher than for extremely fit individuals (HR, 4.09; 95% CI, 3.90-4.20), with the lowest mortality risk at about 14.0 METs for both men (HR, 0.24; 95% CI, 0.23-0.25) and women (HR, 0.23; 95% CI, 0.17-0.29). Extremely high CRF did not increase the risk.

In addition, at 20 years of follow-up, about 80% of men and 95% of women in the highest CRF category (98th percentile) were alive vs. less than 40% of men and approximately 75% of women in the least fit CRF category.

“We know CRF declines by 1% per year after age 30,” Dr. Kokkinos said. “But the age-related decline is cut in half if you are fit, meaning that an expected 10% decline over a decade will be only a 5% decline if you stay active. We cannot stop or reverse the decline, but we can kind of put the brakes on, and that’s a reason for clinicians to continue to encourage fitness.” 

Indeed, “improving CRF should be considered a target in CVD prevention, similar to improving lipids, blood sugar, blood pressure, and weight,” Carl J. Lavie, MD, Ochsner Health, New Orleans, and colleagues affirm in a related editorial.
 

‘A difficult battle’

But that may not happen any time soon. “Unfortunately, despite having been recognized in an American Heart Association scientific statement as a clinical vital sign, aerobic fitness is undervalued and underutilized,” Claudio Gil Araújo, MD, PhD, research director of the Exercise Medicine Clinic-CLINIMEX, Rio de Janeiro, told this news organization.

Dr. Araújo led a recent study showing that the ability to stand on one leg for at least 10 seconds is strongly linked to the risk for death over the next 7 years.

Although physicians should be encouraging fitness, he said that “a substantial part of health professionals are physically unfit and feel uncomfortable talking about and prescribing exercise for their patients. Also, physicians tend to be better trained in treating diseases (using medications and/or prescribing procedures) than in preventing diseases by stimulating adoption of healthy habits. So, this a long road and a difficult battle.”

Nonetheless, he added, “Darwin said a long time ago that only the fittest will survive. If Darwin could read this study, he would surely smile.”

No commercial funding or conflicts of interest related to the study were reported. Dr. Lavie previously served as a speaker and consultant for PAI Health on their PAI (Personalized Activity Intelligence) applications.

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

Cardiorespiratory fitness emerged as a stronger predictor of all-cause mortality than did any traditional risk factor across the spectrum of age, sex, and race in a modeling study that included more than 750,000 U.S. veterans.

In addition, mortality risk was cut in half if individuals achieved a moderate cardiorespiratory fitness (CRF) level – that is, by meeting the current U.S. physical activity recommendations of 150 minutes per week, the authors note.

Furthermore, contrary to some previous research, “extremely high” fitness was not associated with an increased risk for mortality in the study, published online in the Journal of the American College of Cardiology.

“This study has been 15 years in the making,” lead author Peter Kokkinos, PhD, Rutgers University, New Brunswick, N.J., and the VA Medical Center, Washington, told this news organization. “We waited until we had the computer power and the right people to really assess this. We wanted to be very liberal in excluding patients we thought might contaminate the results, such as those with cardiovascular disease in the 6 months prior to a stress test.”

Figuring the time was right, the team analyzed data from the VA’s Exercise Testing and Health Outcomes Study (ETHOS) on individuals aged 30-95 years who underwent exercise treadmill tests between 1999 and 2020.

After exclusions, 750,302 individuals (from among 822,995) were included: 6.5% were women; 73.7% were White individuals; 19% were African American individuals; 4.7% were Hispanic individuals; and 2.1% were Native American, Asian, or Hawaiian individuals. Septuagenarians made up 14.7% of the cohort, and octogenarians made up 3.6%.

CRF categories for age and sex were determined by the peak metabolic equivalent of task (MET) achieved during the treadmill test. One MET is the energy spent at rest – that is the basal metabolic rate.

Although some physicians may resist putting patients through a stress test, “the amount of information we get from it is incredible,” Dr. Kokkinos noted. “We get blood pressure, we get heart rate, we get a response if you’re not doing exercise. This tells us a lot more than having you sit around so we can measure resting heart rate and blood pressure.”

Lowest mortality at 14.0 METs

During a median follow-up of 10.2 years (7,803,861 person-years), 23% of participants died, for an average of 22.4 events per 1,000 person-years.

Higher exercise capacity was inversely related to mortality risk across the cohort and within each age category. Specifically, every 1 MET increase in exercise capacity yielded an adjusted hazard ratio for mortality of 0.86 (95% confidence interval, 0.85-0.87; P < .001) for the entire cohort and similar HRs by sex and race.

The mortality risk for the least-fit individuals (20th percentile) was fourfold higher than for extremely fit individuals (HR, 4.09; 95% CI, 3.90-4.20), with the lowest mortality risk at about 14.0 METs for both men (HR, 0.24; 95% CI, 0.23-0.25) and women (HR, 0.23; 95% CI, 0.17-0.29). Extremely high CRF did not increase the risk.

In addition, at 20 years of follow-up, about 80% of men and 95% of women in the highest CRF category (98th percentile) were alive vs. less than 40% of men and approximately 75% of women in the least fit CRF category.

“We know CRF declines by 1% per year after age 30,” Dr. Kokkinos said. “But the age-related decline is cut in half if you are fit, meaning that an expected 10% decline over a decade will be only a 5% decline if you stay active. We cannot stop or reverse the decline, but we can kind of put the brakes on, and that’s a reason for clinicians to continue to encourage fitness.” 

Indeed, “improving CRF should be considered a target in CVD prevention, similar to improving lipids, blood sugar, blood pressure, and weight,” Carl J. Lavie, MD, Ochsner Health, New Orleans, and colleagues affirm in a related editorial.
 

‘A difficult battle’

But that may not happen any time soon. “Unfortunately, despite having been recognized in an American Heart Association scientific statement as a clinical vital sign, aerobic fitness is undervalued and underutilized,” Claudio Gil Araújo, MD, PhD, research director of the Exercise Medicine Clinic-CLINIMEX, Rio de Janeiro, told this news organization.

Dr. Araújo led a recent study showing that the ability to stand on one leg for at least 10 seconds is strongly linked to the risk for death over the next 7 years.

Although physicians should be encouraging fitness, he said that “a substantial part of health professionals are physically unfit and feel uncomfortable talking about and prescribing exercise for their patients. Also, physicians tend to be better trained in treating diseases (using medications and/or prescribing procedures) than in preventing diseases by stimulating adoption of healthy habits. So, this a long road and a difficult battle.”

Nonetheless, he added, “Darwin said a long time ago that only the fittest will survive. If Darwin could read this study, he would surely smile.”

No commercial funding or conflicts of interest related to the study were reported. Dr. Lavie previously served as a speaker and consultant for PAI Health on their PAI (Personalized Activity Intelligence) applications.

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

Cardiorespiratory fitness emerged as a stronger predictor of all-cause mortality than did any traditional risk factor across the spectrum of age, sex, and race in a modeling study that included more than 750,000 U.S. veterans.

In addition, mortality risk was cut in half if individuals achieved a moderate cardiorespiratory fitness (CRF) level – that is, by meeting the current U.S. physical activity recommendations of 150 minutes per week, the authors note.

Furthermore, contrary to some previous research, “extremely high” fitness was not associated with an increased risk for mortality in the study, published online in the Journal of the American College of Cardiology.

“This study has been 15 years in the making,” lead author Peter Kokkinos, PhD, Rutgers University, New Brunswick, N.J., and the VA Medical Center, Washington, told this news organization. “We waited until we had the computer power and the right people to really assess this. We wanted to be very liberal in excluding patients we thought might contaminate the results, such as those with cardiovascular disease in the 6 months prior to a stress test.”

Figuring the time was right, the team analyzed data from the VA’s Exercise Testing and Health Outcomes Study (ETHOS) on individuals aged 30-95 years who underwent exercise treadmill tests between 1999 and 2020.

After exclusions, 750,302 individuals (from among 822,995) were included: 6.5% were women; 73.7% were White individuals; 19% were African American individuals; 4.7% were Hispanic individuals; and 2.1% were Native American, Asian, or Hawaiian individuals. Septuagenarians made up 14.7% of the cohort, and octogenarians made up 3.6%.

CRF categories for age and sex were determined by the peak metabolic equivalent of task (MET) achieved during the treadmill test. One MET is the energy spent at rest – that is the basal metabolic rate.

Although some physicians may resist putting patients through a stress test, “the amount of information we get from it is incredible,” Dr. Kokkinos noted. “We get blood pressure, we get heart rate, we get a response if you’re not doing exercise. This tells us a lot more than having you sit around so we can measure resting heart rate and blood pressure.”

Lowest mortality at 14.0 METs

During a median follow-up of 10.2 years (7,803,861 person-years), 23% of participants died, for an average of 22.4 events per 1,000 person-years.

Higher exercise capacity was inversely related to mortality risk across the cohort and within each age category. Specifically, every 1 MET increase in exercise capacity yielded an adjusted hazard ratio for mortality of 0.86 (95% confidence interval, 0.85-0.87; P < .001) for the entire cohort and similar HRs by sex and race.

The mortality risk for the least-fit individuals (20th percentile) was fourfold higher than for extremely fit individuals (HR, 4.09; 95% CI, 3.90-4.20), with the lowest mortality risk at about 14.0 METs for both men (HR, 0.24; 95% CI, 0.23-0.25) and women (HR, 0.23; 95% CI, 0.17-0.29). Extremely high CRF did not increase the risk.

In addition, at 20 years of follow-up, about 80% of men and 95% of women in the highest CRF category (98th percentile) were alive vs. less than 40% of men and approximately 75% of women in the least fit CRF category.

“We know CRF declines by 1% per year after age 30,” Dr. Kokkinos said. “But the age-related decline is cut in half if you are fit, meaning that an expected 10% decline over a decade will be only a 5% decline if you stay active. We cannot stop or reverse the decline, but we can kind of put the brakes on, and that’s a reason for clinicians to continue to encourage fitness.” 

Indeed, “improving CRF should be considered a target in CVD prevention, similar to improving lipids, blood sugar, blood pressure, and weight,” Carl J. Lavie, MD, Ochsner Health, New Orleans, and colleagues affirm in a related editorial.
 

‘A difficult battle’

But that may not happen any time soon. “Unfortunately, despite having been recognized in an American Heart Association scientific statement as a clinical vital sign, aerobic fitness is undervalued and underutilized,” Claudio Gil Araújo, MD, PhD, research director of the Exercise Medicine Clinic-CLINIMEX, Rio de Janeiro, told this news organization.

Dr. Araújo led a recent study showing that the ability to stand on one leg for at least 10 seconds is strongly linked to the risk for death over the next 7 years.

Although physicians should be encouraging fitness, he said that “a substantial part of health professionals are physically unfit and feel uncomfortable talking about and prescribing exercise for their patients. Also, physicians tend to be better trained in treating diseases (using medications and/or prescribing procedures) than in preventing diseases by stimulating adoption of healthy habits. So, this a long road and a difficult battle.”

Nonetheless, he added, “Darwin said a long time ago that only the fittest will survive. If Darwin could read this study, he would surely smile.”

No commercial funding or conflicts of interest related to the study were reported. Dr. Lavie previously served as a speaker and consultant for PAI Health on their PAI (Personalized Activity Intelligence) applications.

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

The risk of developing incident heart failure is 1.5-times higher in people with nonalcoholic fatty liver disease (NAFLD) during a median follow-up of 10 years, according to a new meta-analysis.

The risk appears to increase with greater liver disease severity and was independent of age, sex, ethnicity, obesity, and the presence of diabetes, hypertension, and other common cardiovascular risk factors.

“Health care professionals should be aware that the risk of new-onset heart failure is moderately higher in patients with NAFLD,” senior author Giovanni Targher, MD, said in an interview.

“Because of the link between the two conditions, more careful surveillance of these patients will be needed,” said Dr. Targher, who is an associate professor of diabetes and endocrinology at the University of Verona (Italy). “In particular, the results of this meta-analysis highlight the need for a patient-centered, multidisciplinary, and holistic approach to manage both liver disease and cardiovascular risk in patients with NAFLD.”

The study was published online in Gut.
 

Risk calculations

NAFLD has become one of the most common causes of chronic liver disease worldwide (affecting up to about 30% of the world’s adults), and is expected to rise sharply in the next decade, the study authors write. The disease is linked with liver-related conditions, such as nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, as well as complications in other organs.

Previous meta-analyses have found an association between NAFLD and a higher risk of heart failure, though the analyses included a relatively small number of studies and a relatively modest sample size, Dr. Targher and colleagues write.

Since then, several new cohort studies have examined the association, which inspired a new meta-analysis.

The research team analyzed 11 observational cohort studies with aggregate data on more than 11 million middle-aged people from different countries, including nearly 3 million with NAFLD and nearly 98,000 cases of incident heart failure over a median follow-up of 10 years.

In the studies, NAFLD was diagnosed by serum liver enzyme levels, serum biomarkers or scores, diagnostic codes, imaging techniques, or liver histology. Four studies were conducted in the United States, three were conducted in South Korea, and four were carried out in Europe, including Finland, Sweden, and the United Kingdom.

Dr. Targher and colleagues found that the presence of NAFLD was associated with a moderately higher risk of new-onset heart failure, with a pooled random-effects hazard ratio of 1.5. The risk was independent of age, sex, ethnicity, adiposity measures, diabetes, hypertension, and other typical cardiovascular risk factors.

The association between NAFLD and heart failure risk was consistent even when the comparison was stratified by study country, follow-up length, modality of heart failure diagnosis, and modality of NAFLD diagnosis.

In addition, sensitivity analyses didn’t change the results, and a funnel plot suggested that publication bias was unlikely.

“Accumulating evidence supports that NAFLD is part of a multisystem disease that adversely affects several extrahepatic organs, including the heart,” Dr. Targher said.

“NAFLD not only promotes accelerated coronary atherosclerosis but also confers a higher risk of myocardial abnormalities (cardiac remodeling and hypertrophy) and certain arrhythmias (mostly atrial fibrillation), which may precede and promote the development of new-onset heart failure over time,” he said.
 

Future research

Dr. Targher and colleagues also found that the risk of incident heart failure appeared to further increase with more advanced liver disease, particularly with higher levels of liver fibrosis, as assessed by noninvasive fibrosis biomarkers or histology. With only two cohort studies that examined the association, the authors judged there was insufficient data available to combine the studies into a meta-analysis.

But the observations are consistent with other recent meta-analyses that reported a significant association between the presence and severity of NAFLD and the risk of developing adverse cardiovascular outcomes, atrial fibrillation, chronic kidney disease, or other non-liver complications.

“It’s reassuring that the observations that have come from single studies hold true when you look at the totality of evidence,” Ambarish Pandey, MD, a cardiologist and assistant professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas, told this news organization.

Dr. Pandey, who wasn’t involved with this study, conducted one of the recent meta-analyses that found a 1.6-times increased risk of heart failure associated with NAFLD, as well as a further increased risk with more advanced liver disease.

Now Dr. Pandey and colleagues are studying the underlying mechanisms for the link between NAFLD and heart failure risk, including cardiac structure and function, biomarkers of injury and stress, and how proportions of liver fat influence risk. Additional studies should investigate whether resolving NAFLD could reduce the risk of heart failure, he said.

“It’s really important to look for patients with NAFLD in primary care and think about cardiovascular disease in our liver patients,” he said. “Early strategies to implement the prevention of heart failure would go a long way in reducing long-term risks for these patients.”

The study authors did not declare a specific grant for this research from any funding agency in the public, commercial, or nonprofit sectors. Dr. Targher and Dr. Pandey report no relevant financial relationships.

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

The risk of developing incident heart failure is 1.5-times higher in people with nonalcoholic fatty liver disease (NAFLD) during a median follow-up of 10 years, according to a new meta-analysis.

The risk appears to increase with greater liver disease severity and was independent of age, sex, ethnicity, obesity, and the presence of diabetes, hypertension, and other common cardiovascular risk factors.

“Health care professionals should be aware that the risk of new-onset heart failure is moderately higher in patients with NAFLD,” senior author Giovanni Targher, MD, said in an interview.

“Because of the link between the two conditions, more careful surveillance of these patients will be needed,” said Dr. Targher, who is an associate professor of diabetes and endocrinology at the University of Verona (Italy). “In particular, the results of this meta-analysis highlight the need for a patient-centered, multidisciplinary, and holistic approach to manage both liver disease and cardiovascular risk in patients with NAFLD.”

The study was published online in Gut.
 

Risk calculations

NAFLD has become one of the most common causes of chronic liver disease worldwide (affecting up to about 30% of the world’s adults), and is expected to rise sharply in the next decade, the study authors write. The disease is linked with liver-related conditions, such as nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, as well as complications in other organs.

Previous meta-analyses have found an association between NAFLD and a higher risk of heart failure, though the analyses included a relatively small number of studies and a relatively modest sample size, Dr. Targher and colleagues write.

Since then, several new cohort studies have examined the association, which inspired a new meta-analysis.

The research team analyzed 11 observational cohort studies with aggregate data on more than 11 million middle-aged people from different countries, including nearly 3 million with NAFLD and nearly 98,000 cases of incident heart failure over a median follow-up of 10 years.

In the studies, NAFLD was diagnosed by serum liver enzyme levels, serum biomarkers or scores, diagnostic codes, imaging techniques, or liver histology. Four studies were conducted in the United States, three were conducted in South Korea, and four were carried out in Europe, including Finland, Sweden, and the United Kingdom.

Dr. Targher and colleagues found that the presence of NAFLD was associated with a moderately higher risk of new-onset heart failure, with a pooled random-effects hazard ratio of 1.5. The risk was independent of age, sex, ethnicity, adiposity measures, diabetes, hypertension, and other typical cardiovascular risk factors.

The association between NAFLD and heart failure risk was consistent even when the comparison was stratified by study country, follow-up length, modality of heart failure diagnosis, and modality of NAFLD diagnosis.

In addition, sensitivity analyses didn’t change the results, and a funnel plot suggested that publication bias was unlikely.

“Accumulating evidence supports that NAFLD is part of a multisystem disease that adversely affects several extrahepatic organs, including the heart,” Dr. Targher said.

“NAFLD not only promotes accelerated coronary atherosclerosis but also confers a higher risk of myocardial abnormalities (cardiac remodeling and hypertrophy) and certain arrhythmias (mostly atrial fibrillation), which may precede and promote the development of new-onset heart failure over time,” he said.
 

Future research

Dr. Targher and colleagues also found that the risk of incident heart failure appeared to further increase with more advanced liver disease, particularly with higher levels of liver fibrosis, as assessed by noninvasive fibrosis biomarkers or histology. With only two cohort studies that examined the association, the authors judged there was insufficient data available to combine the studies into a meta-analysis.

But the observations are consistent with other recent meta-analyses that reported a significant association between the presence and severity of NAFLD and the risk of developing adverse cardiovascular outcomes, atrial fibrillation, chronic kidney disease, or other non-liver complications.

“It’s reassuring that the observations that have come from single studies hold true when you look at the totality of evidence,” Ambarish Pandey, MD, a cardiologist and assistant professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas, told this news organization.

Dr. Pandey, who wasn’t involved with this study, conducted one of the recent meta-analyses that found a 1.6-times increased risk of heart failure associated with NAFLD, as well as a further increased risk with more advanced liver disease.

Now Dr. Pandey and colleagues are studying the underlying mechanisms for the link between NAFLD and heart failure risk, including cardiac structure and function, biomarkers of injury and stress, and how proportions of liver fat influence risk. Additional studies should investigate whether resolving NAFLD could reduce the risk of heart failure, he said.

“It’s really important to look for patients with NAFLD in primary care and think about cardiovascular disease in our liver patients,” he said. “Early strategies to implement the prevention of heart failure would go a long way in reducing long-term risks for these patients.”

The study authors did not declare a specific grant for this research from any funding agency in the public, commercial, or nonprofit sectors. Dr. Targher and Dr. Pandey report no relevant financial relationships.

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

The risk of developing incident heart failure is 1.5-times higher in people with nonalcoholic fatty liver disease (NAFLD) during a median follow-up of 10 years, according to a new meta-analysis.

The risk appears to increase with greater liver disease severity and was independent of age, sex, ethnicity, obesity, and the presence of diabetes, hypertension, and other common cardiovascular risk factors.

“Health care professionals should be aware that the risk of new-onset heart failure is moderately higher in patients with NAFLD,” senior author Giovanni Targher, MD, said in an interview.

“Because of the link between the two conditions, more careful surveillance of these patients will be needed,” said Dr. Targher, who is an associate professor of diabetes and endocrinology at the University of Verona (Italy). “In particular, the results of this meta-analysis highlight the need for a patient-centered, multidisciplinary, and holistic approach to manage both liver disease and cardiovascular risk in patients with NAFLD.”

The study was published online in Gut.
 

Risk calculations

NAFLD has become one of the most common causes of chronic liver disease worldwide (affecting up to about 30% of the world’s adults), and is expected to rise sharply in the next decade, the study authors write. The disease is linked with liver-related conditions, such as nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, as well as complications in other organs.

Previous meta-analyses have found an association between NAFLD and a higher risk of heart failure, though the analyses included a relatively small number of studies and a relatively modest sample size, Dr. Targher and colleagues write.

Since then, several new cohort studies have examined the association, which inspired a new meta-analysis.

The research team analyzed 11 observational cohort studies with aggregate data on more than 11 million middle-aged people from different countries, including nearly 3 million with NAFLD and nearly 98,000 cases of incident heart failure over a median follow-up of 10 years.

In the studies, NAFLD was diagnosed by serum liver enzyme levels, serum biomarkers or scores, diagnostic codes, imaging techniques, or liver histology. Four studies were conducted in the United States, three were conducted in South Korea, and four were carried out in Europe, including Finland, Sweden, and the United Kingdom.

Dr. Targher and colleagues found that the presence of NAFLD was associated with a moderately higher risk of new-onset heart failure, with a pooled random-effects hazard ratio of 1.5. The risk was independent of age, sex, ethnicity, adiposity measures, diabetes, hypertension, and other typical cardiovascular risk factors.

The association between NAFLD and heart failure risk was consistent even when the comparison was stratified by study country, follow-up length, modality of heart failure diagnosis, and modality of NAFLD diagnosis.

In addition, sensitivity analyses didn’t change the results, and a funnel plot suggested that publication bias was unlikely.

“Accumulating evidence supports that NAFLD is part of a multisystem disease that adversely affects several extrahepatic organs, including the heart,” Dr. Targher said.

“NAFLD not only promotes accelerated coronary atherosclerosis but also confers a higher risk of myocardial abnormalities (cardiac remodeling and hypertrophy) and certain arrhythmias (mostly atrial fibrillation), which may precede and promote the development of new-onset heart failure over time,” he said.
 

Future research

Dr. Targher and colleagues also found that the risk of incident heart failure appeared to further increase with more advanced liver disease, particularly with higher levels of liver fibrosis, as assessed by noninvasive fibrosis biomarkers or histology. With only two cohort studies that examined the association, the authors judged there was insufficient data available to combine the studies into a meta-analysis.

But the observations are consistent with other recent meta-analyses that reported a significant association between the presence and severity of NAFLD and the risk of developing adverse cardiovascular outcomes, atrial fibrillation, chronic kidney disease, or other non-liver complications.

“It’s reassuring that the observations that have come from single studies hold true when you look at the totality of evidence,” Ambarish Pandey, MD, a cardiologist and assistant professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas, told this news organization.

Dr. Pandey, who wasn’t involved with this study, conducted one of the recent meta-analyses that found a 1.6-times increased risk of heart failure associated with NAFLD, as well as a further increased risk with more advanced liver disease.

Now Dr. Pandey and colleagues are studying the underlying mechanisms for the link between NAFLD and heart failure risk, including cardiac structure and function, biomarkers of injury and stress, and how proportions of liver fat influence risk. Additional studies should investigate whether resolving NAFLD could reduce the risk of heart failure, he said.

“It’s really important to look for patients with NAFLD in primary care and think about cardiovascular disease in our liver patients,” he said. “Early strategies to implement the prevention of heart failure would go a long way in reducing long-term risks for these patients.”

The study authors did not declare a specific grant for this research from any funding agency in the public, commercial, or nonprofit sectors. Dr. Targher and Dr. Pandey report no relevant financial relationships.

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

Although cardiovascular disease (CVD) is known to often strike the mortal blow in patients with cancer, a national analysis puts in stark relief the burden of CV-related hospitalizations in this vulnerable population.

Results show that between 2004 and 2017, CV admissions increased 23.2% among patients with a cancer diagnosis, whereas admissions fell 10.9% among those without cancer.

Admissions increased steadily across all cancer types, except prostate cancer, with heart failure being the most common reason for admission.

“Hospital admissions is really important because we know that the size of this group is increasing, given that they live longer and many of the treatments that we offer cause cardiovascular disease or increase the risk of having cardiovascular events. So, from a health care planning perspective, I think it’s really important to see what the burden is likely to be in the next few years,” senior author Mamas Mamas, MD, Keele University, England, told this news organization.

For physicians and the wider population, he said, the findings underscore the need to shift the conversation from saying that patients with cancer are at increased CVD risk to asking how to mitigate this risk. “Because I would say that this increase in cardiovascular admissions, that’s a failure from a preventative perspective.”

The study was published in the European Heart Journal: Quality of Care & Clinical Outcomes.

Individual cancer types

The researchers, led by Ofer Kobo, MD, also with Keele University, used the National Inpatient Sample to identify 42.5 million weighted cases of CV admissions for acute myocardial infarction (AMI), pulmonary embolism, ischemic stroke, heart failure, atrial fibrillation (AFib) or atrial flutter, and intracranial hemorrhage from January 2004 to December 2017. Of these, 1.9 million had a record of cancer.

Patients with cancer were older; had a higher prevalence of valvular disease, anemia, and coagulopathy; and had a lower prevalence of hypertension, diabetes mellitus, and obesity than did patients without cancer.

The most common cancer type was hematologic cancers (26.1%), followed by lung (18.7%), gastrointestinal (12.4%), prostate (11.6%), breast (6.7%), and other in 24.4%.

The admission rate increased across all six admission causes – between 7% for AMI and ischemic stroke and 46% for AFib.

Heart failure was the chief reason for admission among all patients. Annual rates per 100,000 U.S. population increased in patients with cancer (from 13.6 to 16.6; P for trend = .02) and declined in those without (from 352.2 to 349.8; P for trend < .001).

“In the past, patients would be started on medications, and perhaps the importance of monitoring [left ventricular] LV function wasn’t as widely known, whereas now we’re much more aggressive in looking at it and much more aggressive at trying to prevent it,” Dr. Mamas said. “But even with this greater identification and attempting to modify regimens, we’re still getting quite substantial increases in heart failure admissions in this population. And what really surprised me is that it wasn’t just in the breast cancer population, but it was nearly across the board.”

He noted that patients are at highest risk from CV events within the first 2 years of cancer diagnosis. “So that’s really the time where you’ve got to be really aggressive in looking and working up their cardiovascular profile.”

Patients with hematologic cancers (9.7-13.5), lung (7.4-8.9), and gastrointestinal cancer (4.6-6.3) had the highest crude admission rates of CV hospitalizations per 100,000 U.S. population.

The CV admission rate went up from 2.5 to 3.7 per 100,000 U.S. population for breast cancer, and in prostate cancer, the rate dropped from 5.8 to 4.8 per 100,000 U.S. population.

Of note, patients with hematologic cancers also had the highest rate of heart failure hospitalization across all cancer types, which, coupled with their increasing admission rates, likely reflects their exposure to a “constellation of cardiotoxic therapies” as well as pathologic processes related to the cancers themselves, the authors suggest.

In-hospital mortality rates were higher among patients with cancer than those without, ranging from 5% for patients with breast cancer to 9.6% for patients with lung cancer versus 4.2% for those without cancer.

Among patients with cancer, the odds ratio for mortality was highest in those admitted with AFib (4.43), followed by pulmonary embolism (2.36), AMI (2.31), ischemic stroke (2.29), and heart failure (2.24).

In line with prior work and general population trends, in-hospital deaths in primary CV admissions trended lower among patients with cancer over the study period.

Mitigating risk

Commenting on the study, Joerg Herrmann, MD, director of the cardio-oncology clinic at Mayo Clinic, Rochester, Minn., said that the data are “extremely important” because they reflect admissions during a new era of cancer therapy. “Targeted therapies all came out about the turn of the millennium, so we’re not really looking at cancer patients treated with only old and ancient strategies.”

This may be one reason for the increased admissions, but because the study lacked information on specific cancer treatments and the date of cancer diagnosis, it’s not possible to tease out whether the uptick is related to cardiotoxicity or because the oncology outcomes have improved so much that this is a growing population, he said.

One clear implication, however, is that whoever is working on the hospital service will see more patients with a cancer diagnosis, Dr. Herrmann observed.

“Though some may have tried to maybe not get involved with this topic as much, it really calls for some broader scope to get familiar with this very entity,” he said. “And that plays out, in particular, in those patients with a diagnosis of active cancer.”

Dr. Herrmann and colleagues previously reported that patients with active leukemia or lymphoma who were hospitalized with acute coronary syndrome were less likely to receive guideline-directed therapies, even at the Mayo Clinic.

Similarly, a 2020 report by Dr. Mamas and colleagues found that patients with a variety of active cancers derived similar benefit from primary percutaneous coronary intervention for ST-segment–elevation MI as those without cancer but received the treatment less commonly.

Although there’s a greater appreciation that patients with cancer benefit equally from aggressive treatment, much more can be done to mitigate CV risk, Dr. Mamas noted. Valuable coronary information captured by MRI and CT done as part of the cancer investigation is often overlooked. For example, “we know that breast calcification and vascular calcification in the breast are very strong predictors of cardiovascular outcomes and yet people aren’t using this information.”

There are numerous shared risk factors in the development of cancer and coronary artery disease, and patients with cancer often have much worse CV risk profiles but aren’t routinely risk stratified from a CV perspective, he said.

Dr. Mamas said that his team is also studying whether CVD risk prediction tools like the Framingham Risk Score, which were derived from noncancer populations, work as well in patients with cancer. “Often, when you look at the performance of these tools in populations that weren’t covered, they’re much worse.”

“A lot of cancer survivors worry about the recurrence of their cancer and will religiously go and have repeated scans, religiously check themselves, and have all these investigations but don’t think about the actual risk that is greater for them, which is cardiovascular risk,” he said.

The authors report no study funding or relevant financial relationships.

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

Although cardiovascular disease (CVD) is known to often strike the mortal blow in patients with cancer, a national analysis puts in stark relief the burden of CV-related hospitalizations in this vulnerable population.

Results show that between 2004 and 2017, CV admissions increased 23.2% among patients with a cancer diagnosis, whereas admissions fell 10.9% among those without cancer.

Admissions increased steadily across all cancer types, except prostate cancer, with heart failure being the most common reason for admission.

“Hospital admissions is really important because we know that the size of this group is increasing, given that they live longer and many of the treatments that we offer cause cardiovascular disease or increase the risk of having cardiovascular events. So, from a health care planning perspective, I think it’s really important to see what the burden is likely to be in the next few years,” senior author Mamas Mamas, MD, Keele University, England, told this news organization.

For physicians and the wider population, he said, the findings underscore the need to shift the conversation from saying that patients with cancer are at increased CVD risk to asking how to mitigate this risk. “Because I would say that this increase in cardiovascular admissions, that’s a failure from a preventative perspective.”

The study was published in the European Heart Journal: Quality of Care & Clinical Outcomes.

Individual cancer types

The researchers, led by Ofer Kobo, MD, also with Keele University, used the National Inpatient Sample to identify 42.5 million weighted cases of CV admissions for acute myocardial infarction (AMI), pulmonary embolism, ischemic stroke, heart failure, atrial fibrillation (AFib) or atrial flutter, and intracranial hemorrhage from January 2004 to December 2017. Of these, 1.9 million had a record of cancer.

Patients with cancer were older; had a higher prevalence of valvular disease, anemia, and coagulopathy; and had a lower prevalence of hypertension, diabetes mellitus, and obesity than did patients without cancer.

The most common cancer type was hematologic cancers (26.1%), followed by lung (18.7%), gastrointestinal (12.4%), prostate (11.6%), breast (6.7%), and other in 24.4%.

The admission rate increased across all six admission causes – between 7% for AMI and ischemic stroke and 46% for AFib.

Heart failure was the chief reason for admission among all patients. Annual rates per 100,000 U.S. population increased in patients with cancer (from 13.6 to 16.6; P for trend = .02) and declined in those without (from 352.2 to 349.8; P for trend < .001).

“In the past, patients would be started on medications, and perhaps the importance of monitoring [left ventricular] LV function wasn’t as widely known, whereas now we’re much more aggressive in looking at it and much more aggressive at trying to prevent it,” Dr. Mamas said. “But even with this greater identification and attempting to modify regimens, we’re still getting quite substantial increases in heart failure admissions in this population. And what really surprised me is that it wasn’t just in the breast cancer population, but it was nearly across the board.”

He noted that patients are at highest risk from CV events within the first 2 years of cancer diagnosis. “So that’s really the time where you’ve got to be really aggressive in looking and working up their cardiovascular profile.”

Patients with hematologic cancers (9.7-13.5), lung (7.4-8.9), and gastrointestinal cancer (4.6-6.3) had the highest crude admission rates of CV hospitalizations per 100,000 U.S. population.

The CV admission rate went up from 2.5 to 3.7 per 100,000 U.S. population for breast cancer, and in prostate cancer, the rate dropped from 5.8 to 4.8 per 100,000 U.S. population.

Of note, patients with hematologic cancers also had the highest rate of heart failure hospitalization across all cancer types, which, coupled with their increasing admission rates, likely reflects their exposure to a “constellation of cardiotoxic therapies” as well as pathologic processes related to the cancers themselves, the authors suggest.

In-hospital mortality rates were higher among patients with cancer than those without, ranging from 5% for patients with breast cancer to 9.6% for patients with lung cancer versus 4.2% for those without cancer.

Among patients with cancer, the odds ratio for mortality was highest in those admitted with AFib (4.43), followed by pulmonary embolism (2.36), AMI (2.31), ischemic stroke (2.29), and heart failure (2.24).

In line with prior work and general population trends, in-hospital deaths in primary CV admissions trended lower among patients with cancer over the study period.

Mitigating risk

Commenting on the study, Joerg Herrmann, MD, director of the cardio-oncology clinic at Mayo Clinic, Rochester, Minn., said that the data are “extremely important” because they reflect admissions during a new era of cancer therapy. “Targeted therapies all came out about the turn of the millennium, so we’re not really looking at cancer patients treated with only old and ancient strategies.”

This may be one reason for the increased admissions, but because the study lacked information on specific cancer treatments and the date of cancer diagnosis, it’s not possible to tease out whether the uptick is related to cardiotoxicity or because the oncology outcomes have improved so much that this is a growing population, he said.

One clear implication, however, is that whoever is working on the hospital service will see more patients with a cancer diagnosis, Dr. Herrmann observed.

“Though some may have tried to maybe not get involved with this topic as much, it really calls for some broader scope to get familiar with this very entity,” he said. “And that plays out, in particular, in those patients with a diagnosis of active cancer.”

Dr. Herrmann and colleagues previously reported that patients with active leukemia or lymphoma who were hospitalized with acute coronary syndrome were less likely to receive guideline-directed therapies, even at the Mayo Clinic.

Similarly, a 2020 report by Dr. Mamas and colleagues found that patients with a variety of active cancers derived similar benefit from primary percutaneous coronary intervention for ST-segment–elevation MI as those without cancer but received the treatment less commonly.

Although there’s a greater appreciation that patients with cancer benefit equally from aggressive treatment, much more can be done to mitigate CV risk, Dr. Mamas noted. Valuable coronary information captured by MRI and CT done as part of the cancer investigation is often overlooked. For example, “we know that breast calcification and vascular calcification in the breast are very strong predictors of cardiovascular outcomes and yet people aren’t using this information.”

There are numerous shared risk factors in the development of cancer and coronary artery disease, and patients with cancer often have much worse CV risk profiles but aren’t routinely risk stratified from a CV perspective, he said.

Dr. Mamas said that his team is also studying whether CVD risk prediction tools like the Framingham Risk Score, which were derived from noncancer populations, work as well in patients with cancer. “Often, when you look at the performance of these tools in populations that weren’t covered, they’re much worse.”

“A lot of cancer survivors worry about the recurrence of their cancer and will religiously go and have repeated scans, religiously check themselves, and have all these investigations but don’t think about the actual risk that is greater for them, which is cardiovascular risk,” he said.

The authors report no study funding or relevant financial relationships.

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

Although cardiovascular disease (CVD) is known to often strike the mortal blow in patients with cancer, a national analysis puts in stark relief the burden of CV-related hospitalizations in this vulnerable population.

Results show that between 2004 and 2017, CV admissions increased 23.2% among patients with a cancer diagnosis, whereas admissions fell 10.9% among those without cancer.

Admissions increased steadily across all cancer types, except prostate cancer, with heart failure being the most common reason for admission.

“Hospital admissions is really important because we know that the size of this group is increasing, given that they live longer and many of the treatments that we offer cause cardiovascular disease or increase the risk of having cardiovascular events. So, from a health care planning perspective, I think it’s really important to see what the burden is likely to be in the next few years,” senior author Mamas Mamas, MD, Keele University, England, told this news organization.

For physicians and the wider population, he said, the findings underscore the need to shift the conversation from saying that patients with cancer are at increased CVD risk to asking how to mitigate this risk. “Because I would say that this increase in cardiovascular admissions, that’s a failure from a preventative perspective.”

The study was published in the European Heart Journal: Quality of Care & Clinical Outcomes.

Individual cancer types

The researchers, led by Ofer Kobo, MD, also with Keele University, used the National Inpatient Sample to identify 42.5 million weighted cases of CV admissions for acute myocardial infarction (AMI), pulmonary embolism, ischemic stroke, heart failure, atrial fibrillation (AFib) or atrial flutter, and intracranial hemorrhage from January 2004 to December 2017. Of these, 1.9 million had a record of cancer.

Patients with cancer were older; had a higher prevalence of valvular disease, anemia, and coagulopathy; and had a lower prevalence of hypertension, diabetes mellitus, and obesity than did patients without cancer.

The most common cancer type was hematologic cancers (26.1%), followed by lung (18.7%), gastrointestinal (12.4%), prostate (11.6%), breast (6.7%), and other in 24.4%.

The admission rate increased across all six admission causes – between 7% for AMI and ischemic stroke and 46% for AFib.

Heart failure was the chief reason for admission among all patients. Annual rates per 100,000 U.S. population increased in patients with cancer (from 13.6 to 16.6; P for trend = .02) and declined in those without (from 352.2 to 349.8; P for trend < .001).

“In the past, patients would be started on medications, and perhaps the importance of monitoring [left ventricular] LV function wasn’t as widely known, whereas now we’re much more aggressive in looking at it and much more aggressive at trying to prevent it,” Dr. Mamas said. “But even with this greater identification and attempting to modify regimens, we’re still getting quite substantial increases in heart failure admissions in this population. And what really surprised me is that it wasn’t just in the breast cancer population, but it was nearly across the board.”

He noted that patients are at highest risk from CV events within the first 2 years of cancer diagnosis. “So that’s really the time where you’ve got to be really aggressive in looking and working up their cardiovascular profile.”

Patients with hematologic cancers (9.7-13.5), lung (7.4-8.9), and gastrointestinal cancer (4.6-6.3) had the highest crude admission rates of CV hospitalizations per 100,000 U.S. population.

The CV admission rate went up from 2.5 to 3.7 per 100,000 U.S. population for breast cancer, and in prostate cancer, the rate dropped from 5.8 to 4.8 per 100,000 U.S. population.

Of note, patients with hematologic cancers also had the highest rate of heart failure hospitalization across all cancer types, which, coupled with their increasing admission rates, likely reflects their exposure to a “constellation of cardiotoxic therapies” as well as pathologic processes related to the cancers themselves, the authors suggest.

In-hospital mortality rates were higher among patients with cancer than those without, ranging from 5% for patients with breast cancer to 9.6% for patients with lung cancer versus 4.2% for those without cancer.

Among patients with cancer, the odds ratio for mortality was highest in those admitted with AFib (4.43), followed by pulmonary embolism (2.36), AMI (2.31), ischemic stroke (2.29), and heart failure (2.24).

In line with prior work and general population trends, in-hospital deaths in primary CV admissions trended lower among patients with cancer over the study period.

Mitigating risk

Commenting on the study, Joerg Herrmann, MD, director of the cardio-oncology clinic at Mayo Clinic, Rochester, Minn., said that the data are “extremely important” because they reflect admissions during a new era of cancer therapy. “Targeted therapies all came out about the turn of the millennium, so we’re not really looking at cancer patients treated with only old and ancient strategies.”

This may be one reason for the increased admissions, but because the study lacked information on specific cancer treatments and the date of cancer diagnosis, it’s not possible to tease out whether the uptick is related to cardiotoxicity or because the oncology outcomes have improved so much that this is a growing population, he said.

One clear implication, however, is that whoever is working on the hospital service will see more patients with a cancer diagnosis, Dr. Herrmann observed.

“Though some may have tried to maybe not get involved with this topic as much, it really calls for some broader scope to get familiar with this very entity,” he said. “And that plays out, in particular, in those patients with a diagnosis of active cancer.”

Dr. Herrmann and colleagues previously reported that patients with active leukemia or lymphoma who were hospitalized with acute coronary syndrome were less likely to receive guideline-directed therapies, even at the Mayo Clinic.

Similarly, a 2020 report by Dr. Mamas and colleagues found that patients with a variety of active cancers derived similar benefit from primary percutaneous coronary intervention for ST-segment–elevation MI as those without cancer but received the treatment less commonly.

Although there’s a greater appreciation that patients with cancer benefit equally from aggressive treatment, much more can be done to mitigate CV risk, Dr. Mamas noted. Valuable coronary information captured by MRI and CT done as part of the cancer investigation is often overlooked. For example, “we know that breast calcification and vascular calcification in the breast are very strong predictors of cardiovascular outcomes and yet people aren’t using this information.”

There are numerous shared risk factors in the development of cancer and coronary artery disease, and patients with cancer often have much worse CV risk profiles but aren’t routinely risk stratified from a CV perspective, he said.

Dr. Mamas said that his team is also studying whether CVD risk prediction tools like the Framingham Risk Score, which were derived from noncancer populations, work as well in patients with cancer. “Often, when you look at the performance of these tools in populations that weren’t covered, they’re much worse.”

“A lot of cancer survivors worry about the recurrence of their cancer and will religiously go and have repeated scans, religiously check themselves, and have all these investigations but don’t think about the actual risk that is greater for them, which is cardiovascular risk,” he said.

The authors report no study funding or relevant financial relationships.

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

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Treatment with the novel agent omecamtiv mecarbil did not improve exercise capacity in people with chronic heart failure with reduced ejection fraction (HFrEF), in the METEORIC-HF trial.

The double-blind, phase 3 study failed to achieve its primary endpoint of change in peak oxygen uptake (VO₂) after 20 weeks of treatment with omecamtiv mecarbil, compared with placebo.

There also was no benefit on secondary measures of total workload, ventilatory efficiency, and daily physical activity, according to results presented earlier this year at ACC 2022 and formally published this month in JAMA.

“These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity,” lead author Gregory D. Lewis, MD, Massachusetts General Hospital, Boston, and colleagues conclude in the paper.

Researchers had hoped that the oral selective myosin activator would prove useful in this subset of patients, having previously shown in the GALACTIC-HF trial to provide a significant improvement in heart failure (HF) events and cardiovascular death.

A prespecified subgroup analysis from that trial also found that HF patients with the lowest ejection fraction derived the greatest relative benefit from omecamtiv mecarbil.

“The lack of effect of omecamtiv mecarbil on exercise performance is inconsistent with its known mechanism of action of directly enhancing ventricular performance and reducing the risk of cardiovascular events,” Dr. Lewis and colleagues observe.

The drug’s novel mechanism of action, direct activation of myosin, contrasts with that of currently available inotropic agents, such as dobutamine or milrinone. It is not yet approved by the U.S. Food and Drug Administration but is scheduled for an advisory committee meeting on Dec. 13, 2022, and has been assigned a Prescription Drug User Fee Act date of Feb. 28, 2023.

METEORIC-HF randomly assigned 276 patients with New York Heart Association class II or III symptoms and a left ventricular ejection fraction of 35% or less to omecamtiv mecarbil (n = 185) or placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels for 20 weeks, on top of guideline-directed medical therapy.

The patients’ median age was 64 years and 15% were women. The median ejection fraction was 28% and median baseline peak VO₂ was 14.2 mL/kg per minute in the omecamtiv mecarbil group and 15.0 mL/kg per minute in the control group.

At 20 weeks, the mean change in peak VO₂ in the omecamtiv mecarbil group was –0.24 mL/kg per minute and 0.21 mL/kg per minute in the placebo group (95% confidence interval, –1.02-0.13; P = .13).

For the secondary outcomes, the change in workload achieved on stress testing declined in the omecamtiv mecarbil group (–3.8 vs. 1.6). The drug had a neutral effect on minute ventilation relative to carbon dioxide production throughout exercise (0.28 vs. –0.14 VE/VCO₂ slope) and average total daily activity units, measured over 2 weeks by accelerometer (–0.2 vs. –0.5).

The authors suggest that “one possible explanation for discordance between clinical events in a long-term follow-up study and exercise capacity improvement is that cardiac performance was not exclusively responsible for limiting exercise capacity in trial participants with HFrEF who were stable and very well treated with both pharmacologic and device HFrEF therapy.”

In an accompanying editorial, Mark H. Drazner, MD, MSc, University of Texas Southwestern Medical Center, Dallas, writes that another possible explanation is that participants in METEORIC-HF had less severe heart failure, compared with participants in GALACTIC-HF, and so were less likely to benefit from omecamtiv mecarbil.

METEORIC-HF excluded participants who had a HF hospitalization that required intravenous diuretics in the preceding 3 months, whereas 25% of participants in GALACTIC-HF were inpatients for decompensated HF and 36% had a HF hospitalization within the preceding 3 months.

Another plausible explanation for the differing results is that a therapy that improves long-term clinical outcomes may not improve exercise capacity, Dr. Drazner writes. “The available data are persuasive to suggest this may be the case.”

Some pharmacologic therapies, such as flosequinan, improved exercise capacity in patients with HF yet increased long-term mortality, he noted. Several medications that have a class I recommendation in the 2022 Heart Failure Guideline for the treatment of HFrEF also have not been shown to improve exercise capacity, as measured by peak VO₂ or by 6-minute walk distance.

In this context, Dr. Drazner said he doesn’t anticipate the METEORIC-HF findings to derail FDA approval. However, should the drug be approved, clinicians will have increasingly complex decisions to make about which therapies should be prescribed to which patients.

“Some clinicians may contemplate using omecamtiv mecarbil either in the subgroup of patients with very low ejection fractions or more severe disease, believing this strategy will maximize the benefits of this therapy, but those approaches should be pursued with caution given they are predicated on subgroup and post hoc analyses, respectively,” he wrote.

Dr. Drazner concludes that medications known to improve survival in patients with HFrEF are used at “disappointingly low rates and suboptimal doses in the United States. Implementation strategies to improve use of such therapies are needed, and those efforts should be prioritized before adoption of therapies that reduce morbidity but not cardiovascular mortality.”

The study was sponsored by Amgen and Cytokinetics. Dr. Lewis reports financial relationships with the National Institutes of Health, American Heart Association, Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, SoniVie, Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, MyoKardia, Novo Nordisk, and UpToDate. Dr. Drazner reports being a member of the writing committee of the 2022 Heart Failure guidelines; and that he is supported by the James M. Wooten Chair in Cardiology at the University of Texas Southwestern Medical Center, which was a clinical site in METEORIC-HF. However, Dr. Drazner was not a study investigator in the trial.

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

Treatment with the novel agent omecamtiv mecarbil did not improve exercise capacity in people with chronic heart failure with reduced ejection fraction (HFrEF), in the METEORIC-HF trial.

The double-blind, phase 3 study failed to achieve its primary endpoint of change in peak oxygen uptake (VO₂) after 20 weeks of treatment with omecamtiv mecarbil, compared with placebo.

There also was no benefit on secondary measures of total workload, ventilatory efficiency, and daily physical activity, according to results presented earlier this year at ACC 2022 and formally published this month in JAMA.

“These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity,” lead author Gregory D. Lewis, MD, Massachusetts General Hospital, Boston, and colleagues conclude in the paper.

Researchers had hoped that the oral selective myosin activator would prove useful in this subset of patients, having previously shown in the GALACTIC-HF trial to provide a significant improvement in heart failure (HF) events and cardiovascular death.

A prespecified subgroup analysis from that trial also found that HF patients with the lowest ejection fraction derived the greatest relative benefit from omecamtiv mecarbil.

“The lack of effect of omecamtiv mecarbil on exercise performance is inconsistent with its known mechanism of action of directly enhancing ventricular performance and reducing the risk of cardiovascular events,” Dr. Lewis and colleagues observe.

The drug’s novel mechanism of action, direct activation of myosin, contrasts with that of currently available inotropic agents, such as dobutamine or milrinone. It is not yet approved by the U.S. Food and Drug Administration but is scheduled for an advisory committee meeting on Dec. 13, 2022, and has been assigned a Prescription Drug User Fee Act date of Feb. 28, 2023.

METEORIC-HF randomly assigned 276 patients with New York Heart Association class II or III symptoms and a left ventricular ejection fraction of 35% or less to omecamtiv mecarbil (n = 185) or placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels for 20 weeks, on top of guideline-directed medical therapy.

The patients’ median age was 64 years and 15% were women. The median ejection fraction was 28% and median baseline peak VO₂ was 14.2 mL/kg per minute in the omecamtiv mecarbil group and 15.0 mL/kg per minute in the control group.

At 20 weeks, the mean change in peak VO₂ in the omecamtiv mecarbil group was –0.24 mL/kg per minute and 0.21 mL/kg per minute in the placebo group (95% confidence interval, –1.02-0.13; P = .13).

For the secondary outcomes, the change in workload achieved on stress testing declined in the omecamtiv mecarbil group (–3.8 vs. 1.6). The drug had a neutral effect on minute ventilation relative to carbon dioxide production throughout exercise (0.28 vs. –0.14 VE/VCO₂ slope) and average total daily activity units, measured over 2 weeks by accelerometer (–0.2 vs. –0.5).

The authors suggest that “one possible explanation for discordance between clinical events in a long-term follow-up study and exercise capacity improvement is that cardiac performance was not exclusively responsible for limiting exercise capacity in trial participants with HFrEF who were stable and very well treated with both pharmacologic and device HFrEF therapy.”

In an accompanying editorial, Mark H. Drazner, MD, MSc, University of Texas Southwestern Medical Center, Dallas, writes that another possible explanation is that participants in METEORIC-HF had less severe heart failure, compared with participants in GALACTIC-HF, and so were less likely to benefit from omecamtiv mecarbil.

METEORIC-HF excluded participants who had a HF hospitalization that required intravenous diuretics in the preceding 3 months, whereas 25% of participants in GALACTIC-HF were inpatients for decompensated HF and 36% had a HF hospitalization within the preceding 3 months.

Another plausible explanation for the differing results is that a therapy that improves long-term clinical outcomes may not improve exercise capacity, Dr. Drazner writes. “The available data are persuasive to suggest this may be the case.”

Some pharmacologic therapies, such as flosequinan, improved exercise capacity in patients with HF yet increased long-term mortality, he noted. Several medications that have a class I recommendation in the 2022 Heart Failure Guideline for the treatment of HFrEF also have not been shown to improve exercise capacity, as measured by peak VO₂ or by 6-minute walk distance.

In this context, Dr. Drazner said he doesn’t anticipate the METEORIC-HF findings to derail FDA approval. However, should the drug be approved, clinicians will have increasingly complex decisions to make about which therapies should be prescribed to which patients.

“Some clinicians may contemplate using omecamtiv mecarbil either in the subgroup of patients with very low ejection fractions or more severe disease, believing this strategy will maximize the benefits of this therapy, but those approaches should be pursued with caution given they are predicated on subgroup and post hoc analyses, respectively,” he wrote.

Dr. Drazner concludes that medications known to improve survival in patients with HFrEF are used at “disappointingly low rates and suboptimal doses in the United States. Implementation strategies to improve use of such therapies are needed, and those efforts should be prioritized before adoption of therapies that reduce morbidity but not cardiovascular mortality.”

The study was sponsored by Amgen and Cytokinetics. Dr. Lewis reports financial relationships with the National Institutes of Health, American Heart Association, Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, SoniVie, Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, MyoKardia, Novo Nordisk, and UpToDate. Dr. Drazner reports being a member of the writing committee of the 2022 Heart Failure guidelines; and that he is supported by the James M. Wooten Chair in Cardiology at the University of Texas Southwestern Medical Center, which was a clinical site in METEORIC-HF. However, Dr. Drazner was not a study investigator in the trial.

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

Treatment with the novel agent omecamtiv mecarbil did not improve exercise capacity in people with chronic heart failure with reduced ejection fraction (HFrEF), in the METEORIC-HF trial.

The double-blind, phase 3 study failed to achieve its primary endpoint of change in peak oxygen uptake (VO₂) after 20 weeks of treatment with omecamtiv mecarbil, compared with placebo.

There also was no benefit on secondary measures of total workload, ventilatory efficiency, and daily physical activity, according to results presented earlier this year at ACC 2022 and formally published this month in JAMA.

“These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity,” lead author Gregory D. Lewis, MD, Massachusetts General Hospital, Boston, and colleagues conclude in the paper.

Researchers had hoped that the oral selective myosin activator would prove useful in this subset of patients, having previously shown in the GALACTIC-HF trial to provide a significant improvement in heart failure (HF) events and cardiovascular death.

A prespecified subgroup analysis from that trial also found that HF patients with the lowest ejection fraction derived the greatest relative benefit from omecamtiv mecarbil.

“The lack of effect of omecamtiv mecarbil on exercise performance is inconsistent with its known mechanism of action of directly enhancing ventricular performance and reducing the risk of cardiovascular events,” Dr. Lewis and colleagues observe.

The drug’s novel mechanism of action, direct activation of myosin, contrasts with that of currently available inotropic agents, such as dobutamine or milrinone. It is not yet approved by the U.S. Food and Drug Administration but is scheduled for an advisory committee meeting on Dec. 13, 2022, and has been assigned a Prescription Drug User Fee Act date of Feb. 28, 2023.

METEORIC-HF randomly assigned 276 patients with New York Heart Association class II or III symptoms and a left ventricular ejection fraction of 35% or less to omecamtiv mecarbil (n = 185) or placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels for 20 weeks, on top of guideline-directed medical therapy.

The patients’ median age was 64 years and 15% were women. The median ejection fraction was 28% and median baseline peak VO₂ was 14.2 mL/kg per minute in the omecamtiv mecarbil group and 15.0 mL/kg per minute in the control group.

At 20 weeks, the mean change in peak VO₂ in the omecamtiv mecarbil group was –0.24 mL/kg per minute and 0.21 mL/kg per minute in the placebo group (95% confidence interval, –1.02-0.13; P = .13).

For the secondary outcomes, the change in workload achieved on stress testing declined in the omecamtiv mecarbil group (–3.8 vs. 1.6). The drug had a neutral effect on minute ventilation relative to carbon dioxide production throughout exercise (0.28 vs. –0.14 VE/VCO₂ slope) and average total daily activity units, measured over 2 weeks by accelerometer (–0.2 vs. –0.5).

The authors suggest that “one possible explanation for discordance between clinical events in a long-term follow-up study and exercise capacity improvement is that cardiac performance was not exclusively responsible for limiting exercise capacity in trial participants with HFrEF who were stable and very well treated with both pharmacologic and device HFrEF therapy.”

In an accompanying editorial, Mark H. Drazner, MD, MSc, University of Texas Southwestern Medical Center, Dallas, writes that another possible explanation is that participants in METEORIC-HF had less severe heart failure, compared with participants in GALACTIC-HF, and so were less likely to benefit from omecamtiv mecarbil.

METEORIC-HF excluded participants who had a HF hospitalization that required intravenous diuretics in the preceding 3 months, whereas 25% of participants in GALACTIC-HF were inpatients for decompensated HF and 36% had a HF hospitalization within the preceding 3 months.

Another plausible explanation for the differing results is that a therapy that improves long-term clinical outcomes may not improve exercise capacity, Dr. Drazner writes. “The available data are persuasive to suggest this may be the case.”

Some pharmacologic therapies, such as flosequinan, improved exercise capacity in patients with HF yet increased long-term mortality, he noted. Several medications that have a class I recommendation in the 2022 Heart Failure Guideline for the treatment of HFrEF also have not been shown to improve exercise capacity, as measured by peak VO₂ or by 6-minute walk distance.

In this context, Dr. Drazner said he doesn’t anticipate the METEORIC-HF findings to derail FDA approval. However, should the drug be approved, clinicians will have increasingly complex decisions to make about which therapies should be prescribed to which patients.

“Some clinicians may contemplate using omecamtiv mecarbil either in the subgroup of patients with very low ejection fractions or more severe disease, believing this strategy will maximize the benefits of this therapy, but those approaches should be pursued with caution given they are predicated on subgroup and post hoc analyses, respectively,” he wrote.

Dr. Drazner concludes that medications known to improve survival in patients with HFrEF are used at “disappointingly low rates and suboptimal doses in the United States. Implementation strategies to improve use of such therapies are needed, and those efforts should be prioritized before adoption of therapies that reduce morbidity but not cardiovascular mortality.”

The study was sponsored by Amgen and Cytokinetics. Dr. Lewis reports financial relationships with the National Institutes of Health, American Heart Association, Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, SoniVie, Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, MyoKardia, Novo Nordisk, and UpToDate. Dr. Drazner reports being a member of the writing committee of the 2022 Heart Failure guidelines; and that he is supported by the James M. Wooten Chair in Cardiology at the University of Texas Southwestern Medical Center, which was a clinical site in METEORIC-HF. However, Dr. Drazner was not a study investigator in the trial.

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