Cardiology

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.

“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.

“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.

“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.

“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
 

No RCTs have included patients older than 70

For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.

Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
 

Primary prevention: CV events increase with elevated LDL cholesterol in older age

Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.

Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.

In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.

“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.

“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”

“These robust findings are novel,” he and his colleagues stressed.

Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
 

Unequivocal reductions in events in elderly, comparable with younger patients

In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).

“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.

“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”

The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”

The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

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

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.

“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.

“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.

“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.

“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
 

No RCTs have included patients older than 70

For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.

Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
 

Primary prevention: CV events increase with elevated LDL cholesterol in older age

Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.

Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.

In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.

“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.

“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”

“These robust findings are novel,” he and his colleagues stressed.

Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
 

Unequivocal reductions in events in elderly, comparable with younger patients

In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).

“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.

“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”

The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”

The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

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

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.

“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.

“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.

“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.

“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
 

No RCTs have included patients older than 70

For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.

Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
 

Primary prevention: CV events increase with elevated LDL cholesterol in older age

Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.

Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.

In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.

“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.

“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”

“These robust findings are novel,” he and his colleagues stressed.

Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
 

Unequivocal reductions in events in elderly, comparable with younger patients

In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).

“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.

“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”

The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”

The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

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

The more time older women spent sitting or lying down, the more likely their risk of hospitalization for heart failure, based on data from more than 80,000 postmenopausal women.

Cecilie_Arcurs/E+

The 2018 Physical Activity Guidelines show evidence of the impact of physical activity on reducing heart failure risk, but the association between activity, sedentary behavior (SB) and heart failure (HF) in older women in particular has not been well studied, wrote Michael J. LaMonte, PhD, MPH, of the State University of New York at Buffalo, and colleagues in a study published in Circulation: Heart Failure. “Given the high prevalence of prolonged sedentary time among U.S. adults aged 65 and older, among whom HF burden is substantial, understanding the role SB has in HF development is relevant to future HF prevention strategies,” the researchers wrote.

The researchers identified 80,982 women aged 50-79 years who were enrolled in the Women’s Health Initiative Observational Study, had no known HF, and could walk at least one block unassisted. The average follow-up period was 9 years, and a total of 1,402 women were hospitalized for heart failure during the period of time they were observed.

The time spent sedentary (combined sitting or lying down) was divided into tertiles of 6.5 hours or less, 6.6-9.5 hours, and more than 9.5 hours. Time spent sitting was divided into tertiles of 4.5 hours or less; 4.6-8.5 hours; and more than 8.5 hours.
 

Heart failure risk goes up with more down time

After controlling for multiple variables including age, race, education, income, smoking status alcohol use, menopausal hormone therapy, and hysterectomy status, the researchers found that patients in the second tertile for sedentary behavior had a significantly increased heart failure risk than patients in the first tertile for sedentary behavior. This risk was even greater for patients falling in the third tertile for sedentary behavior. Odds ratios were 1.00 (referent), 1.15, and 1.42 for the lowest to highest tertiles for total sedentary behavior, respectively, and 1.00 (referent), 1.14, and 1.54 for sitting (P < .001 for both total sedentary behavior and sitting only).

The trends remained significant after controlling for comorbidities including MI and coronary revascularization, and the associations were similar among categories of women with additional HF risk factors, including body mass index, diabetes, hypertension, and coronary heart disease.

Notably, the association between hours spent sitting or lying down and HF risk persisted even in women who met recommended activity levels, the researchers wrote.

The study findings were limited by the use of self-reports and by the inability to evaluate SB patterns or SB and HF subtypes, the researchers noted. However, the results were strengthened by the large sample size, use of time-varying SB exposure, and extensive controlling, and the data support the risk of increased SB on adverse cardiovascular outcomes.

“Results of this study underscore the need for effective strategies to reduce daily SB time, in addition to increasing recreational physical activity, as part of population efforts for HF prevention,” they concluded.

Clinicians know the value of a physically active lifestyle for heart health, said lead author Dr. LaMonte in a statement accompanying the study’s release. “However, our study clearly shows that we also need to increase efforts to reduce daily sedentary time and encourage adults to frequently interrupt their sedentary time. This does not necessarily require an extended bout of physical activity; it might simply be standing up for 5 minutes or standing and moving one’s feet in place.

“We do not have sufficient evidence on the best approach to recommend for interrupting sedentary time. However, accumulating data suggest that habitual activities such as steps taken during household and other activities of daily living are an important aspect of cardiovascular disease prevention and healthy aging,” Dr. LaMonte added.
 

Promote more movement and less sitting

“This is the first study to assess sedentary time and the risk for incident heart failure hospitalization in postmenopausal women,” said Robert H. Hopkins Jr., MD, of the University of Arkansas for Medical Sciences, Little Rock, in an interview.

“Heart failure is the cause of approximately 35% of cardiovascular mortalities in women, and sedentary behaviors are common in older adults,” he noted.

Kashif J. Piracha, MD, of Houston Methodist Willowbrook Hospital, agreed that there is a lack of existing data looking at the relationship between sedentary behavior and the risk of the development of heart failure in postmenopausal women. In an interview, he cited this as a reason “it was important to conduct this study.”

Dr. Hopkins added that he was not surprised by the study results “There are a number of studies which have demonstrated reduction in risk for heart failure in men and in combined populations of men and women with increased physical activity.” There are fewer data (but similar outcomes) in studies of men with increased levels of sedentary behaviors, he said.

“This study adds one more reason that other clinicians in primary care and me need to encourage our older patients to get up and move,” said Dr. Hopkins, who also serves on the editorial advisory board of Internal Medicine News. “Many of us have focused our efforts in the past on achieving exercise goals and this study provides a foundation for a recommendation that ‘it is not just about exercise;’ we need to also encourage our patients to minimize their time in sedentary pursuits in addition to exercise if we are to optimize their health into older age.”

Dr. Hopkins noted that the large size of the study was a strength, but the observational design and use of patient surveys were limitations.

“We need further studies to better tease out whether there are risk differences in different sedentary behavior patterns, whether this applies across heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction, and whether there are additional ways we can mitigate these risks as our society ages,” he said.
 

Findings differ from California Men’s Health Study’s

“The results corroborate the fact that there is less risk of heart failure in physically active patients,” Dr. Piracha noted.

The message for clinicians is to encourage postmenopausal female patients to engage in physical activity as much as possible, said Dr. Piracha. “Also, it appears that in this population, even with good physical activity, prolonged sedentary behavior of more than 8.5 hours a day was still associated with a higher risk of incident HF hospitalization. Therefore, a case can be made to focus on carrying out physical activity with an intensity that can be sustained for longer, rather than shorter periods of time.”

Notably, the finding of increased HF hospitalization in women who reported high amounts of physical activity but were still sedentary for more than 8.5 hours a day “is contrary to what was seen in the California Men’s Health Study.” In that study, “men with high physical activity levels who also had prolonged sitting time did not have increased risk of HF hospitalization,” Dr. Piracha noted. “Further research is needed to elucidate what hormonal or other factors contribute to this difference.”

The new study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Dr. Hopkins and Dr. Piracha had no financial conflicts to disclose.

SOURCE: LaMonte MJ et al. Circ Heart Fail. 2020 Nov 24. doi: 10.1161/CIRCHEARTFAILURE.120.007508.

The more time older women spent sitting or lying down, the more likely their risk of hospitalization for heart failure, based on data from more than 80,000 postmenopausal women.

Cecilie_Arcurs/E+

The 2018 Physical Activity Guidelines show evidence of the impact of physical activity on reducing heart failure risk, but the association between activity, sedentary behavior (SB) and heart failure (HF) in older women in particular has not been well studied, wrote Michael J. LaMonte, PhD, MPH, of the State University of New York at Buffalo, and colleagues in a study published in Circulation: Heart Failure. “Given the high prevalence of prolonged sedentary time among U.S. adults aged 65 and older, among whom HF burden is substantial, understanding the role SB has in HF development is relevant to future HF prevention strategies,” the researchers wrote.

The researchers identified 80,982 women aged 50-79 years who were enrolled in the Women’s Health Initiative Observational Study, had no known HF, and could walk at least one block unassisted. The average follow-up period was 9 years, and a total of 1,402 women were hospitalized for heart failure during the period of time they were observed.

The time spent sedentary (combined sitting or lying down) was divided into tertiles of 6.5 hours or less, 6.6-9.5 hours, and more than 9.5 hours. Time spent sitting was divided into tertiles of 4.5 hours or less; 4.6-8.5 hours; and more than 8.5 hours.
 

Heart failure risk goes up with more down time

After controlling for multiple variables including age, race, education, income, smoking status alcohol use, menopausal hormone therapy, and hysterectomy status, the researchers found that patients in the second tertile for sedentary behavior had a significantly increased heart failure risk than patients in the first tertile for sedentary behavior. This risk was even greater for patients falling in the third tertile for sedentary behavior. Odds ratios were 1.00 (referent), 1.15, and 1.42 for the lowest to highest tertiles for total sedentary behavior, respectively, and 1.00 (referent), 1.14, and 1.54 for sitting (P < .001 for both total sedentary behavior and sitting only).

The trends remained significant after controlling for comorbidities including MI and coronary revascularization, and the associations were similar among categories of women with additional HF risk factors, including body mass index, diabetes, hypertension, and coronary heart disease.

Notably, the association between hours spent sitting or lying down and HF risk persisted even in women who met recommended activity levels, the researchers wrote.

The study findings were limited by the use of self-reports and by the inability to evaluate SB patterns or SB and HF subtypes, the researchers noted. However, the results were strengthened by the large sample size, use of time-varying SB exposure, and extensive controlling, and the data support the risk of increased SB on adverse cardiovascular outcomes.

“Results of this study underscore the need for effective strategies to reduce daily SB time, in addition to increasing recreational physical activity, as part of population efforts for HF prevention,” they concluded.

Clinicians know the value of a physically active lifestyle for heart health, said lead author Dr. LaMonte in a statement accompanying the study’s release. “However, our study clearly shows that we also need to increase efforts to reduce daily sedentary time and encourage adults to frequently interrupt their sedentary time. This does not necessarily require an extended bout of physical activity; it might simply be standing up for 5 minutes or standing and moving one’s feet in place.

“We do not have sufficient evidence on the best approach to recommend for interrupting sedentary time. However, accumulating data suggest that habitual activities such as steps taken during household and other activities of daily living are an important aspect of cardiovascular disease prevention and healthy aging,” Dr. LaMonte added.
 

Promote more movement and less sitting

“This is the first study to assess sedentary time and the risk for incident heart failure hospitalization in postmenopausal women,” said Robert H. Hopkins Jr., MD, of the University of Arkansas for Medical Sciences, Little Rock, in an interview.

“Heart failure is the cause of approximately 35% of cardiovascular mortalities in women, and sedentary behaviors are common in older adults,” he noted.

Kashif J. Piracha, MD, of Houston Methodist Willowbrook Hospital, agreed that there is a lack of existing data looking at the relationship between sedentary behavior and the risk of the development of heart failure in postmenopausal women. In an interview, he cited this as a reason “it was important to conduct this study.”

Dr. Hopkins added that he was not surprised by the study results “There are a number of studies which have demonstrated reduction in risk for heart failure in men and in combined populations of men and women with increased physical activity.” There are fewer data (but similar outcomes) in studies of men with increased levels of sedentary behaviors, he said.

“This study adds one more reason that other clinicians in primary care and me need to encourage our older patients to get up and move,” said Dr. Hopkins, who also serves on the editorial advisory board of Internal Medicine News. “Many of us have focused our efforts in the past on achieving exercise goals and this study provides a foundation for a recommendation that ‘it is not just about exercise;’ we need to also encourage our patients to minimize their time in sedentary pursuits in addition to exercise if we are to optimize their health into older age.”

Dr. Hopkins noted that the large size of the study was a strength, but the observational design and use of patient surveys were limitations.

“We need further studies to better tease out whether there are risk differences in different sedentary behavior patterns, whether this applies across heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction, and whether there are additional ways we can mitigate these risks as our society ages,” he said.
 

Findings differ from California Men’s Health Study’s

“The results corroborate the fact that there is less risk of heart failure in physically active patients,” Dr. Piracha noted.

The message for clinicians is to encourage postmenopausal female patients to engage in physical activity as much as possible, said Dr. Piracha. “Also, it appears that in this population, even with good physical activity, prolonged sedentary behavior of more than 8.5 hours a day was still associated with a higher risk of incident HF hospitalization. Therefore, a case can be made to focus on carrying out physical activity with an intensity that can be sustained for longer, rather than shorter periods of time.”

Notably, the finding of increased HF hospitalization in women who reported high amounts of physical activity but were still sedentary for more than 8.5 hours a day “is contrary to what was seen in the California Men’s Health Study.” In that study, “men with high physical activity levels who also had prolonged sitting time did not have increased risk of HF hospitalization,” Dr. Piracha noted. “Further research is needed to elucidate what hormonal or other factors contribute to this difference.”

The new study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Dr. Hopkins and Dr. Piracha had no financial conflicts to disclose.

SOURCE: LaMonte MJ et al. Circ Heart Fail. 2020 Nov 24. doi: 10.1161/CIRCHEARTFAILURE.120.007508.

The more time older women spent sitting or lying down, the more likely their risk of hospitalization for heart failure, based on data from more than 80,000 postmenopausal women.

Cecilie_Arcurs/E+

The 2018 Physical Activity Guidelines show evidence of the impact of physical activity on reducing heart failure risk, but the association between activity, sedentary behavior (SB) and heart failure (HF) in older women in particular has not been well studied, wrote Michael J. LaMonte, PhD, MPH, of the State University of New York at Buffalo, and colleagues in a study published in Circulation: Heart Failure. “Given the high prevalence of prolonged sedentary time among U.S. adults aged 65 and older, among whom HF burden is substantial, understanding the role SB has in HF development is relevant to future HF prevention strategies,” the researchers wrote.

The researchers identified 80,982 women aged 50-79 years who were enrolled in the Women’s Health Initiative Observational Study, had no known HF, and could walk at least one block unassisted. The average follow-up period was 9 years, and a total of 1,402 women were hospitalized for heart failure during the period of time they were observed.

The time spent sedentary (combined sitting or lying down) was divided into tertiles of 6.5 hours or less, 6.6-9.5 hours, and more than 9.5 hours. Time spent sitting was divided into tertiles of 4.5 hours or less; 4.6-8.5 hours; and more than 8.5 hours.
 

Heart failure risk goes up with more down time

After controlling for multiple variables including age, race, education, income, smoking status alcohol use, menopausal hormone therapy, and hysterectomy status, the researchers found that patients in the second tertile for sedentary behavior had a significantly increased heart failure risk than patients in the first tertile for sedentary behavior. This risk was even greater for patients falling in the third tertile for sedentary behavior. Odds ratios were 1.00 (referent), 1.15, and 1.42 for the lowest to highest tertiles for total sedentary behavior, respectively, and 1.00 (referent), 1.14, and 1.54 for sitting (P < .001 for both total sedentary behavior and sitting only).

The trends remained significant after controlling for comorbidities including MI and coronary revascularization, and the associations were similar among categories of women with additional HF risk factors, including body mass index, diabetes, hypertension, and coronary heart disease.

Notably, the association between hours spent sitting or lying down and HF risk persisted even in women who met recommended activity levels, the researchers wrote.

The study findings were limited by the use of self-reports and by the inability to evaluate SB patterns or SB and HF subtypes, the researchers noted. However, the results were strengthened by the large sample size, use of time-varying SB exposure, and extensive controlling, and the data support the risk of increased SB on adverse cardiovascular outcomes.

“Results of this study underscore the need for effective strategies to reduce daily SB time, in addition to increasing recreational physical activity, as part of population efforts for HF prevention,” they concluded.

Clinicians know the value of a physically active lifestyle for heart health, said lead author Dr. LaMonte in a statement accompanying the study’s release. “However, our study clearly shows that we also need to increase efforts to reduce daily sedentary time and encourage adults to frequently interrupt their sedentary time. This does not necessarily require an extended bout of physical activity; it might simply be standing up for 5 minutes or standing and moving one’s feet in place.

“We do not have sufficient evidence on the best approach to recommend for interrupting sedentary time. However, accumulating data suggest that habitual activities such as steps taken during household and other activities of daily living are an important aspect of cardiovascular disease prevention and healthy aging,” Dr. LaMonte added.
 

Promote more movement and less sitting

“This is the first study to assess sedentary time and the risk for incident heart failure hospitalization in postmenopausal women,” said Robert H. Hopkins Jr., MD, of the University of Arkansas for Medical Sciences, Little Rock, in an interview.

“Heart failure is the cause of approximately 35% of cardiovascular mortalities in women, and sedentary behaviors are common in older adults,” he noted.

Kashif J. Piracha, MD, of Houston Methodist Willowbrook Hospital, agreed that there is a lack of existing data looking at the relationship between sedentary behavior and the risk of the development of heart failure in postmenopausal women. In an interview, he cited this as a reason “it was important to conduct this study.”

Dr. Hopkins added that he was not surprised by the study results “There are a number of studies which have demonstrated reduction in risk for heart failure in men and in combined populations of men and women with increased physical activity.” There are fewer data (but similar outcomes) in studies of men with increased levels of sedentary behaviors, he said.

“This study adds one more reason that other clinicians in primary care and me need to encourage our older patients to get up and move,” said Dr. Hopkins, who also serves on the editorial advisory board of Internal Medicine News. “Many of us have focused our efforts in the past on achieving exercise goals and this study provides a foundation for a recommendation that ‘it is not just about exercise;’ we need to also encourage our patients to minimize their time in sedentary pursuits in addition to exercise if we are to optimize their health into older age.”

Dr. Hopkins noted that the large size of the study was a strength, but the observational design and use of patient surveys were limitations.

“We need further studies to better tease out whether there are risk differences in different sedentary behavior patterns, whether this applies across heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction, and whether there are additional ways we can mitigate these risks as our society ages,” he said.
 

Findings differ from California Men’s Health Study’s

“The results corroborate the fact that there is less risk of heart failure in physically active patients,” Dr. Piracha noted.

The message for clinicians is to encourage postmenopausal female patients to engage in physical activity as much as possible, said Dr. Piracha. “Also, it appears that in this population, even with good physical activity, prolonged sedentary behavior of more than 8.5 hours a day was still associated with a higher risk of incident HF hospitalization. Therefore, a case can be made to focus on carrying out physical activity with an intensity that can be sustained for longer, rather than shorter periods of time.”

Notably, the finding of increased HF hospitalization in women who reported high amounts of physical activity but were still sedentary for more than 8.5 hours a day “is contrary to what was seen in the California Men’s Health Study.” In that study, “men with high physical activity levels who also had prolonged sitting time did not have increased risk of HF hospitalization,” Dr. Piracha noted. “Further research is needed to elucidate what hormonal or other factors contribute to this difference.”

The new study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Dr. Hopkins and Dr. Piracha had no financial conflicts to disclose.

SOURCE: LaMonte MJ et al. Circ Heart Fail. 2020 Nov 24. doi: 10.1161/CIRCHEARTFAILURE.120.007508.

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents, the U.S. Preventive Services Task Force reported in JAMA.

©Vishnu Kumar/Thinkstock

However, two experts in this area suggested there is evidence if you know where to look, and pediatric BP testing is crucial now.

In this update to the 2013 statement, the USPSTF’s systematic review focused on evidence surrounding the benefits of screening, test accuracy, treatment effectiveness and harms, and links between hypertension and cardiovascular disease (CVD) markers in childhood and adulthood.

Limited information was available on the accuracy of screening tests. No studies were found that directly evaluated screening for pediatric high BP or reported effectiveness in delayed onset or risk reduction for cardiovascular outcomes related to hypertension. Additionally, no studies were found that addressed screening for secondary hypertension in asymptomatic pediatric patients. No studies were found that evaluated the treatment of primary childhood hypertension and BP reduction or other outcomes in adulthood. The panel also was unable to identify any studies that reported on harms of screening and treatment.

When the adult framework for cardiovascular risk reduction is extended in pediatric patients, there are methodological challenges that make it harder to determine how much of the potential burden can actually be prevented, the panel said. The clinical and epidemiologic significance of percentile thresholds that are used to determine their ties to adult CVD has limited supporting evidence. Inconsistent performance characteristics of current diagnostic methods, of which there are few, tend to yield unfavorable high false-positive rates. Such false positives are potentially harmful, because they lead to “unnecessary secondary evaluations or treatments.” Because pharmacologic management of pediatric hypertension is continued for a much longer period, it is the increased likelihood of adverse events that should be cause for concern.
 

Should the focus for screening be shifted to significant risk factors?

In an accompanying editorial, Joseph T. Flynn, MD, MS, of Seattle Children’s Hospital, said that the outcome of the latest statement is expected, “given how the key questions were framed and the analysis performed.” To begin, he suggested restating the question: “What is the best approach to assess whether childhood BP measurement is associated with adult CVD or whether treatment of high BP in childhood is associated with reducing the burden of adult CVD?” The answer is to tackle these questions with randomized clinical trials that compare screening to no screening and treatment to no treatment. But such studies are likely infeasible, partly because of the required length of follow-up of 5-6 decades.

Perhaps a better question would be: “Does BP measurement in childhood identify children and adolescents who already have markers of CVD or who are at risk of developing them as adults?” Were these youth to be identified, they would become candidates for approaches that seek to prevent disease progression. Reframing the question in this manner better positions physicians to focus on prevention and sidestep “the requirement that the only acceptable outcome is prevention of CVD events in adulthood,” he explained.

The next step would be to identify data already available to address the reframed question. Cross-sectional studies could be used to make the association between BP levels and cardiovascular risk markers already present. For example, several publications from the multicenter Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY), which enrolled roughly 400 youth, provided data that reinforce prior single-center studies that essentially proved there are adverse consequences for youth with high BP, and they “set the stage for the institution of measures designed to reverse target-organ damage and reduce cardiovascular risk in youth,” said Dr. Flynn.

More specifically, results from SHIP-AHOY “have demonstrated that increased left ventricular mass can be demonstrated at BP levels currently classified as normotensive and that abnormal left ventricular function can be seen at similar BP levels,” Dr. Flynn noted. In addition, “they have established a substantial association between an abnormal metabolic phenotype and several forms of target-organ damage associated with high BP.”
 

One approach is to analyze longitudinal cohort studies

Because there is a paucity of prospective clinical trials, Dr. Flynn suggested that analyzing longitudinal cohort studies would be the most effective approach for evaluating the potential link between current BP levels and future CVD. Such studies already have “data that address an important point raised in the USPSTF statement, namely whether the pediatric percentile-based BP cut points, such as those in the 2017 AAP [American Academy of Pediatrics] guideline, are associated with adult hypertension and CVD,” noted Dr. Flynn. “In the International Childhood Cardiovascular Cohort Consortium study, the specific childhood BP levels that were associated with increased adult carotid intima-medial thickness were remarkably similar to the BP percentile cut points in the AAP guideline for children of similar ages.”

Analysis of data from the Bogalusa Heart Study found looking at children classified as having high BP by the 2017 AAP guideline had “increased relative risks of having hypertension, left ventricular hypertrophy, or metabolic syndrome as adults 36 years later.”

“The conclusions of the USPSTF statement underscore the need for additional research on childhood high BP and its association with adult CVD. The starting points for such research can be deduced from currently available cross-sectional and longitudinal data, which demonstrate the detrimental outcomes associated with high BP in youth. Using these data to reframe and answer the questions raised by the USPSTF should point the way toward effective prevention of adult CVD,” concluded Dr. Flynn.

In a separate interview, Kristen Sexson Tejtel, MD, PhD, MPH, medical director of the preventive cardiology clinic at Texas Children’s Hospital and Baylor College of Medicine, both in Houston, noted that in spite of USPSTF’s findings, there is actually an association between children with high blood pressure and intermediate outcomes in adults.

“Dr. Flynn suggests reframing the question. In fact, evidence exists that children with high blood pressure are at higher risk of left ventricular hypertrophy, increased arterial stiffness, and changes in retinal arteries,” noted Dr. Sexson Tejtel.
 

Evidence of pediatric heart damage has been documented in autopsies

“It is imperative that children have blood pressure evaluation,” she urged. “There is evidence that there are changes similar to those seen in adults with cardiovascular compromise. It has been shown that children dying of other causes [accidents] who have these problems also have more plaque on autopsy, indicating that those with high blood pressure are more likely to have markers of CVD already present in childhood.

“One of the keys of pediatric medicine is prevention and the counseling for prevention of adult diseases. The duration of study necessary to objectively determine whether treatment of hypertension in childhood reduces the risk of adult cardiac problems is extensive. If nothing is done now, we are putting more future generations in danger. We must provide appropriate counseling for children and their families regarding lifestyle improvements, to have a chance to improve cardiovascular risk factors in adults, including hypertension, hyperlipidemia and/or obesity,” urged Dr. Sexson Tejtel.

All members of the USPSTF received travel reimbursement and honoraria. Dr. Barry received grants and personal fees from Healthwise. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. Dr. Flynn reported receiving grants from the National Institutes of Health and royalties from UpToDate and Springer outside the submitted work. Dr. Sexson Tejtel said she had no relevant financial disclosures or conflicts of interest.

SOURCE: USPSTF. JAMA. 2020 Nov 10. doi: 10.1001/jama.2020.20122.

Current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents, the U.S. Preventive Services Task Force reported in JAMA.

©Vishnu Kumar/Thinkstock

However, two experts in this area suggested there is evidence if you know where to look, and pediatric BP testing is crucial now.

In this update to the 2013 statement, the USPSTF’s systematic review focused on evidence surrounding the benefits of screening, test accuracy, treatment effectiveness and harms, and links between hypertension and cardiovascular disease (CVD) markers in childhood and adulthood.

Limited information was available on the accuracy of screening tests. No studies were found that directly evaluated screening for pediatric high BP or reported effectiveness in delayed onset or risk reduction for cardiovascular outcomes related to hypertension. Additionally, no studies were found that addressed screening for secondary hypertension in asymptomatic pediatric patients. No studies were found that evaluated the treatment of primary childhood hypertension and BP reduction or other outcomes in adulthood. The panel also was unable to identify any studies that reported on harms of screening and treatment.

When the adult framework for cardiovascular risk reduction is extended in pediatric patients, there are methodological challenges that make it harder to determine how much of the potential burden can actually be prevented, the panel said. The clinical and epidemiologic significance of percentile thresholds that are used to determine their ties to adult CVD has limited supporting evidence. Inconsistent performance characteristics of current diagnostic methods, of which there are few, tend to yield unfavorable high false-positive rates. Such false positives are potentially harmful, because they lead to “unnecessary secondary evaluations or treatments.” Because pharmacologic management of pediatric hypertension is continued for a much longer period, it is the increased likelihood of adverse events that should be cause for concern.
 

Should the focus for screening be shifted to significant risk factors?

In an accompanying editorial, Joseph T. Flynn, MD, MS, of Seattle Children’s Hospital, said that the outcome of the latest statement is expected, “given how the key questions were framed and the analysis performed.” To begin, he suggested restating the question: “What is the best approach to assess whether childhood BP measurement is associated with adult CVD or whether treatment of high BP in childhood is associated with reducing the burden of adult CVD?” The answer is to tackle these questions with randomized clinical trials that compare screening to no screening and treatment to no treatment. But such studies are likely infeasible, partly because of the required length of follow-up of 5-6 decades.

Perhaps a better question would be: “Does BP measurement in childhood identify children and adolescents who already have markers of CVD or who are at risk of developing them as adults?” Were these youth to be identified, they would become candidates for approaches that seek to prevent disease progression. Reframing the question in this manner better positions physicians to focus on prevention and sidestep “the requirement that the only acceptable outcome is prevention of CVD events in adulthood,” he explained.

The next step would be to identify data already available to address the reframed question. Cross-sectional studies could be used to make the association between BP levels and cardiovascular risk markers already present. For example, several publications from the multicenter Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY), which enrolled roughly 400 youth, provided data that reinforce prior single-center studies that essentially proved there are adverse consequences for youth with high BP, and they “set the stage for the institution of measures designed to reverse target-organ damage and reduce cardiovascular risk in youth,” said Dr. Flynn.

More specifically, results from SHIP-AHOY “have demonstrated that increased left ventricular mass can be demonstrated at BP levels currently classified as normotensive and that abnormal left ventricular function can be seen at similar BP levels,” Dr. Flynn noted. In addition, “they have established a substantial association between an abnormal metabolic phenotype and several forms of target-organ damage associated with high BP.”
 

One approach is to analyze longitudinal cohort studies

Because there is a paucity of prospective clinical trials, Dr. Flynn suggested that analyzing longitudinal cohort studies would be the most effective approach for evaluating the potential link between current BP levels and future CVD. Such studies already have “data that address an important point raised in the USPSTF statement, namely whether the pediatric percentile-based BP cut points, such as those in the 2017 AAP [American Academy of Pediatrics] guideline, are associated with adult hypertension and CVD,” noted Dr. Flynn. “In the International Childhood Cardiovascular Cohort Consortium study, the specific childhood BP levels that were associated with increased adult carotid intima-medial thickness were remarkably similar to the BP percentile cut points in the AAP guideline for children of similar ages.”

Analysis of data from the Bogalusa Heart Study found looking at children classified as having high BP by the 2017 AAP guideline had “increased relative risks of having hypertension, left ventricular hypertrophy, or metabolic syndrome as adults 36 years later.”

“The conclusions of the USPSTF statement underscore the need for additional research on childhood high BP and its association with adult CVD. The starting points for such research can be deduced from currently available cross-sectional and longitudinal data, which demonstrate the detrimental outcomes associated with high BP in youth. Using these data to reframe and answer the questions raised by the USPSTF should point the way toward effective prevention of adult CVD,” concluded Dr. Flynn.

In a separate interview, Kristen Sexson Tejtel, MD, PhD, MPH, medical director of the preventive cardiology clinic at Texas Children’s Hospital and Baylor College of Medicine, both in Houston, noted that in spite of USPSTF’s findings, there is actually an association between children with high blood pressure and intermediate outcomes in adults.

“Dr. Flynn suggests reframing the question. In fact, evidence exists that children with high blood pressure are at higher risk of left ventricular hypertrophy, increased arterial stiffness, and changes in retinal arteries,” noted Dr. Sexson Tejtel.
 

Evidence of pediatric heart damage has been documented in autopsies

“It is imperative that children have blood pressure evaluation,” she urged. “There is evidence that there are changes similar to those seen in adults with cardiovascular compromise. It has been shown that children dying of other causes [accidents] who have these problems also have more plaque on autopsy, indicating that those with high blood pressure are more likely to have markers of CVD already present in childhood.

“One of the keys of pediatric medicine is prevention and the counseling for prevention of adult diseases. The duration of study necessary to objectively determine whether treatment of hypertension in childhood reduces the risk of adult cardiac problems is extensive. If nothing is done now, we are putting more future generations in danger. We must provide appropriate counseling for children and their families regarding lifestyle improvements, to have a chance to improve cardiovascular risk factors in adults, including hypertension, hyperlipidemia and/or obesity,” urged Dr. Sexson Tejtel.

All members of the USPSTF received travel reimbursement and honoraria. Dr. Barry received grants and personal fees from Healthwise. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. Dr. Flynn reported receiving grants from the National Institutes of Health and royalties from UpToDate and Springer outside the submitted work. Dr. Sexson Tejtel said she had no relevant financial disclosures or conflicts of interest.

SOURCE: USPSTF. JAMA. 2020 Nov 10. doi: 10.1001/jama.2020.20122.

Current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents, the U.S. Preventive Services Task Force reported in JAMA.

©Vishnu Kumar/Thinkstock

However, two experts in this area suggested there is evidence if you know where to look, and pediatric BP testing is crucial now.

In this update to the 2013 statement, the USPSTF’s systematic review focused on evidence surrounding the benefits of screening, test accuracy, treatment effectiveness and harms, and links between hypertension and cardiovascular disease (CVD) markers in childhood and adulthood.

Limited information was available on the accuracy of screening tests. No studies were found that directly evaluated screening for pediatric high BP or reported effectiveness in delayed onset or risk reduction for cardiovascular outcomes related to hypertension. Additionally, no studies were found that addressed screening for secondary hypertension in asymptomatic pediatric patients. No studies were found that evaluated the treatment of primary childhood hypertension and BP reduction or other outcomes in adulthood. The panel also was unable to identify any studies that reported on harms of screening and treatment.

When the adult framework for cardiovascular risk reduction is extended in pediatric patients, there are methodological challenges that make it harder to determine how much of the potential burden can actually be prevented, the panel said. The clinical and epidemiologic significance of percentile thresholds that are used to determine their ties to adult CVD has limited supporting evidence. Inconsistent performance characteristics of current diagnostic methods, of which there are few, tend to yield unfavorable high false-positive rates. Such false positives are potentially harmful, because they lead to “unnecessary secondary evaluations or treatments.” Because pharmacologic management of pediatric hypertension is continued for a much longer period, it is the increased likelihood of adverse events that should be cause for concern.
 

Should the focus for screening be shifted to significant risk factors?

In an accompanying editorial, Joseph T. Flynn, MD, MS, of Seattle Children’s Hospital, said that the outcome of the latest statement is expected, “given how the key questions were framed and the analysis performed.” To begin, he suggested restating the question: “What is the best approach to assess whether childhood BP measurement is associated with adult CVD or whether treatment of high BP in childhood is associated with reducing the burden of adult CVD?” The answer is to tackle these questions with randomized clinical trials that compare screening to no screening and treatment to no treatment. But such studies are likely infeasible, partly because of the required length of follow-up of 5-6 decades.

Perhaps a better question would be: “Does BP measurement in childhood identify children and adolescents who already have markers of CVD or who are at risk of developing them as adults?” Were these youth to be identified, they would become candidates for approaches that seek to prevent disease progression. Reframing the question in this manner better positions physicians to focus on prevention and sidestep “the requirement that the only acceptable outcome is prevention of CVD events in adulthood,” he explained.

The next step would be to identify data already available to address the reframed question. Cross-sectional studies could be used to make the association between BP levels and cardiovascular risk markers already present. For example, several publications from the multicenter Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY), which enrolled roughly 400 youth, provided data that reinforce prior single-center studies that essentially proved there are adverse consequences for youth with high BP, and they “set the stage for the institution of measures designed to reverse target-organ damage and reduce cardiovascular risk in youth,” said Dr. Flynn.

More specifically, results from SHIP-AHOY “have demonstrated that increased left ventricular mass can be demonstrated at BP levels currently classified as normotensive and that abnormal left ventricular function can be seen at similar BP levels,” Dr. Flynn noted. In addition, “they have established a substantial association between an abnormal metabolic phenotype and several forms of target-organ damage associated with high BP.”
 

One approach is to analyze longitudinal cohort studies

Because there is a paucity of prospective clinical trials, Dr. Flynn suggested that analyzing longitudinal cohort studies would be the most effective approach for evaluating the potential link between current BP levels and future CVD. Such studies already have “data that address an important point raised in the USPSTF statement, namely whether the pediatric percentile-based BP cut points, such as those in the 2017 AAP [American Academy of Pediatrics] guideline, are associated with adult hypertension and CVD,” noted Dr. Flynn. “In the International Childhood Cardiovascular Cohort Consortium study, the specific childhood BP levels that were associated with increased adult carotid intima-medial thickness were remarkably similar to the BP percentile cut points in the AAP guideline for children of similar ages.”

Analysis of data from the Bogalusa Heart Study found looking at children classified as having high BP by the 2017 AAP guideline had “increased relative risks of having hypertension, left ventricular hypertrophy, or metabolic syndrome as adults 36 years later.”

“The conclusions of the USPSTF statement underscore the need for additional research on childhood high BP and its association with adult CVD. The starting points for such research can be deduced from currently available cross-sectional and longitudinal data, which demonstrate the detrimental outcomes associated with high BP in youth. Using these data to reframe and answer the questions raised by the USPSTF should point the way toward effective prevention of adult CVD,” concluded Dr. Flynn.

In a separate interview, Kristen Sexson Tejtel, MD, PhD, MPH, medical director of the preventive cardiology clinic at Texas Children’s Hospital and Baylor College of Medicine, both in Houston, noted that in spite of USPSTF’s findings, there is actually an association between children with high blood pressure and intermediate outcomes in adults.

“Dr. Flynn suggests reframing the question. In fact, evidence exists that children with high blood pressure are at higher risk of left ventricular hypertrophy, increased arterial stiffness, and changes in retinal arteries,” noted Dr. Sexson Tejtel.
 

Evidence of pediatric heart damage has been documented in autopsies

“It is imperative that children have blood pressure evaluation,” she urged. “There is evidence that there are changes similar to those seen in adults with cardiovascular compromise. It has been shown that children dying of other causes [accidents] who have these problems also have more plaque on autopsy, indicating that those with high blood pressure are more likely to have markers of CVD already present in childhood.

“One of the keys of pediatric medicine is prevention and the counseling for prevention of adult diseases. The duration of study necessary to objectively determine whether treatment of hypertension in childhood reduces the risk of adult cardiac problems is extensive. If nothing is done now, we are putting more future generations in danger. We must provide appropriate counseling for children and their families regarding lifestyle improvements, to have a chance to improve cardiovascular risk factors in adults, including hypertension, hyperlipidemia and/or obesity,” urged Dr. Sexson Tejtel.

All members of the USPSTF received travel reimbursement and honoraria. Dr. Barry received grants and personal fees from Healthwise. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. Dr. Flynn reported receiving grants from the National Institutes of Health and royalties from UpToDate and Springer outside the submitted work. Dr. Sexson Tejtel said she had no relevant financial disclosures or conflicts of interest.

SOURCE: USPSTF. JAMA. 2020 Nov 10. doi: 10.1001/jama.2020.20122.

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

[email protected]

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

[email protected]

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

[email protected]