TBD Meeting (3243-23)

PHILADELPHIA – In two studies run in parallel fashion to test different strategies, one that employed automatic referral to a pharmacist appeared to be superior to one using alerts from the electronic health record (EHR) in increasing the number of at-risk patients receiving a prescription for statins.

When outcomes were compared across these related studies, the pharmacist referrals had a greater positive impact on statin prescriptions while also increasing the proportion of patients on an appropriate statin dose, reported Alexander C. Faranoff, MD, assistant professor of cardiovascular medicine at Penn Medicine, Philadelphia.

The parallel studies were part of the SUPER LIPID program, created to generate evidence-based strategies for increasing the proportion of at-risk patients on statins. Dr. Faranoff said current data show that at least 50% of patients indicated for high-intensity statins in the United States are not taking them.

The two studies were presented together in a late breaking presentation at the American Heart Association scientific sessions.
 

EHR algorithm identifies statin candidates

The candidates for statin therapy were identified through an EHR algorithm for both studies. Both compared the impact of the intervention against a baseline period of usual care, although the study of EHR alerts also randomized physicians to provide usual care for 3 months or 6 months prior to intervention.

Dr. Faranoff described these interventions as non–visit related and visit related.

In the study of the non–visit-related strategy, referrals were generated by EHR and sent directly to the pharmacist. Upon receipt, the pharmacist verified the order was appropriate and called the patient directly to discuss starting therapy. Patients agreeing to start a statin were provided with a prescription and followed by the pharmacist.

In the study of the patient-visit approach, physicians seeing EHR-identified candidates received interruptive pop-up alerts during patient encounters. The physicians were randomized to provide usual care for 3 or 6 months before they began receiving alerts. The alerts recommended referral to a pharmacist.

During usual care in the non–visit-related study, only 15.2% of the 975 candidates for statins received a prescription. During the intervention period, the rate climbed to 31.6%. Statistically, the intervention more than doubled the odds ratio (OR) of receiving a statin prescription relative to usual care (OR 2.22; 95% confidence interval [CI] 1.47-3.37).

In addition, the proportion of patients receiving an appropriate dose of statins climbed from 7.7% in the period of usual care to 24.8% in the intervention period (OR 6.79; 95% CI 4.00-11.53).
 

Visit-based study also randomized

In the study evaluating a visit-based intervention, 16 physicians were randomized to deliver usual care for 3 or 6 months. Of physicians randomized to 3 months, 970 candidates for statins were treated during the 6-month intervention period. The physicians randomized to usual care for 6 months treated 672 candidates for statins during a 3-month intervention period,

More than 3,000 alerts were sent to both groups of physicians over the intervention period. Only 165 (4.6%) were associated with a prescription.

For the group randomized to 3 months of usual care, the proportion of candidates for statins who received a prescription rose from 14.9% during the period of usual care to 17.6% in the first 3 months of intervention and then fell slightly to 15.5% in the second 3 months.

For the group randomized to usual care for 6 months, the proportion of candidates for statins who received a prescription rose from about 11% during the period of usual care to 14.6%. Combining data from both arms, the small gain in prescriptions was significant but modest (OR 1.43; 95% CI 1.02-2.00).

In addition, the visit-based EHR notifications failed to yield a significant gain in the proportion of patients on an appropriate statin dose. During the intervention period, this proportion was only about 9% of patients treated by either of the two groups of randomized physicians,

The SUPER LIPID program involved 11 internal medicine and family medicine clinics in rural Pennsylvania. In the visit-based intervention, 16 primary care physicians (PCPs) were randomized. In the asynchronous intervention, 10 primary care practices participated. The EHR identified a total of 1,950 candidates for a statin.

Although the gain in statin prescriptions was disappointing for the visit-based intervention, the strategy of using the EHR to refer statin-eligible patients to pharmacists “could be an effective adjunct to visit-based clinical interactions in increasing statin prescribing for high-risk patients,” Dr. Faranoff maintained.
 

Overcoming clinical inertia a challenge

The greater efficacy of a pharmacist-based approach did not surprise the AHA-invited discussant, Benjamin M. Scirica, MD, associate professor of medicine at Harvard Medical School, Boston.

Pointing out that the pharmacist-based strategy of increasing statin prescriptions is more complicated and more costly, he said, “You get what you pay for.” In his opinion, simple solutions are unlikely ever to be effective due to the complex reasons for clinical inertia. Overall, he thinks a multifaceted approach to placing more patients who need statins on therapy is essential.

“Implementation science is hard,” Dr. Scirica said. Even though the referral-to-a-pharmacist approach ended up putting more patients on statins and putting them on an appropriate dose, he said even this more effective strategy “is still not getting to the majority of patients.”

This does not mean that this approach is without merit or should not be one of many strategies employed, but Dr. Scirica said “there is so much more to be done,” and that it should be employed along with other initiatives.

Faranoff reports no potential conflicts of interest. Dr. Scirica reports financial relationships with AbbVie, Aktiia, AstraZeneca, Better Therapeutics, Boehringer-Ingelheim, Eisai, GlaxoSmithKline, Hanmi, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi.

PHILADELPHIA – In two studies run in parallel fashion to test different strategies, one that employed automatic referral to a pharmacist appeared to be superior to one using alerts from the electronic health record (EHR) in increasing the number of at-risk patients receiving a prescription for statins.

When outcomes were compared across these related studies, the pharmacist referrals had a greater positive impact on statin prescriptions while also increasing the proportion of patients on an appropriate statin dose, reported Alexander C. Faranoff, MD, assistant professor of cardiovascular medicine at Penn Medicine, Philadelphia.

The parallel studies were part of the SUPER LIPID program, created to generate evidence-based strategies for increasing the proportion of at-risk patients on statins. Dr. Faranoff said current data show that at least 50% of patients indicated for high-intensity statins in the United States are not taking them.

The two studies were presented together in a late breaking presentation at the American Heart Association scientific sessions.
 

EHR algorithm identifies statin candidates

The candidates for statin therapy were identified through an EHR algorithm for both studies. Both compared the impact of the intervention against a baseline period of usual care, although the study of EHR alerts also randomized physicians to provide usual care for 3 months or 6 months prior to intervention.

Dr. Faranoff described these interventions as non–visit related and visit related.

In the study of the non–visit-related strategy, referrals were generated by EHR and sent directly to the pharmacist. Upon receipt, the pharmacist verified the order was appropriate and called the patient directly to discuss starting therapy. Patients agreeing to start a statin were provided with a prescription and followed by the pharmacist.

In the study of the patient-visit approach, physicians seeing EHR-identified candidates received interruptive pop-up alerts during patient encounters. The physicians were randomized to provide usual care for 3 or 6 months before they began receiving alerts. The alerts recommended referral to a pharmacist.

During usual care in the non–visit-related study, only 15.2% of the 975 candidates for statins received a prescription. During the intervention period, the rate climbed to 31.6%. Statistically, the intervention more than doubled the odds ratio (OR) of receiving a statin prescription relative to usual care (OR 2.22; 95% confidence interval [CI] 1.47-3.37).

In addition, the proportion of patients receiving an appropriate dose of statins climbed from 7.7% in the period of usual care to 24.8% in the intervention period (OR 6.79; 95% CI 4.00-11.53).
 

Visit-based study also randomized

In the study evaluating a visit-based intervention, 16 physicians were randomized to deliver usual care for 3 or 6 months. Of physicians randomized to 3 months, 970 candidates for statins were treated during the 6-month intervention period. The physicians randomized to usual care for 6 months treated 672 candidates for statins during a 3-month intervention period,

More than 3,000 alerts were sent to both groups of physicians over the intervention period. Only 165 (4.6%) were associated with a prescription.

For the group randomized to 3 months of usual care, the proportion of candidates for statins who received a prescription rose from 14.9% during the period of usual care to 17.6% in the first 3 months of intervention and then fell slightly to 15.5% in the second 3 months.

For the group randomized to usual care for 6 months, the proportion of candidates for statins who received a prescription rose from about 11% during the period of usual care to 14.6%. Combining data from both arms, the small gain in prescriptions was significant but modest (OR 1.43; 95% CI 1.02-2.00).

In addition, the visit-based EHR notifications failed to yield a significant gain in the proportion of patients on an appropriate statin dose. During the intervention period, this proportion was only about 9% of patients treated by either of the two groups of randomized physicians,

The SUPER LIPID program involved 11 internal medicine and family medicine clinics in rural Pennsylvania. In the visit-based intervention, 16 primary care physicians (PCPs) were randomized. In the asynchronous intervention, 10 primary care practices participated. The EHR identified a total of 1,950 candidates for a statin.

Although the gain in statin prescriptions was disappointing for the visit-based intervention, the strategy of using the EHR to refer statin-eligible patients to pharmacists “could be an effective adjunct to visit-based clinical interactions in increasing statin prescribing for high-risk patients,” Dr. Faranoff maintained.
 

Overcoming clinical inertia a challenge

The greater efficacy of a pharmacist-based approach did not surprise the AHA-invited discussant, Benjamin M. Scirica, MD, associate professor of medicine at Harvard Medical School, Boston.

Pointing out that the pharmacist-based strategy of increasing statin prescriptions is more complicated and more costly, he said, “You get what you pay for.” In his opinion, simple solutions are unlikely ever to be effective due to the complex reasons for clinical inertia. Overall, he thinks a multifaceted approach to placing more patients who need statins on therapy is essential.

“Implementation science is hard,” Dr. Scirica said. Even though the referral-to-a-pharmacist approach ended up putting more patients on statins and putting them on an appropriate dose, he said even this more effective strategy “is still not getting to the majority of patients.”

This does not mean that this approach is without merit or should not be one of many strategies employed, but Dr. Scirica said “there is so much more to be done,” and that it should be employed along with other initiatives.

Faranoff reports no potential conflicts of interest. Dr. Scirica reports financial relationships with AbbVie, Aktiia, AstraZeneca, Better Therapeutics, Boehringer-Ingelheim, Eisai, GlaxoSmithKline, Hanmi, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi.

PHILADELPHIA – In two studies run in parallel fashion to test different strategies, one that employed automatic referral to a pharmacist appeared to be superior to one using alerts from the electronic health record (EHR) in increasing the number of at-risk patients receiving a prescription for statins.

When outcomes were compared across these related studies, the pharmacist referrals had a greater positive impact on statin prescriptions while also increasing the proportion of patients on an appropriate statin dose, reported Alexander C. Faranoff, MD, assistant professor of cardiovascular medicine at Penn Medicine, Philadelphia.

The parallel studies were part of the SUPER LIPID program, created to generate evidence-based strategies for increasing the proportion of at-risk patients on statins. Dr. Faranoff said current data show that at least 50% of patients indicated for high-intensity statins in the United States are not taking them.

The two studies were presented together in a late breaking presentation at the American Heart Association scientific sessions.
 

EHR algorithm identifies statin candidates

The candidates for statin therapy were identified through an EHR algorithm for both studies. Both compared the impact of the intervention against a baseline period of usual care, although the study of EHR alerts also randomized physicians to provide usual care for 3 months or 6 months prior to intervention.

Dr. Faranoff described these interventions as non–visit related and visit related.

In the study of the non–visit-related strategy, referrals were generated by EHR and sent directly to the pharmacist. Upon receipt, the pharmacist verified the order was appropriate and called the patient directly to discuss starting therapy. Patients agreeing to start a statin were provided with a prescription and followed by the pharmacist.

In the study of the patient-visit approach, physicians seeing EHR-identified candidates received interruptive pop-up alerts during patient encounters. The physicians were randomized to provide usual care for 3 or 6 months before they began receiving alerts. The alerts recommended referral to a pharmacist.

During usual care in the non–visit-related study, only 15.2% of the 975 candidates for statins received a prescription. During the intervention period, the rate climbed to 31.6%. Statistically, the intervention more than doubled the odds ratio (OR) of receiving a statin prescription relative to usual care (OR 2.22; 95% confidence interval [CI] 1.47-3.37).

In addition, the proportion of patients receiving an appropriate dose of statins climbed from 7.7% in the period of usual care to 24.8% in the intervention period (OR 6.79; 95% CI 4.00-11.53).
 

Visit-based study also randomized

In the study evaluating a visit-based intervention, 16 physicians were randomized to deliver usual care for 3 or 6 months. Of physicians randomized to 3 months, 970 candidates for statins were treated during the 6-month intervention period. The physicians randomized to usual care for 6 months treated 672 candidates for statins during a 3-month intervention period,

More than 3,000 alerts were sent to both groups of physicians over the intervention period. Only 165 (4.6%) were associated with a prescription.

For the group randomized to 3 months of usual care, the proportion of candidates for statins who received a prescription rose from 14.9% during the period of usual care to 17.6% in the first 3 months of intervention and then fell slightly to 15.5% in the second 3 months.

For the group randomized to usual care for 6 months, the proportion of candidates for statins who received a prescription rose from about 11% during the period of usual care to 14.6%. Combining data from both arms, the small gain in prescriptions was significant but modest (OR 1.43; 95% CI 1.02-2.00).

In addition, the visit-based EHR notifications failed to yield a significant gain in the proportion of patients on an appropriate statin dose. During the intervention period, this proportion was only about 9% of patients treated by either of the two groups of randomized physicians,

The SUPER LIPID program involved 11 internal medicine and family medicine clinics in rural Pennsylvania. In the visit-based intervention, 16 primary care physicians (PCPs) were randomized. In the asynchronous intervention, 10 primary care practices participated. The EHR identified a total of 1,950 candidates for a statin.

Although the gain in statin prescriptions was disappointing for the visit-based intervention, the strategy of using the EHR to refer statin-eligible patients to pharmacists “could be an effective adjunct to visit-based clinical interactions in increasing statin prescribing for high-risk patients,” Dr. Faranoff maintained.
 

Overcoming clinical inertia a challenge

The greater efficacy of a pharmacist-based approach did not surprise the AHA-invited discussant, Benjamin M. Scirica, MD, associate professor of medicine at Harvard Medical School, Boston.

Pointing out that the pharmacist-based strategy of increasing statin prescriptions is more complicated and more costly, he said, “You get what you pay for.” In his opinion, simple solutions are unlikely ever to be effective due to the complex reasons for clinical inertia. Overall, he thinks a multifaceted approach to placing more patients who need statins on therapy is essential.

“Implementation science is hard,” Dr. Scirica said. Even though the referral-to-a-pharmacist approach ended up putting more patients on statins and putting them on an appropriate dose, he said even this more effective strategy “is still not getting to the majority of patients.”

This does not mean that this approach is without merit or should not be one of many strategies employed, but Dr. Scirica said “there is so much more to be done,” and that it should be employed along with other initiatives.

Faranoff reports no potential conflicts of interest. Dr. Scirica reports financial relationships with AbbVie, Aktiia, AstraZeneca, Better Therapeutics, Boehringer-Ingelheim, Eisai, GlaxoSmithKline, Hanmi, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi.

People who followed a low-salt diet for just a week experienced a reduction in systolic blood pressure of about 6 mm Hg, in a new study.

The CARDIA-SSBP trial involved 213 individuals aged 50-75 years, including those with and those without hypertension, and showed that the decline in blood pressure brought about by a low-salt diet was independent of hypertension status and antihypertensive medication use. It was also generally consistent across subgroups and did not result in excess adverse events.

“The blood pressure reduction we see here is meaningful, and comparable to that produced by one antihypertensive medication,” lead investigator Deepak Gupta, MD, Vanderbilt University Medical Center, Nashville, Tenn., said in an interview.

Dr. Gupta presented the CARDIA-SSBP study on Nov. 11 at the American Heart Association scientific sessions, held in Philadelphia. The study was published online in JAMA. The exact menus used in the study are available in a supplement to the JAMA paper.

“In order to live a healthy lifestyle, understanding what we eat has important health effects. Raised blood pressure contributes to one out of every eight deaths worldwide,” Dr. Gupta noted. “If people want to lower their blood pressure, attention to dietary sodium is one part of that. If individuals can stick with a low sodium diet, they may be able to stop taking one of their antihypertensive medications, and those who are normotensive will be less likely to develop hypertension.”

Commentators said the study had significant implications for public health, but they pointed out that maintaining a low-sodium diet over the long term is challenging, given the high salt content of generally available foods.

Dr. Gupta noted that the study did use commercially available products in the low-sodium diets and the menus are available for people to follow, making it more accessible than some diets used in previous studies.

“What may also be attractive to people is that you don’t have to wait for months to see an effect. If you start to consume a low-sodium diet, you can see results on blood pressure rapidly, within a week,” he said.

The diet in this study brought about a large reduction in dietary sodium, but Dr. Gupta says any reduction in dietary sodium is likely to be beneficial.

“If you go to the level that we got to, you could expect to see a reduction of around 6 mm Hg. But it’s like walking – you don’t necessarily need to get to 10,000 steps every day. Any amount of walking or physical activity is of benefit. The same is probably true for salt: Any reduction that you can make is probably of benefit.”

For the study, participants had their blood pressure measured by 24-hour ambulatory monitoring while on their usual diets. They were then randomly assigned to either a high-sodium diet or a low-sodium diet for 1 week. Participants then crossed over to the opposite diet for 1 week, with blood pressure measured over a 24-hour period on the last day of each diet.

As assessed by 24-hour urine excretion, the usual diet of participants was found to already be high in sodium (median, 4.45 g/d). This increased to a median of 5.00 g/d when on the high-sodium diet in the study and decreased to 1.27 g/d while on the low-sodium diet.

Results found participants had a median systolic blood pressure of 125 mm Hg on their usual diets. This was raised to 126 mm Hg on the high-sodium diet and lowered to 119 mm Hg on the low-sodium diet.

The researchers also reported that 75% of individuals showed a blood pressure reduction on the low-sodium diet and are thus defined as “salt-sensitive.” This is a higher percentage than found in previous studies.

“Of those that didn’t show a blood pressure reduction with a low-sodium diet in this study, it appears that they may not have been so adherent to the diet as those who did show a blood pressure reduction,” Dr. Gupta said.

He noted that hypertension is the most common chronic disease condition worldwide, with about 1.3 billion people affected, and although it has been known for some time that dietary sodium affects blood pressure, there have been some gaps in previous studies.

For example, many studies have excluded individuals who were already taking antihypertensive medications and people with diabetes, and they have generally not included many older individuals. The current study found that all of these groups showed significant blood pressure reductions by reducing dietary sodium.
 

Large effect in people with diabetes

Subgroup analysis largely showed consistent results across the population, regardless of age, sex, race, and body mass index and whether participants were taking antihypertensive medication or not, but there were a couple of exceptions. Individuals with higher blood pressure at baseline seemed to have a greater effect of lowering dietary sodium, although those who were normotensive at baseline still showed significant blood pressure reduction, Dr. Gupta reported.

The researchers found a particularly large reduction in blood pressure from lowering sodium intake in people with diabetes, who made up about 21% of the overall cohort. Their average reduction in systolic blood pressure between the high and low sodium diet was close to 17 mm Hg rather than the 7-8 mm Hg in the whole cohort.

Dr. Gupta said that the results are applicable to most of the population.

“The people who will be most motivated to follow a low-sodium diet are those with hypertension. But even in normotensive individuals, there is likely to be benefit.”

To help people follow a low-sodium diet, Dr. Gupta says education campaigns are needed “to show people that they can do it and make it work.” But there are bigger structural issues that need to be addressed at policy and governmental levels.

“Most of our food available in grocery stores and restaurants is high in salt. We now have a preponderance of evidence showing us that we need to change what’s available in the food supply,” he said. “There is a push going on for this now, and the U.S. has introduced some guidelines for the food industry on sodium content of foods. These are voluntary at this point, but it’s a start.”
 

Difficult to maintain long term

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, noted that sodium reduction is known to reduce blood pressure, with greater sodium reductions giving greater blood pressure decreases, and that some people are more sensitive to the effects of sodium than others.

He described CARDIA-SSBP as a “well-done study.”

“They managed to get a very low sodium intake and a large difference between the two groups, which translated into a big reduction in systolic blood pressure,” Dr. Whelton said. “However, the problem with these sorts of trials where the diets are provided to the participants is that although they show proof of concept, it is difficult to generalize because we can’t normally provide patients with their meals. In this type of ‘feeding’ study, we find it difficult to maintain people on their behavioral intervention over the long term.”

Dr. Whelton said that he was more excited about this trial knowing that the food given was commercially available. “That makes it more practical, but you still have to be quite motivated to follow a diet like this. Buying low-sodium products in the supermarket does require quite a lot of work to read the labels, and sometimes the low-sodium foods are specialty products and are more expensive.”

He pointed out that older people in higher socioeconomic classes are more likely to attempt this and do better from behavioral interventions in general. “Unfortunately, people who don’t do well from behavioral interventions like this are those from lower socioeconomic groups, who are ones at most at risk for cardiovascular disease.”

Dr. Whelton noted that the food industry has been reluctant to lower sodium content because high-salt foods sell better. “Unfortunately, foods high in saturated fat and salt taste good to most people. We are generally attuned to a high salt intake. But when people have been following a low-salt diet for a while, they generally don’t like high-salt foods anymore. They become attuned to lower-sodium diet,” he added.
 

New U.S. sodium reduction guidelines

Discussant of the CARDIA-SSBP study at the AHA meeting, Cheryl Anderson, MD, University of California, San Diego, said that the findings were important and consistent with prior studies.

“These studies have global implications because salt is ubiquitous in the food supply in much of the world,” she noted, adding that, “Americans consume almost 50% more sodium than recommended, and there has been a persistent lack of adherence to healthy diet recommendations for reductions in salt, sugar, and fats.”

Dr. Anderson pointed out that in 2021, the Food and Drug Administration issued guidance for voluntary sodium reduction, which uses a gradual approach, with targets to reach a population goal of 3,000 mg/d of sodium by 2023 and 2,300 mg/d by 2031.

“These targets apply to 150 categories of food that are sales-weighted to focus on dominant sellers in each category. They apply to food manufacturers, restaurants and food service operations,” she concluded. “These targets serve as a basis for continued dialogue. The research community eagerly awaits the review of population-based data to help refine this approach and goals.”

This study was supported by grants from the National Heart, Lung, and Blood Institute, the National Institutes of Health, the American Heart Association, and the National Center for Advancing Translational Sciences. The authors report no disclosures.

A version of this article appeared on Medscape.com.

People who followed a low-salt diet for just a week experienced a reduction in systolic blood pressure of about 6 mm Hg, in a new study.

The CARDIA-SSBP trial involved 213 individuals aged 50-75 years, including those with and those without hypertension, and showed that the decline in blood pressure brought about by a low-salt diet was independent of hypertension status and antihypertensive medication use. It was also generally consistent across subgroups and did not result in excess adverse events.

“The blood pressure reduction we see here is meaningful, and comparable to that produced by one antihypertensive medication,” lead investigator Deepak Gupta, MD, Vanderbilt University Medical Center, Nashville, Tenn., said in an interview.

Dr. Gupta presented the CARDIA-SSBP study on Nov. 11 at the American Heart Association scientific sessions, held in Philadelphia. The study was published online in JAMA. The exact menus used in the study are available in a supplement to the JAMA paper.

“In order to live a healthy lifestyle, understanding what we eat has important health effects. Raised blood pressure contributes to one out of every eight deaths worldwide,” Dr. Gupta noted. “If people want to lower their blood pressure, attention to dietary sodium is one part of that. If individuals can stick with a low sodium diet, they may be able to stop taking one of their antihypertensive medications, and those who are normotensive will be less likely to develop hypertension.”

Commentators said the study had significant implications for public health, but they pointed out that maintaining a low-sodium diet over the long term is challenging, given the high salt content of generally available foods.

Dr. Gupta noted that the study did use commercially available products in the low-sodium diets and the menus are available for people to follow, making it more accessible than some diets used in previous studies.

“What may also be attractive to people is that you don’t have to wait for months to see an effect. If you start to consume a low-sodium diet, you can see results on blood pressure rapidly, within a week,” he said.

The diet in this study brought about a large reduction in dietary sodium, but Dr. Gupta says any reduction in dietary sodium is likely to be beneficial.

“If you go to the level that we got to, you could expect to see a reduction of around 6 mm Hg. But it’s like walking – you don’t necessarily need to get to 10,000 steps every day. Any amount of walking or physical activity is of benefit. The same is probably true for salt: Any reduction that you can make is probably of benefit.”

For the study, participants had their blood pressure measured by 24-hour ambulatory monitoring while on their usual diets. They were then randomly assigned to either a high-sodium diet or a low-sodium diet for 1 week. Participants then crossed over to the opposite diet for 1 week, with blood pressure measured over a 24-hour period on the last day of each diet.

As assessed by 24-hour urine excretion, the usual diet of participants was found to already be high in sodium (median, 4.45 g/d). This increased to a median of 5.00 g/d when on the high-sodium diet in the study and decreased to 1.27 g/d while on the low-sodium diet.

Results found participants had a median systolic blood pressure of 125 mm Hg on their usual diets. This was raised to 126 mm Hg on the high-sodium diet and lowered to 119 mm Hg on the low-sodium diet.

The researchers also reported that 75% of individuals showed a blood pressure reduction on the low-sodium diet and are thus defined as “salt-sensitive.” This is a higher percentage than found in previous studies.

“Of those that didn’t show a blood pressure reduction with a low-sodium diet in this study, it appears that they may not have been so adherent to the diet as those who did show a blood pressure reduction,” Dr. Gupta said.

He noted that hypertension is the most common chronic disease condition worldwide, with about 1.3 billion people affected, and although it has been known for some time that dietary sodium affects blood pressure, there have been some gaps in previous studies.

For example, many studies have excluded individuals who were already taking antihypertensive medications and people with diabetes, and they have generally not included many older individuals. The current study found that all of these groups showed significant blood pressure reductions by reducing dietary sodium.
 

Large effect in people with diabetes

Subgroup analysis largely showed consistent results across the population, regardless of age, sex, race, and body mass index and whether participants were taking antihypertensive medication or not, but there were a couple of exceptions. Individuals with higher blood pressure at baseline seemed to have a greater effect of lowering dietary sodium, although those who were normotensive at baseline still showed significant blood pressure reduction, Dr. Gupta reported.

The researchers found a particularly large reduction in blood pressure from lowering sodium intake in people with diabetes, who made up about 21% of the overall cohort. Their average reduction in systolic blood pressure between the high and low sodium diet was close to 17 mm Hg rather than the 7-8 mm Hg in the whole cohort.

Dr. Gupta said that the results are applicable to most of the population.

“The people who will be most motivated to follow a low-sodium diet are those with hypertension. But even in normotensive individuals, there is likely to be benefit.”

To help people follow a low-sodium diet, Dr. Gupta says education campaigns are needed “to show people that they can do it and make it work.” But there are bigger structural issues that need to be addressed at policy and governmental levels.

“Most of our food available in grocery stores and restaurants is high in salt. We now have a preponderance of evidence showing us that we need to change what’s available in the food supply,” he said. “There is a push going on for this now, and the U.S. has introduced some guidelines for the food industry on sodium content of foods. These are voluntary at this point, but it’s a start.”
 

Difficult to maintain long term

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, noted that sodium reduction is known to reduce blood pressure, with greater sodium reductions giving greater blood pressure decreases, and that some people are more sensitive to the effects of sodium than others.

He described CARDIA-SSBP as a “well-done study.”

“They managed to get a very low sodium intake and a large difference between the two groups, which translated into a big reduction in systolic blood pressure,” Dr. Whelton said. “However, the problem with these sorts of trials where the diets are provided to the participants is that although they show proof of concept, it is difficult to generalize because we can’t normally provide patients with their meals. In this type of ‘feeding’ study, we find it difficult to maintain people on their behavioral intervention over the long term.”

Dr. Whelton said that he was more excited about this trial knowing that the food given was commercially available. “That makes it more practical, but you still have to be quite motivated to follow a diet like this. Buying low-sodium products in the supermarket does require quite a lot of work to read the labels, and sometimes the low-sodium foods are specialty products and are more expensive.”

He pointed out that older people in higher socioeconomic classes are more likely to attempt this and do better from behavioral interventions in general. “Unfortunately, people who don’t do well from behavioral interventions like this are those from lower socioeconomic groups, who are ones at most at risk for cardiovascular disease.”

Dr. Whelton noted that the food industry has been reluctant to lower sodium content because high-salt foods sell better. “Unfortunately, foods high in saturated fat and salt taste good to most people. We are generally attuned to a high salt intake. But when people have been following a low-salt diet for a while, they generally don’t like high-salt foods anymore. They become attuned to lower-sodium diet,” he added.
 

New U.S. sodium reduction guidelines

Discussant of the CARDIA-SSBP study at the AHA meeting, Cheryl Anderson, MD, University of California, San Diego, said that the findings were important and consistent with prior studies.

“These studies have global implications because salt is ubiquitous in the food supply in much of the world,” she noted, adding that, “Americans consume almost 50% more sodium than recommended, and there has been a persistent lack of adherence to healthy diet recommendations for reductions in salt, sugar, and fats.”

Dr. Anderson pointed out that in 2021, the Food and Drug Administration issued guidance for voluntary sodium reduction, which uses a gradual approach, with targets to reach a population goal of 3,000 mg/d of sodium by 2023 and 2,300 mg/d by 2031.

“These targets apply to 150 categories of food that are sales-weighted to focus on dominant sellers in each category. They apply to food manufacturers, restaurants and food service operations,” she concluded. “These targets serve as a basis for continued dialogue. The research community eagerly awaits the review of population-based data to help refine this approach and goals.”

This study was supported by grants from the National Heart, Lung, and Blood Institute, the National Institutes of Health, the American Heart Association, and the National Center for Advancing Translational Sciences. The authors report no disclosures.

A version of this article appeared on Medscape.com.

People who followed a low-salt diet for just a week experienced a reduction in systolic blood pressure of about 6 mm Hg, in a new study.

The CARDIA-SSBP trial involved 213 individuals aged 50-75 years, including those with and those without hypertension, and showed that the decline in blood pressure brought about by a low-salt diet was independent of hypertension status and antihypertensive medication use. It was also generally consistent across subgroups and did not result in excess adverse events.

“The blood pressure reduction we see here is meaningful, and comparable to that produced by one antihypertensive medication,” lead investigator Deepak Gupta, MD, Vanderbilt University Medical Center, Nashville, Tenn., said in an interview.

Dr. Gupta presented the CARDIA-SSBP study on Nov. 11 at the American Heart Association scientific sessions, held in Philadelphia. The study was published online in JAMA. The exact menus used in the study are available in a supplement to the JAMA paper.

“In order to live a healthy lifestyle, understanding what we eat has important health effects. Raised blood pressure contributes to one out of every eight deaths worldwide,” Dr. Gupta noted. “If people want to lower their blood pressure, attention to dietary sodium is one part of that. If individuals can stick with a low sodium diet, they may be able to stop taking one of their antihypertensive medications, and those who are normotensive will be less likely to develop hypertension.”

Commentators said the study had significant implications for public health, but they pointed out that maintaining a low-sodium diet over the long term is challenging, given the high salt content of generally available foods.

Dr. Gupta noted that the study did use commercially available products in the low-sodium diets and the menus are available for people to follow, making it more accessible than some diets used in previous studies.

“What may also be attractive to people is that you don’t have to wait for months to see an effect. If you start to consume a low-sodium diet, you can see results on blood pressure rapidly, within a week,” he said.

The diet in this study brought about a large reduction in dietary sodium, but Dr. Gupta says any reduction in dietary sodium is likely to be beneficial.

“If you go to the level that we got to, you could expect to see a reduction of around 6 mm Hg. But it’s like walking – you don’t necessarily need to get to 10,000 steps every day. Any amount of walking or physical activity is of benefit. The same is probably true for salt: Any reduction that you can make is probably of benefit.”

For the study, participants had their blood pressure measured by 24-hour ambulatory monitoring while on their usual diets. They were then randomly assigned to either a high-sodium diet or a low-sodium diet for 1 week. Participants then crossed over to the opposite diet for 1 week, with blood pressure measured over a 24-hour period on the last day of each diet.

As assessed by 24-hour urine excretion, the usual diet of participants was found to already be high in sodium (median, 4.45 g/d). This increased to a median of 5.00 g/d when on the high-sodium diet in the study and decreased to 1.27 g/d while on the low-sodium diet.

Results found participants had a median systolic blood pressure of 125 mm Hg on their usual diets. This was raised to 126 mm Hg on the high-sodium diet and lowered to 119 mm Hg on the low-sodium diet.

The researchers also reported that 75% of individuals showed a blood pressure reduction on the low-sodium diet and are thus defined as “salt-sensitive.” This is a higher percentage than found in previous studies.

“Of those that didn’t show a blood pressure reduction with a low-sodium diet in this study, it appears that they may not have been so adherent to the diet as those who did show a blood pressure reduction,” Dr. Gupta said.

He noted that hypertension is the most common chronic disease condition worldwide, with about 1.3 billion people affected, and although it has been known for some time that dietary sodium affects blood pressure, there have been some gaps in previous studies.

For example, many studies have excluded individuals who were already taking antihypertensive medications and people with diabetes, and they have generally not included many older individuals. The current study found that all of these groups showed significant blood pressure reductions by reducing dietary sodium.
 

Large effect in people with diabetes

Subgroup analysis largely showed consistent results across the population, regardless of age, sex, race, and body mass index and whether participants were taking antihypertensive medication or not, but there were a couple of exceptions. Individuals with higher blood pressure at baseline seemed to have a greater effect of lowering dietary sodium, although those who were normotensive at baseline still showed significant blood pressure reduction, Dr. Gupta reported.

The researchers found a particularly large reduction in blood pressure from lowering sodium intake in people with diabetes, who made up about 21% of the overall cohort. Their average reduction in systolic blood pressure between the high and low sodium diet was close to 17 mm Hg rather than the 7-8 mm Hg in the whole cohort.

Dr. Gupta said that the results are applicable to most of the population.

“The people who will be most motivated to follow a low-sodium diet are those with hypertension. But even in normotensive individuals, there is likely to be benefit.”

To help people follow a low-sodium diet, Dr. Gupta says education campaigns are needed “to show people that they can do it and make it work.” But there are bigger structural issues that need to be addressed at policy and governmental levels.

“Most of our food available in grocery stores and restaurants is high in salt. We now have a preponderance of evidence showing us that we need to change what’s available in the food supply,” he said. “There is a push going on for this now, and the U.S. has introduced some guidelines for the food industry on sodium content of foods. These are voluntary at this point, but it’s a start.”
 

Difficult to maintain long term

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, noted that sodium reduction is known to reduce blood pressure, with greater sodium reductions giving greater blood pressure decreases, and that some people are more sensitive to the effects of sodium than others.

He described CARDIA-SSBP as a “well-done study.”

“They managed to get a very low sodium intake and a large difference between the two groups, which translated into a big reduction in systolic blood pressure,” Dr. Whelton said. “However, the problem with these sorts of trials where the diets are provided to the participants is that although they show proof of concept, it is difficult to generalize because we can’t normally provide patients with their meals. In this type of ‘feeding’ study, we find it difficult to maintain people on their behavioral intervention over the long term.”

Dr. Whelton said that he was more excited about this trial knowing that the food given was commercially available. “That makes it more practical, but you still have to be quite motivated to follow a diet like this. Buying low-sodium products in the supermarket does require quite a lot of work to read the labels, and sometimes the low-sodium foods are specialty products and are more expensive.”

He pointed out that older people in higher socioeconomic classes are more likely to attempt this and do better from behavioral interventions in general. “Unfortunately, people who don’t do well from behavioral interventions like this are those from lower socioeconomic groups, who are ones at most at risk for cardiovascular disease.”

Dr. Whelton noted that the food industry has been reluctant to lower sodium content because high-salt foods sell better. “Unfortunately, foods high in saturated fat and salt taste good to most people. We are generally attuned to a high salt intake. But when people have been following a low-salt diet for a while, they generally don’t like high-salt foods anymore. They become attuned to lower-sodium diet,” he added.
 

New U.S. sodium reduction guidelines

Discussant of the CARDIA-SSBP study at the AHA meeting, Cheryl Anderson, MD, University of California, San Diego, said that the findings were important and consistent with prior studies.

“These studies have global implications because salt is ubiquitous in the food supply in much of the world,” she noted, adding that, “Americans consume almost 50% more sodium than recommended, and there has been a persistent lack of adherence to healthy diet recommendations for reductions in salt, sugar, and fats.”

Dr. Anderson pointed out that in 2021, the Food and Drug Administration issued guidance for voluntary sodium reduction, which uses a gradual approach, with targets to reach a population goal of 3,000 mg/d of sodium by 2023 and 2,300 mg/d by 2031.

“These targets apply to 150 categories of food that are sales-weighted to focus on dominant sellers in each category. They apply to food manufacturers, restaurants and food service operations,” she concluded. “These targets serve as a basis for continued dialogue. The research community eagerly awaits the review of population-based data to help refine this approach and goals.”

This study was supported by grants from the National Heart, Lung, and Blood Institute, the National Institutes of Health, the American Heart Association, and the National Center for Advancing Translational Sciences. The authors report no disclosures.

A version of this article appeared on Medscape.com.

Self-monitoring blood pressure during the early postpartum period may take advantage of a “critical window” when better BP monitoring could prevent later cardiovascular events in women who have hypertensive pregnancies, new research suggests.

In a randomized trial of 220 women with preeclampsia or gestational hypertension, those who took daily postpartum BP readings and received clinician-guided advice for titrating antihypertensives had a 5 mm Hg–lower average diastolic BP at 9 months, compared with those receiving usual care.

Jamie Kitt, DPhil, from the University of Oxford (England) presented these findings from the Physicians Optimized Postpartum Hypertension Treatment (POP-HT, NCT04273854) clinical trial at the American Heart Association scientific sessions. The study was simultaneously published online in JAMA, and a cardiac imaging substudy was published online in Circulation.

“This trial identifies a potential need for a paradigm shift in the way women affected by hypertensive pregnancy are managed postnatally,” Dr. Kitt said. “If a 5–mm Hg improvement in BP is maintained longer term, it can result in about a 20% reduction in lifetime cardiovascular risk.”

The imaging substudy suggests that short-term postnatal optimization of BP control following hypertensive pregnancy through self-monitoring and physician-guided antihypertensive titration is linked with better cardiac remodeling changes seen by cardiovascular magnetic resonance and echocardiography.

POP-HT “proves for the first time that the first few weeks after delivery are a critical time that can determine the long-term cardiovascular health of the mother,” senior author Paul Leeson, PhD, also from the University of Oxford, who presented the findings in a press briefing, said in an interview.

“Interventions during this period can have long-term beneficial impacts on cardiovascular health,” he said. “These findings rewrite the textbook on our understanding of how and why hypertensive pregnancies associate with later cardiovascular disease in the mother.”

Next, Dr. Leeson said, “We need to work out the best ways to implement these interventions “at scale. Then we can ensure all women who have hypertensive pregnancies can get access to the long-term cardiovascular benefits we have demonstrated are possible through improving postpartum cardiac care,” he said, adding that “this is entirely achievable using current available technologies.”
 

Hypertension in pregnancy

About 1 in 10 pregnant women develop hypertension in pregnancy (preeclampsia or gestational hypertension), and 1 in 3 such women go on to develop chronic hypertension within 10 years, “when they are usually still in their 30s or 40s,” Dr. Leeson said.

During pregnancy, the heart remodels to cope with pregnancy, and it undergoes more severe changes if BP is high. Then during the 6 weeks after giving birth, this remodeling rapidly reverses.

Higher blood pressure in young adulthood is associated with a twofold higher risk of subsequent myocardial infarction and stroke. And abnormal cardiac remodeling postpartum is also linked with higher cardiovascular risk.

Self-monitoring blood pressure during the postpartum period may be a “critical window” for intervention.

Previously, the research group performed a pilot study, the Self-Management of Postnatal Antihypertensive Treatment (SNAP-HT) trial and the SNAP-extension trial, which compared a BP self-monitoring intervention with usual care in 91 women with gestational hypertension or preeclampsia requiring postnatal antihypertensive treatment.

Diastolic BP, which drives cardiovascular risk in younger populations, was 4.5–mm Hg lower at 6 months postpartum and 7–mm Hg lower at 4 years post partum in patients randomly assigned to BP self-management vs. usual care – even after they were no longer taking antihypertensives.

Building on these findings, the POP-HT trial enrolled 220 pregnant women seen at Oxford University Hospitals in the United Kingdom who were age 18 years or older, had either gestational hypertension or preeclampsia, and still required antihypertensives when they were being discharged from hospital after giving birth.

Following a baseline visit at day 1-6 after delivery, while in the postnatal ward, the patients were randomly assigned 1:1 to the intervention group (112 women) or usual-care group (108 women).

They had an average age of 32.6 years; 40% had gestational hypertension, and 60% had preeclampsia.

Women in the usual-care group typically received a BP review at 7-10 days after hospital discharge with a community midwife, and another at 6-8 weeks with their general practitioner.

The women in the intervention group were given and taught to use a Bluetooth-enabled OMRON Evolv BP monitor (Omron Healthcare Europe) while on the postnatal ward, and they installed a smartphone app on their mobile phones that transmitted self-monitored BP readings to a National Health Service-hosted, web-based platform.

They were instructed to take daily BP measurements (twice daily if out of target range). Dose titration of antihypertensives after hospital discharge was guided remotely by research clinicians, according to a guideline-based algorithm.

Patients in both groups had four study visits when their BP was measured: visit 1 (baseline) between days 1 and 6 post partum; visit 2 at week 1; visit 3 at week 6; and visit 4 between months 6 and 9 post partum.

Similar antihypertensive classes were prescribed in each group (enalapril 57%, nifedipine 27%, and labetalol 30% for intervention vs. enalapril 43%, nifedipine 30%, and labetalol 27% for control).

At 6 weeks, approximately 30% of participants in each group were still taking medication; this dropped to approximately 12% by visit 4.

The primary outcome – the mean 24-hour diastolic BP at visit 4 (roughly 9 months post partum), adjusted for baseline postnatal diastolic blood pressure – was 5.8–mm Hg lower in the intervention group than in the control group (71.2 mm Hg vs. 76.6 mm Hg; P < .001).

Secondary outcomes – between-group differences in systolic BP at 9 months, BP-related postnatal admission, and cardiac remodeling assessed by cardiac magnetic resonance – were all better in the intervention group.

The mean 24-hour average systolic BP at 9 months post partum, adjusted for baseline postnatal systolic BP was 6.5–mm Hg lower in the intervention group than in the control group (114.0 mm Hg vs. 120.3 mm Hg; P < .001).

There was an absolute risk reduction of 20% and a relative risk reduction of 73.5% in postnatal readmission. The number needed to treat to avoid one postnatal readmission was five, which “has potential for big cost savings,” said Dr. Leeson.

Blood pressure post partum can be improved with self-monitoring and physician-guided medication adjustment, Dr. Leeson summarized. The blood pressure remains low for at least 9 months, even when medication is stopped, and the intervention leads to beneficial cardiac remodeling.
 

U.S. pilot study

Non-Hispanic Black adults have a high hypertension and cardiovascular disease burden, and a related small U.S. study showed benefits of BP self-monitoring in a population comprising mainly Black women, Keith Ferdinand, MD, discussant of the POP-HT trial in the press briefing, said in an interview.

Dr. Ferdinand, from Tulane University, New Orleans, Louisiana, was lead author of the Text My Hypertension BP Meds NOLA pilot study that was published in February in the American Heart Journal Plus: Cardiology Research and Practice.

The study showed that text-messaging and social support increased hypertension medication adherence.

They enrolled 36 individuals, of whom 32 (89%) were non-Hispanic Black, and 23 (64%) were women. The participants received validated Bluetooth-enabled BP-monitoring devices that were synced to smartphones via a secured cloud-based application. The participants could send and receive messages to health care practitioners.

This intervention significantly improved medication adherence and systolic BP without modifying pharmacotherapy.
 

‘Need to be passionate about monitoring BP’

“The take-home messages from these exciting findings is that physicians and women who have had high BP during pregnancy need to be passionate about monitoring and controlling their blood pressure and not ignore it,” Anastasia Mihailidou, PhD, Royal North Shore Hospital, Sydney, the assigned discussant in the late-breaking trial session, said in an interview.

“It also resulted in fewer postpartum hospital readmissions for high blood pressure and benefit at 9 months in the structure and function of the heart and blood vessels of the women,” she said.

“While we need to see further studies in ethnically diverse women to see that they are reproducible, there are simple measures that clinicians can implement, and women can ask to have their BP monitored more frequently than the current practice. In the U.K. it is 5-10 days after delivery and then at 6-8 weeks after giving birth when changes in heart structure have already started,” Dr. Mihailidou noted.

“The procedure will need to be modified if there are no telemedicine facilities, but that should not stop having close monitoring of BP and treating it adequately. Monitoring requires an accurate BP monitor. There also has to be monitoring BP for the children.”

The trial was funded by a BHF Clinical Research Training Fellowship to Dr. Kitt, with additional support from the NIHR Oxford Biomedical Research Centre and Oxford BHF Centre for Research Excellence.

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

Self-monitoring blood pressure during the early postpartum period may take advantage of a “critical window” when better BP monitoring could prevent later cardiovascular events in women who have hypertensive pregnancies, new research suggests.

In a randomized trial of 220 women with preeclampsia or gestational hypertension, those who took daily postpartum BP readings and received clinician-guided advice for titrating antihypertensives had a 5 mm Hg–lower average diastolic BP at 9 months, compared with those receiving usual care.

Jamie Kitt, DPhil, from the University of Oxford (England) presented these findings from the Physicians Optimized Postpartum Hypertension Treatment (POP-HT, NCT04273854) clinical trial at the American Heart Association scientific sessions. The study was simultaneously published online in JAMA, and a cardiac imaging substudy was published online in Circulation.

“This trial identifies a potential need for a paradigm shift in the way women affected by hypertensive pregnancy are managed postnatally,” Dr. Kitt said. “If a 5–mm Hg improvement in BP is maintained longer term, it can result in about a 20% reduction in lifetime cardiovascular risk.”

The imaging substudy suggests that short-term postnatal optimization of BP control following hypertensive pregnancy through self-monitoring and physician-guided antihypertensive titration is linked with better cardiac remodeling changes seen by cardiovascular magnetic resonance and echocardiography.

POP-HT “proves for the first time that the first few weeks after delivery are a critical time that can determine the long-term cardiovascular health of the mother,” senior author Paul Leeson, PhD, also from the University of Oxford, who presented the findings in a press briefing, said in an interview.

“Interventions during this period can have long-term beneficial impacts on cardiovascular health,” he said. “These findings rewrite the textbook on our understanding of how and why hypertensive pregnancies associate with later cardiovascular disease in the mother.”

Next, Dr. Leeson said, “We need to work out the best ways to implement these interventions “at scale. Then we can ensure all women who have hypertensive pregnancies can get access to the long-term cardiovascular benefits we have demonstrated are possible through improving postpartum cardiac care,” he said, adding that “this is entirely achievable using current available technologies.”
 

Hypertension in pregnancy

About 1 in 10 pregnant women develop hypertension in pregnancy (preeclampsia or gestational hypertension), and 1 in 3 such women go on to develop chronic hypertension within 10 years, “when they are usually still in their 30s or 40s,” Dr. Leeson said.

During pregnancy, the heart remodels to cope with pregnancy, and it undergoes more severe changes if BP is high. Then during the 6 weeks after giving birth, this remodeling rapidly reverses.

Higher blood pressure in young adulthood is associated with a twofold higher risk of subsequent myocardial infarction and stroke. And abnormal cardiac remodeling postpartum is also linked with higher cardiovascular risk.

Self-monitoring blood pressure during the postpartum period may be a “critical window” for intervention.

Previously, the research group performed a pilot study, the Self-Management of Postnatal Antihypertensive Treatment (SNAP-HT) trial and the SNAP-extension trial, which compared a BP self-monitoring intervention with usual care in 91 women with gestational hypertension or preeclampsia requiring postnatal antihypertensive treatment.

Diastolic BP, which drives cardiovascular risk in younger populations, was 4.5–mm Hg lower at 6 months postpartum and 7–mm Hg lower at 4 years post partum in patients randomly assigned to BP self-management vs. usual care – even after they were no longer taking antihypertensives.

Building on these findings, the POP-HT trial enrolled 220 pregnant women seen at Oxford University Hospitals in the United Kingdom who were age 18 years or older, had either gestational hypertension or preeclampsia, and still required antihypertensives when they were being discharged from hospital after giving birth.

Following a baseline visit at day 1-6 after delivery, while in the postnatal ward, the patients were randomly assigned 1:1 to the intervention group (112 women) or usual-care group (108 women).

They had an average age of 32.6 years; 40% had gestational hypertension, and 60% had preeclampsia.

Women in the usual-care group typically received a BP review at 7-10 days after hospital discharge with a community midwife, and another at 6-8 weeks with their general practitioner.

The women in the intervention group were given and taught to use a Bluetooth-enabled OMRON Evolv BP monitor (Omron Healthcare Europe) while on the postnatal ward, and they installed a smartphone app on their mobile phones that transmitted self-monitored BP readings to a National Health Service-hosted, web-based platform.

They were instructed to take daily BP measurements (twice daily if out of target range). Dose titration of antihypertensives after hospital discharge was guided remotely by research clinicians, according to a guideline-based algorithm.

Patients in both groups had four study visits when their BP was measured: visit 1 (baseline) between days 1 and 6 post partum; visit 2 at week 1; visit 3 at week 6; and visit 4 between months 6 and 9 post partum.

Similar antihypertensive classes were prescribed in each group (enalapril 57%, nifedipine 27%, and labetalol 30% for intervention vs. enalapril 43%, nifedipine 30%, and labetalol 27% for control).

At 6 weeks, approximately 30% of participants in each group were still taking medication; this dropped to approximately 12% by visit 4.

The primary outcome – the mean 24-hour diastolic BP at visit 4 (roughly 9 months post partum), adjusted for baseline postnatal diastolic blood pressure – was 5.8–mm Hg lower in the intervention group than in the control group (71.2 mm Hg vs. 76.6 mm Hg; P < .001).

Secondary outcomes – between-group differences in systolic BP at 9 months, BP-related postnatal admission, and cardiac remodeling assessed by cardiac magnetic resonance – were all better in the intervention group.

The mean 24-hour average systolic BP at 9 months post partum, adjusted for baseline postnatal systolic BP was 6.5–mm Hg lower in the intervention group than in the control group (114.0 mm Hg vs. 120.3 mm Hg; P < .001).

There was an absolute risk reduction of 20% and a relative risk reduction of 73.5% in postnatal readmission. The number needed to treat to avoid one postnatal readmission was five, which “has potential for big cost savings,” said Dr. Leeson.

Blood pressure post partum can be improved with self-monitoring and physician-guided medication adjustment, Dr. Leeson summarized. The blood pressure remains low for at least 9 months, even when medication is stopped, and the intervention leads to beneficial cardiac remodeling.
 

U.S. pilot study

Non-Hispanic Black adults have a high hypertension and cardiovascular disease burden, and a related small U.S. study showed benefits of BP self-monitoring in a population comprising mainly Black women, Keith Ferdinand, MD, discussant of the POP-HT trial in the press briefing, said in an interview.

Dr. Ferdinand, from Tulane University, New Orleans, Louisiana, was lead author of the Text My Hypertension BP Meds NOLA pilot study that was published in February in the American Heart Journal Plus: Cardiology Research and Practice.

The study showed that text-messaging and social support increased hypertension medication adherence.

They enrolled 36 individuals, of whom 32 (89%) were non-Hispanic Black, and 23 (64%) were women. The participants received validated Bluetooth-enabled BP-monitoring devices that were synced to smartphones via a secured cloud-based application. The participants could send and receive messages to health care practitioners.

This intervention significantly improved medication adherence and systolic BP without modifying pharmacotherapy.
 

‘Need to be passionate about monitoring BP’

“The take-home messages from these exciting findings is that physicians and women who have had high BP during pregnancy need to be passionate about monitoring and controlling their blood pressure and not ignore it,” Anastasia Mihailidou, PhD, Royal North Shore Hospital, Sydney, the assigned discussant in the late-breaking trial session, said in an interview.

“It also resulted in fewer postpartum hospital readmissions for high blood pressure and benefit at 9 months in the structure and function of the heart and blood vessels of the women,” she said.

“While we need to see further studies in ethnically diverse women to see that they are reproducible, there are simple measures that clinicians can implement, and women can ask to have their BP monitored more frequently than the current practice. In the U.K. it is 5-10 days after delivery and then at 6-8 weeks after giving birth when changes in heart structure have already started,” Dr. Mihailidou noted.

“The procedure will need to be modified if there are no telemedicine facilities, but that should not stop having close monitoring of BP and treating it adequately. Monitoring requires an accurate BP monitor. There also has to be monitoring BP for the children.”

The trial was funded by a BHF Clinical Research Training Fellowship to Dr. Kitt, with additional support from the NIHR Oxford Biomedical Research Centre and Oxford BHF Centre for Research Excellence.

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

Self-monitoring blood pressure during the early postpartum period may take advantage of a “critical window” when better BP monitoring could prevent later cardiovascular events in women who have hypertensive pregnancies, new research suggests.

In a randomized trial of 220 women with preeclampsia or gestational hypertension, those who took daily postpartum BP readings and received clinician-guided advice for titrating antihypertensives had a 5 mm Hg–lower average diastolic BP at 9 months, compared with those receiving usual care.

Jamie Kitt, DPhil, from the University of Oxford (England) presented these findings from the Physicians Optimized Postpartum Hypertension Treatment (POP-HT, NCT04273854) clinical trial at the American Heart Association scientific sessions. The study was simultaneously published online in JAMA, and a cardiac imaging substudy was published online in Circulation.

“This trial identifies a potential need for a paradigm shift in the way women affected by hypertensive pregnancy are managed postnatally,” Dr. Kitt said. “If a 5–mm Hg improvement in BP is maintained longer term, it can result in about a 20% reduction in lifetime cardiovascular risk.”

The imaging substudy suggests that short-term postnatal optimization of BP control following hypertensive pregnancy through self-monitoring and physician-guided antihypertensive titration is linked with better cardiac remodeling changes seen by cardiovascular magnetic resonance and echocardiography.

POP-HT “proves for the first time that the first few weeks after delivery are a critical time that can determine the long-term cardiovascular health of the mother,” senior author Paul Leeson, PhD, also from the University of Oxford, who presented the findings in a press briefing, said in an interview.

“Interventions during this period can have long-term beneficial impacts on cardiovascular health,” he said. “These findings rewrite the textbook on our understanding of how and why hypertensive pregnancies associate with later cardiovascular disease in the mother.”

Next, Dr. Leeson said, “We need to work out the best ways to implement these interventions “at scale. Then we can ensure all women who have hypertensive pregnancies can get access to the long-term cardiovascular benefits we have demonstrated are possible through improving postpartum cardiac care,” he said, adding that “this is entirely achievable using current available technologies.”
 

Hypertension in pregnancy

About 1 in 10 pregnant women develop hypertension in pregnancy (preeclampsia or gestational hypertension), and 1 in 3 such women go on to develop chronic hypertension within 10 years, “when they are usually still in their 30s or 40s,” Dr. Leeson said.

During pregnancy, the heart remodels to cope with pregnancy, and it undergoes more severe changes if BP is high. Then during the 6 weeks after giving birth, this remodeling rapidly reverses.

Higher blood pressure in young adulthood is associated with a twofold higher risk of subsequent myocardial infarction and stroke. And abnormal cardiac remodeling postpartum is also linked with higher cardiovascular risk.

Self-monitoring blood pressure during the postpartum period may be a “critical window” for intervention.

Previously, the research group performed a pilot study, the Self-Management of Postnatal Antihypertensive Treatment (SNAP-HT) trial and the SNAP-extension trial, which compared a BP self-monitoring intervention with usual care in 91 women with gestational hypertension or preeclampsia requiring postnatal antihypertensive treatment.

Diastolic BP, which drives cardiovascular risk in younger populations, was 4.5–mm Hg lower at 6 months postpartum and 7–mm Hg lower at 4 years post partum in patients randomly assigned to BP self-management vs. usual care – even after they were no longer taking antihypertensives.

Building on these findings, the POP-HT trial enrolled 220 pregnant women seen at Oxford University Hospitals in the United Kingdom who were age 18 years or older, had either gestational hypertension or preeclampsia, and still required antihypertensives when they were being discharged from hospital after giving birth.

Following a baseline visit at day 1-6 after delivery, while in the postnatal ward, the patients were randomly assigned 1:1 to the intervention group (112 women) or usual-care group (108 women).

They had an average age of 32.6 years; 40% had gestational hypertension, and 60% had preeclampsia.

Women in the usual-care group typically received a BP review at 7-10 days after hospital discharge with a community midwife, and another at 6-8 weeks with their general practitioner.

The women in the intervention group were given and taught to use a Bluetooth-enabled OMRON Evolv BP monitor (Omron Healthcare Europe) while on the postnatal ward, and they installed a smartphone app on their mobile phones that transmitted self-monitored BP readings to a National Health Service-hosted, web-based platform.

They were instructed to take daily BP measurements (twice daily if out of target range). Dose titration of antihypertensives after hospital discharge was guided remotely by research clinicians, according to a guideline-based algorithm.

Patients in both groups had four study visits when their BP was measured: visit 1 (baseline) between days 1 and 6 post partum; visit 2 at week 1; visit 3 at week 6; and visit 4 between months 6 and 9 post partum.

Similar antihypertensive classes were prescribed in each group (enalapril 57%, nifedipine 27%, and labetalol 30% for intervention vs. enalapril 43%, nifedipine 30%, and labetalol 27% for control).

At 6 weeks, approximately 30% of participants in each group were still taking medication; this dropped to approximately 12% by visit 4.

The primary outcome – the mean 24-hour diastolic BP at visit 4 (roughly 9 months post partum), adjusted for baseline postnatal diastolic blood pressure – was 5.8–mm Hg lower in the intervention group than in the control group (71.2 mm Hg vs. 76.6 mm Hg; P < .001).

Secondary outcomes – between-group differences in systolic BP at 9 months, BP-related postnatal admission, and cardiac remodeling assessed by cardiac magnetic resonance – were all better in the intervention group.

The mean 24-hour average systolic BP at 9 months post partum, adjusted for baseline postnatal systolic BP was 6.5–mm Hg lower in the intervention group than in the control group (114.0 mm Hg vs. 120.3 mm Hg; P < .001).

There was an absolute risk reduction of 20% and a relative risk reduction of 73.5% in postnatal readmission. The number needed to treat to avoid one postnatal readmission was five, which “has potential for big cost savings,” said Dr. Leeson.

Blood pressure post partum can be improved with self-monitoring and physician-guided medication adjustment, Dr. Leeson summarized. The blood pressure remains low for at least 9 months, even when medication is stopped, and the intervention leads to beneficial cardiac remodeling.
 

U.S. pilot study

Non-Hispanic Black adults have a high hypertension and cardiovascular disease burden, and a related small U.S. study showed benefits of BP self-monitoring in a population comprising mainly Black women, Keith Ferdinand, MD, discussant of the POP-HT trial in the press briefing, said in an interview.

Dr. Ferdinand, from Tulane University, New Orleans, Louisiana, was lead author of the Text My Hypertension BP Meds NOLA pilot study that was published in February in the American Heart Journal Plus: Cardiology Research and Practice.

The study showed that text-messaging and social support increased hypertension medication adherence.

They enrolled 36 individuals, of whom 32 (89%) were non-Hispanic Black, and 23 (64%) were women. The participants received validated Bluetooth-enabled BP-monitoring devices that were synced to smartphones via a secured cloud-based application. The participants could send and receive messages to health care practitioners.

This intervention significantly improved medication adherence and systolic BP without modifying pharmacotherapy.
 

‘Need to be passionate about monitoring BP’

“The take-home messages from these exciting findings is that physicians and women who have had high BP during pregnancy need to be passionate about monitoring and controlling their blood pressure and not ignore it,” Anastasia Mihailidou, PhD, Royal North Shore Hospital, Sydney, the assigned discussant in the late-breaking trial session, said in an interview.

“It also resulted in fewer postpartum hospital readmissions for high blood pressure and benefit at 9 months in the structure and function of the heart and blood vessels of the women,” she said.

“While we need to see further studies in ethnically diverse women to see that they are reproducible, there are simple measures that clinicians can implement, and women can ask to have their BP monitored more frequently than the current practice. In the U.K. it is 5-10 days after delivery and then at 6-8 weeks after giving birth when changes in heart structure have already started,” Dr. Mihailidou noted.

“The procedure will need to be modified if there are no telemedicine facilities, but that should not stop having close monitoring of BP and treating it adequately. Monitoring requires an accurate BP monitor. There also has to be monitoring BP for the children.”

The trial was funded by a BHF Clinical Research Training Fellowship to Dr. Kitt, with additional support from the NIHR Oxford Biomedical Research Centre and Oxford BHF Centre for Research Excellence.

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

In patients with subclinical atrial fibrillation (AFib) detected by implanted devices such as pacemakers or loop recorders, oral anticoagulation with apixaban resulted in a lower risk of stroke or systemic embolism than aspirin, but a higher risk of major bleeding in the ARTESIA study.

The results appear to contrast somewhat with the recently reported NOAH-AFNET 6 trial, which failed to show a reduction in stroke with the anticoagulant edoxaban versus placebo in a similar patient group, but that trial was stopped early and so was underpowered.

However, the lead investigators of both trials say the studies actually show consistent results – both found a lower rate of stroke than expected in this population, but the confidence intervals for stroke reduction with anticoagulation overlap, suggesting there is likely some effect, albeit less than that in clinical AFib.

The big question is whether the reduction in stroke with anticoagulation outweighs the increase in major bleeding.

A new meta-analysis of the two trials showed that “oral anticoagulation with edoxaban or apixaban reduces the risk of ischemic stroke by approximately one-third and increases major bleeding by roughly double.”

In absolute numbers, there were three fewer ischemic strokes per 1,000 patient-years with anticoagulation in the two trials combined, at the cost of seven more major bleeds.

The lead investigators of the two trials have somewhat different opinions on how these findings may translate into clinical practice.

Jeff Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ont., lead investigator of the ARTESIA trial, believes that the risks and benefits need to be assessed in individual patients, but there should be some patient groups that will benefit from anticoagulation treatment.

“In patients with pacemakers or implantable loop recorders with continuous monitoring, subclinical AF[ib] is detected in about one third of patients, so this is extremely common,” he said in an interview. “The question is whether this is just a normal feature of getting older or is this like AF[ib] that we see in the clinic which increases stroke risk, and I think we can conclude from ARTESIA that this subclinical AF[ib] is associated with an increased risk of stroke, although that is lower than the risk with clinical AF[ib], and that it can be reduced by anticoagulation.”

Until recently it hasn’t been possible to quantify the risk associated with subclinical AFib, he noted. “But now we have a rich dataset to use to see if we can tease out some specifics on this. Future analyses of this dataset will help define patients where the benefits outweigh the risks of bleeding. For now, I think we can look at the data in a qualitative way and consider the totality of risk factors in each patient – their bleeding risk, stroke risk, how much AF[ib] they have, and make a decision as to whether to give anticoagulation or not.”

But Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), lead investigator of the NOAH-AFNET 6 trial said: “Both trials showed the stroke rate is low in these patients – about 1% per year – and that anticoagulation can reduce it a bit further at the expense of increasing major bleeding. I don’t believe the AF[ib] episodes picked up on these devices constitute a sufficient stroke risk to warrant anticoagulation, given the bleeding risk.”

Dr. Kirchhof suggests an alternate approach of performing further traditional AFib monitoring on these patients.

“I think going forward in my practice, when we come across this device-detected AF[ib], we will do further investigations with an established method for detecting AF[ib] involving surface ECG monitoring – maybe a 3-day or 7-day Holter. If that shows AF[ib], then we will be on firm ground to start anticoagulation. If that doesn’t show AF[ib], we will probably not use anticoagulation.”

The ARTESIA trial and the meta-analysis of the two trials were both presented at the annual scientific sessions of the American Heart Association. Both studies were also simultaneously published online – ARTESIA in the New England Journal of Medicine and the meta-analysis in Circulation.
 

ARTESIA

For the ARTESIA study, 4012 patients with device-detected AFib and other clinical risk factors for stroke were randomly assigned to treatment with apixaban (5 mg twice daily) or aspirin (81 mg daily).

After a mean follow-up of 3.5 years, the primary endpoint – stroke or systemic embolism – occurred in 55 patients in the apixaban group (0.78% per patient-year), compared with 86 patients in the aspirin group (1.24% per patient-year), giving a hazard ratio of 0.63 (95% confidence interval, 0.45-0.88; P = .007).

“The risk of stroke or systemic embolism was lower by 37% with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49%,” Dr. Healey reported.

In the “on-treatment” population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001).

Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.

One of the main findings of the trial is the lower-than-expected risk of ischemic stroke in this population – about 1% per year in the aspirin group, which was reduced to 0.64% per year in the apixaban group.

The authors noted that “simply counting strokes as compared with bleeding events might suggest a neutral overall effect. With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis.”

However, they pointed out that strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery, which was the case in this study.

“Thus, on the basis of the considerably greater severity of the stroke events prevented than the bleeding events caused, we believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops,” they concluded.
 

First well-powered trial addressing this question

Discussing the ARTESIA trial at an AHA press conference, Christine Albert, MD, Cedars-Sinai Medical Center, Los Angeles, said: “I want to emphasize how important this trial is.”

She explained that current guidelines do not recommend any treatment for patients with device-detected AFib that is not shown on ECG, even though it is known this confers some excess risk of stroke.

“ARTESIA is the first well-powered, long-term trial looking at this question,” she said. “It found a clear reduction in the risk of stroke/systemic embolism with apixaban vs aspirin, but there was also a significant amount of bleeding – about an 80% increase. The question is whether the benefit on stroke is worth it given the bleeding risk.”

Dr. Albert highlighted the low absolute risk of stroke in this study population of around 1.2%, pointing out that even with the 37% relative reduction with anticoagulation, stroke is only reduced in absolute terms by 0.4%.

“We are going to have to take this back to committees and guidelines and look at the balance between the benefit on stroke and the increase in bleeding,” she concluded.

Noting that observational studies have shown that the duration of AFib impacts the risk of stroke, Dr. Albert suggested that patients with longer-duration AFib may benefit from anticoagulation to a greater extent; and given that the bleeding seen in ARTESIA was mainly GI bleeding, it might be possible to screen out patients at high risk of GI bleeding.

She also pointed out that a lot of patients discontinued anticoagulation treatment in both ARTESIA and NOAH-AFNET 6, showing that this is not an easy strategy for elderly patients.

In an editorial accompanying publication of the ARTESIA trial, Emma Svennberg, MD, Karolinska Institute, Stockholm, also concluded that, “going forward, we must balance the increased bleeding risks with the risk for disabling strokes,” and that “future substudies and meta-analyses may provide further insights regarding treatment benefits in specific subgroups.”
 

NOAH-AFNET 6: New subgroup analysis

The previously reported NOAH-AFNET 6 study randomly assigned 2,538 patients with subclinical AFib and additional risk factors for stroke to anticoagulation with edoxaban or placebo. The trial was stopped early, so it was underpowered – but it found no difference between groups in the incidence of the composite endpoint of stroke, systemic embolism, or death from cardiovascular causes or in the incidence of stroke, although there was higher risk of major bleeding.

Again, there was a low rate of stroke in this trial with just 49 strokes in total in the whole study. The NOAH-AFNET-6 investigators concluded that these patients should not receive anticoagulation because the risk of bleeding outweighed any potential benefits.

A new subanalysis of the 259 patients who had durations of subclinical AFib of 24 hours or longer in the NOAH-AFNET 6 trial was presented at the AHA meeting, and simultaneously published online in the European Heart Journal.

This showed that the rate of stroke also appeared low in patients with these long durations of subclinical AFib, and that there was no interaction between the duration of subclinical AFib and the efficacy and safety of oral anticoagulation.

But with such a low number of events in the study as a whole and in the long duration subclinical AFib subgroup (in which there were just two strokes in each treatment group), this analysis was unlikely to show a difference, Dr. Kirchhof commented.

The subgroup analysis did, however, show that patients experiencing subclinical AFib durations of 24 hours or more were more likely to develop clinical AFib over time than those with shorter durations, suggesting the need for regular ECGs in these patients.

Dr. Kirchhof said better methods are needed to detect patients with subclinical AFib at high risk of stroke. “I don’t think our clinical stroke risk factor scores such as CHA2DS2-VASc are sufficient to detect high-risk patients. Patients in both NOAH-AFNET 6 and ARTESIA had a median CHA2DS2-VASc score of 4, but they had a stroke rate of just 1% per year,” he noted.

The meta-analysis of the two trials showed that the results from both are consistent, with an overall reduction in ischemic stroke with oral anticoagulation (relative risk, 0.68). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85).

There was no significant difference in cardiovascular death (RR, 0.95) or all-cause mortality (RR, 1.08), but anticoagulation significantly increased major bleeding (RR, 1.62).
 

Aspirin use complicates results

Dr. Healey said further analyses of the ARTESIA data will try to tease out the effect of concomitant aspirin use in the trial.

He explained that patients in this trial were allowed to take a single antiplatelet agent on top of study therapy.

“It is difficult to work out the exact use of antiplatelet therapy as it changed throughout the study,” he said. “About two-thirds were taking antiplatelet agents at the time of enrollment into the trial, but this decreased throughout the study. Many clinicians stopped open-label antiplatelet therapy during the trial when new evidence came out to suggest that there was no added benefit of adding aspirin on top of anticoagulants.

“We need to look carefully as to what impact that may have had,” Dr. Healey added. “We know from other studies that adding an antiplatelet on top of an anticoagulant doesn’t do much to thromboembolic events, but it approximately doubles the risk of major bleeding.”

In contrast, the NOAH-AFNET trial did not allow aspirin use in the anticoagulation group and aspirin was taken by around half the patients in the placebo group who had an indication for its use.

The authors of the meta-analysis pointed out that the omission of aspirin in nearly half of the control patients in NOAH-AFNET 6 and the early termination of the trial may have led to a slightly higher estimate for excess major bleeding with anticoagulation.

The ARTESIA study was supported by the Canadian Institutes for Health Research, the Bristol Myers Squibb-Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Advancing Clinical Trials Network and the Population Health Research Institute. Dr. Healey reported research grants and speaking fees from BMS/Pfizer Alliance, Servier, Novartis, Boston Scientific, Medtronic; and acts as a consultant to Bayer, Servier and Boston Scientific. The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.

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

In patients with subclinical atrial fibrillation (AFib) detected by implanted devices such as pacemakers or loop recorders, oral anticoagulation with apixaban resulted in a lower risk of stroke or systemic embolism than aspirin, but a higher risk of major bleeding in the ARTESIA study.

The results appear to contrast somewhat with the recently reported NOAH-AFNET 6 trial, which failed to show a reduction in stroke with the anticoagulant edoxaban versus placebo in a similar patient group, but that trial was stopped early and so was underpowered.

However, the lead investigators of both trials say the studies actually show consistent results – both found a lower rate of stroke than expected in this population, but the confidence intervals for stroke reduction with anticoagulation overlap, suggesting there is likely some effect, albeit less than that in clinical AFib.

The big question is whether the reduction in stroke with anticoagulation outweighs the increase in major bleeding.

A new meta-analysis of the two trials showed that “oral anticoagulation with edoxaban or apixaban reduces the risk of ischemic stroke by approximately one-third and increases major bleeding by roughly double.”

In absolute numbers, there were three fewer ischemic strokes per 1,000 patient-years with anticoagulation in the two trials combined, at the cost of seven more major bleeds.

The lead investigators of the two trials have somewhat different opinions on how these findings may translate into clinical practice.

Jeff Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ont., lead investigator of the ARTESIA trial, believes that the risks and benefits need to be assessed in individual patients, but there should be some patient groups that will benefit from anticoagulation treatment.

“In patients with pacemakers or implantable loop recorders with continuous monitoring, subclinical AF[ib] is detected in about one third of patients, so this is extremely common,” he said in an interview. “The question is whether this is just a normal feature of getting older or is this like AF[ib] that we see in the clinic which increases stroke risk, and I think we can conclude from ARTESIA that this subclinical AF[ib] is associated with an increased risk of stroke, although that is lower than the risk with clinical AF[ib], and that it can be reduced by anticoagulation.”

Until recently it hasn’t been possible to quantify the risk associated with subclinical AFib, he noted. “But now we have a rich dataset to use to see if we can tease out some specifics on this. Future analyses of this dataset will help define patients where the benefits outweigh the risks of bleeding. For now, I think we can look at the data in a qualitative way and consider the totality of risk factors in each patient – their bleeding risk, stroke risk, how much AF[ib] they have, and make a decision as to whether to give anticoagulation or not.”

But Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), lead investigator of the NOAH-AFNET 6 trial said: “Both trials showed the stroke rate is low in these patients – about 1% per year – and that anticoagulation can reduce it a bit further at the expense of increasing major bleeding. I don’t believe the AF[ib] episodes picked up on these devices constitute a sufficient stroke risk to warrant anticoagulation, given the bleeding risk.”

Dr. Kirchhof suggests an alternate approach of performing further traditional AFib monitoring on these patients.

“I think going forward in my practice, when we come across this device-detected AF[ib], we will do further investigations with an established method for detecting AF[ib] involving surface ECG monitoring – maybe a 3-day or 7-day Holter. If that shows AF[ib], then we will be on firm ground to start anticoagulation. If that doesn’t show AF[ib], we will probably not use anticoagulation.”

The ARTESIA trial and the meta-analysis of the two trials were both presented at the annual scientific sessions of the American Heart Association. Both studies were also simultaneously published online – ARTESIA in the New England Journal of Medicine and the meta-analysis in Circulation.
 

ARTESIA

For the ARTESIA study, 4012 patients with device-detected AFib and other clinical risk factors for stroke were randomly assigned to treatment with apixaban (5 mg twice daily) or aspirin (81 mg daily).

After a mean follow-up of 3.5 years, the primary endpoint – stroke or systemic embolism – occurred in 55 patients in the apixaban group (0.78% per patient-year), compared with 86 patients in the aspirin group (1.24% per patient-year), giving a hazard ratio of 0.63 (95% confidence interval, 0.45-0.88; P = .007).

“The risk of stroke or systemic embolism was lower by 37% with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49%,” Dr. Healey reported.

In the “on-treatment” population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001).

Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.

One of the main findings of the trial is the lower-than-expected risk of ischemic stroke in this population – about 1% per year in the aspirin group, which was reduced to 0.64% per year in the apixaban group.

The authors noted that “simply counting strokes as compared with bleeding events might suggest a neutral overall effect. With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis.”

However, they pointed out that strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery, which was the case in this study.

“Thus, on the basis of the considerably greater severity of the stroke events prevented than the bleeding events caused, we believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops,” they concluded.
 

First well-powered trial addressing this question

Discussing the ARTESIA trial at an AHA press conference, Christine Albert, MD, Cedars-Sinai Medical Center, Los Angeles, said: “I want to emphasize how important this trial is.”

She explained that current guidelines do not recommend any treatment for patients with device-detected AFib that is not shown on ECG, even though it is known this confers some excess risk of stroke.

“ARTESIA is the first well-powered, long-term trial looking at this question,” she said. “It found a clear reduction in the risk of stroke/systemic embolism with apixaban vs aspirin, but there was also a significant amount of bleeding – about an 80% increase. The question is whether the benefit on stroke is worth it given the bleeding risk.”

Dr. Albert highlighted the low absolute risk of stroke in this study population of around 1.2%, pointing out that even with the 37% relative reduction with anticoagulation, stroke is only reduced in absolute terms by 0.4%.

“We are going to have to take this back to committees and guidelines and look at the balance between the benefit on stroke and the increase in bleeding,” she concluded.

Noting that observational studies have shown that the duration of AFib impacts the risk of stroke, Dr. Albert suggested that patients with longer-duration AFib may benefit from anticoagulation to a greater extent; and given that the bleeding seen in ARTESIA was mainly GI bleeding, it might be possible to screen out patients at high risk of GI bleeding.

She also pointed out that a lot of patients discontinued anticoagulation treatment in both ARTESIA and NOAH-AFNET 6, showing that this is not an easy strategy for elderly patients.

In an editorial accompanying publication of the ARTESIA trial, Emma Svennberg, MD, Karolinska Institute, Stockholm, also concluded that, “going forward, we must balance the increased bleeding risks with the risk for disabling strokes,” and that “future substudies and meta-analyses may provide further insights regarding treatment benefits in specific subgroups.”
 

NOAH-AFNET 6: New subgroup analysis

The previously reported NOAH-AFNET 6 study randomly assigned 2,538 patients with subclinical AFib and additional risk factors for stroke to anticoagulation with edoxaban or placebo. The trial was stopped early, so it was underpowered – but it found no difference between groups in the incidence of the composite endpoint of stroke, systemic embolism, or death from cardiovascular causes or in the incidence of stroke, although there was higher risk of major bleeding.

Again, there was a low rate of stroke in this trial with just 49 strokes in total in the whole study. The NOAH-AFNET-6 investigators concluded that these patients should not receive anticoagulation because the risk of bleeding outweighed any potential benefits.

A new subanalysis of the 259 patients who had durations of subclinical AFib of 24 hours or longer in the NOAH-AFNET 6 trial was presented at the AHA meeting, and simultaneously published online in the European Heart Journal.

This showed that the rate of stroke also appeared low in patients with these long durations of subclinical AFib, and that there was no interaction between the duration of subclinical AFib and the efficacy and safety of oral anticoagulation.

But with such a low number of events in the study as a whole and in the long duration subclinical AFib subgroup (in which there were just two strokes in each treatment group), this analysis was unlikely to show a difference, Dr. Kirchhof commented.

The subgroup analysis did, however, show that patients experiencing subclinical AFib durations of 24 hours or more were more likely to develop clinical AFib over time than those with shorter durations, suggesting the need for regular ECGs in these patients.

Dr. Kirchhof said better methods are needed to detect patients with subclinical AFib at high risk of stroke. “I don’t think our clinical stroke risk factor scores such as CHA2DS2-VASc are sufficient to detect high-risk patients. Patients in both NOAH-AFNET 6 and ARTESIA had a median CHA2DS2-VASc score of 4, but they had a stroke rate of just 1% per year,” he noted.

The meta-analysis of the two trials showed that the results from both are consistent, with an overall reduction in ischemic stroke with oral anticoagulation (relative risk, 0.68). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85).

There was no significant difference in cardiovascular death (RR, 0.95) or all-cause mortality (RR, 1.08), but anticoagulation significantly increased major bleeding (RR, 1.62).
 

Aspirin use complicates results

Dr. Healey said further analyses of the ARTESIA data will try to tease out the effect of concomitant aspirin use in the trial.

He explained that patients in this trial were allowed to take a single antiplatelet agent on top of study therapy.

“It is difficult to work out the exact use of antiplatelet therapy as it changed throughout the study,” he said. “About two-thirds were taking antiplatelet agents at the time of enrollment into the trial, but this decreased throughout the study. Many clinicians stopped open-label antiplatelet therapy during the trial when new evidence came out to suggest that there was no added benefit of adding aspirin on top of anticoagulants.

“We need to look carefully as to what impact that may have had,” Dr. Healey added. “We know from other studies that adding an antiplatelet on top of an anticoagulant doesn’t do much to thromboembolic events, but it approximately doubles the risk of major bleeding.”

In contrast, the NOAH-AFNET trial did not allow aspirin use in the anticoagulation group and aspirin was taken by around half the patients in the placebo group who had an indication for its use.

The authors of the meta-analysis pointed out that the omission of aspirin in nearly half of the control patients in NOAH-AFNET 6 and the early termination of the trial may have led to a slightly higher estimate for excess major bleeding with anticoagulation.

The ARTESIA study was supported by the Canadian Institutes for Health Research, the Bristol Myers Squibb-Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Advancing Clinical Trials Network and the Population Health Research Institute. Dr. Healey reported research grants and speaking fees from BMS/Pfizer Alliance, Servier, Novartis, Boston Scientific, Medtronic; and acts as a consultant to Bayer, Servier and Boston Scientific. The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.

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

In patients with subclinical atrial fibrillation (AFib) detected by implanted devices such as pacemakers or loop recorders, oral anticoagulation with apixaban resulted in a lower risk of stroke or systemic embolism than aspirin, but a higher risk of major bleeding in the ARTESIA study.

The results appear to contrast somewhat with the recently reported NOAH-AFNET 6 trial, which failed to show a reduction in stroke with the anticoagulant edoxaban versus placebo in a similar patient group, but that trial was stopped early and so was underpowered.

However, the lead investigators of both trials say the studies actually show consistent results – both found a lower rate of stroke than expected in this population, but the confidence intervals for stroke reduction with anticoagulation overlap, suggesting there is likely some effect, albeit less than that in clinical AFib.

The big question is whether the reduction in stroke with anticoagulation outweighs the increase in major bleeding.

A new meta-analysis of the two trials showed that “oral anticoagulation with edoxaban or apixaban reduces the risk of ischemic stroke by approximately one-third and increases major bleeding by roughly double.”

In absolute numbers, there were three fewer ischemic strokes per 1,000 patient-years with anticoagulation in the two trials combined, at the cost of seven more major bleeds.

The lead investigators of the two trials have somewhat different opinions on how these findings may translate into clinical practice.

Jeff Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ont., lead investigator of the ARTESIA trial, believes that the risks and benefits need to be assessed in individual patients, but there should be some patient groups that will benefit from anticoagulation treatment.

“In patients with pacemakers or implantable loop recorders with continuous monitoring, subclinical AF[ib] is detected in about one third of patients, so this is extremely common,” he said in an interview. “The question is whether this is just a normal feature of getting older or is this like AF[ib] that we see in the clinic which increases stroke risk, and I think we can conclude from ARTESIA that this subclinical AF[ib] is associated with an increased risk of stroke, although that is lower than the risk with clinical AF[ib], and that it can be reduced by anticoagulation.”

Until recently it hasn’t been possible to quantify the risk associated with subclinical AFib, he noted. “But now we have a rich dataset to use to see if we can tease out some specifics on this. Future analyses of this dataset will help define patients where the benefits outweigh the risks of bleeding. For now, I think we can look at the data in a qualitative way and consider the totality of risk factors in each patient – their bleeding risk, stroke risk, how much AF[ib] they have, and make a decision as to whether to give anticoagulation or not.”

But Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), lead investigator of the NOAH-AFNET 6 trial said: “Both trials showed the stroke rate is low in these patients – about 1% per year – and that anticoagulation can reduce it a bit further at the expense of increasing major bleeding. I don’t believe the AF[ib] episodes picked up on these devices constitute a sufficient stroke risk to warrant anticoagulation, given the bleeding risk.”

Dr. Kirchhof suggests an alternate approach of performing further traditional AFib monitoring on these patients.

“I think going forward in my practice, when we come across this device-detected AF[ib], we will do further investigations with an established method for detecting AF[ib] involving surface ECG monitoring – maybe a 3-day or 7-day Holter. If that shows AF[ib], then we will be on firm ground to start anticoagulation. If that doesn’t show AF[ib], we will probably not use anticoagulation.”

The ARTESIA trial and the meta-analysis of the two trials were both presented at the annual scientific sessions of the American Heart Association. Both studies were also simultaneously published online – ARTESIA in the New England Journal of Medicine and the meta-analysis in Circulation.
 

ARTESIA

For the ARTESIA study, 4012 patients with device-detected AFib and other clinical risk factors for stroke were randomly assigned to treatment with apixaban (5 mg twice daily) or aspirin (81 mg daily).

After a mean follow-up of 3.5 years, the primary endpoint – stroke or systemic embolism – occurred in 55 patients in the apixaban group (0.78% per patient-year), compared with 86 patients in the aspirin group (1.24% per patient-year), giving a hazard ratio of 0.63 (95% confidence interval, 0.45-0.88; P = .007).

“The risk of stroke or systemic embolism was lower by 37% with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49%,” Dr. Healey reported.

In the “on-treatment” population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001).

Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.

One of the main findings of the trial is the lower-than-expected risk of ischemic stroke in this population – about 1% per year in the aspirin group, which was reduced to 0.64% per year in the apixaban group.

The authors noted that “simply counting strokes as compared with bleeding events might suggest a neutral overall effect. With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis.”

However, they pointed out that strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery, which was the case in this study.

“Thus, on the basis of the considerably greater severity of the stroke events prevented than the bleeding events caused, we believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops,” they concluded.
 

First well-powered trial addressing this question

Discussing the ARTESIA trial at an AHA press conference, Christine Albert, MD, Cedars-Sinai Medical Center, Los Angeles, said: “I want to emphasize how important this trial is.”

She explained that current guidelines do not recommend any treatment for patients with device-detected AFib that is not shown on ECG, even though it is known this confers some excess risk of stroke.

“ARTESIA is the first well-powered, long-term trial looking at this question,” she said. “It found a clear reduction in the risk of stroke/systemic embolism with apixaban vs aspirin, but there was also a significant amount of bleeding – about an 80% increase. The question is whether the benefit on stroke is worth it given the bleeding risk.”

Dr. Albert highlighted the low absolute risk of stroke in this study population of around 1.2%, pointing out that even with the 37% relative reduction with anticoagulation, stroke is only reduced in absolute terms by 0.4%.

“We are going to have to take this back to committees and guidelines and look at the balance between the benefit on stroke and the increase in bleeding,” she concluded.

Noting that observational studies have shown that the duration of AFib impacts the risk of stroke, Dr. Albert suggested that patients with longer-duration AFib may benefit from anticoagulation to a greater extent; and given that the bleeding seen in ARTESIA was mainly GI bleeding, it might be possible to screen out patients at high risk of GI bleeding.

She also pointed out that a lot of patients discontinued anticoagulation treatment in both ARTESIA and NOAH-AFNET 6, showing that this is not an easy strategy for elderly patients.

In an editorial accompanying publication of the ARTESIA trial, Emma Svennberg, MD, Karolinska Institute, Stockholm, also concluded that, “going forward, we must balance the increased bleeding risks with the risk for disabling strokes,” and that “future substudies and meta-analyses may provide further insights regarding treatment benefits in specific subgroups.”
 

NOAH-AFNET 6: New subgroup analysis

The previously reported NOAH-AFNET 6 study randomly assigned 2,538 patients with subclinical AFib and additional risk factors for stroke to anticoagulation with edoxaban or placebo. The trial was stopped early, so it was underpowered – but it found no difference between groups in the incidence of the composite endpoint of stroke, systemic embolism, or death from cardiovascular causes or in the incidence of stroke, although there was higher risk of major bleeding.

Again, there was a low rate of stroke in this trial with just 49 strokes in total in the whole study. The NOAH-AFNET-6 investigators concluded that these patients should not receive anticoagulation because the risk of bleeding outweighed any potential benefits.

A new subanalysis of the 259 patients who had durations of subclinical AFib of 24 hours or longer in the NOAH-AFNET 6 trial was presented at the AHA meeting, and simultaneously published online in the European Heart Journal.

This showed that the rate of stroke also appeared low in patients with these long durations of subclinical AFib, and that there was no interaction between the duration of subclinical AFib and the efficacy and safety of oral anticoagulation.

But with such a low number of events in the study as a whole and in the long duration subclinical AFib subgroup (in which there were just two strokes in each treatment group), this analysis was unlikely to show a difference, Dr. Kirchhof commented.

The subgroup analysis did, however, show that patients experiencing subclinical AFib durations of 24 hours or more were more likely to develop clinical AFib over time than those with shorter durations, suggesting the need for regular ECGs in these patients.

Dr. Kirchhof said better methods are needed to detect patients with subclinical AFib at high risk of stroke. “I don’t think our clinical stroke risk factor scores such as CHA2DS2-VASc are sufficient to detect high-risk patients. Patients in both NOAH-AFNET 6 and ARTESIA had a median CHA2DS2-VASc score of 4, but they had a stroke rate of just 1% per year,” he noted.

The meta-analysis of the two trials showed that the results from both are consistent, with an overall reduction in ischemic stroke with oral anticoagulation (relative risk, 0.68). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85).

There was no significant difference in cardiovascular death (RR, 0.95) or all-cause mortality (RR, 1.08), but anticoagulation significantly increased major bleeding (RR, 1.62).
 

Aspirin use complicates results

Dr. Healey said further analyses of the ARTESIA data will try to tease out the effect of concomitant aspirin use in the trial.

He explained that patients in this trial were allowed to take a single antiplatelet agent on top of study therapy.

“It is difficult to work out the exact use of antiplatelet therapy as it changed throughout the study,” he said. “About two-thirds were taking antiplatelet agents at the time of enrollment into the trial, but this decreased throughout the study. Many clinicians stopped open-label antiplatelet therapy during the trial when new evidence came out to suggest that there was no added benefit of adding aspirin on top of anticoagulants.

“We need to look carefully as to what impact that may have had,” Dr. Healey added. “We know from other studies that adding an antiplatelet on top of an anticoagulant doesn’t do much to thromboembolic events, but it approximately doubles the risk of major bleeding.”

In contrast, the NOAH-AFNET trial did not allow aspirin use in the anticoagulation group and aspirin was taken by around half the patients in the placebo group who had an indication for its use.

The authors of the meta-analysis pointed out that the omission of aspirin in nearly half of the control patients in NOAH-AFNET 6 and the early termination of the trial may have led to a slightly higher estimate for excess major bleeding with anticoagulation.

The ARTESIA study was supported by the Canadian Institutes for Health Research, the Bristol Myers Squibb-Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Advancing Clinical Trials Network and the Population Health Research Institute. Dr. Healey reported research grants and speaking fees from BMS/Pfizer Alliance, Servier, Novartis, Boston Scientific, Medtronic; and acts as a consultant to Bayer, Servier and Boston Scientific. The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.

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

Further details from the phase 2b AZALEA trial with the factor XI inhibitor abelacimab (Anthos) show significant reductions in major and clinically relevant nonmajor bleeding, compared with rivaroxaban, for patients with atrial fibrillation (AFib); the risk of stroke was moderate to high.

The trial was stopped earlier this year because of an “overwhelming” reduction in bleeding with abelacimab in comparison to rivaroxaban. Abelacimab is a monoclonal antibody given by subcutaneous injection once a month.

“Details of the bleeding results have now shown that the 150-mg dose of abelacimab, which is the dose being carried forward to phase 3 trials, was associated with a 67% reduction in major or clinically relevant nonmajor bleeding, the primary endpoint of the study.”

In addition, major bleeding was reduced by 74%, and major gastrointestinal bleeding was reduced by 93%.

“We are seeing really profound reductions in bleeding with this agent vs. a NOAC [novel oral anticoagulant],” lead AZALEA investigator Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, said in an interview.

“Major bleeding – effectively the type of bleeding that results in hospitalization – is reduced by more than two-thirds, and major GI bleeding – which is the most common type of bleeding experienced by AF patients on anticoagulants – is almost eliminated. This gives us real hope that we have finally found an anticoagulant that is remarkably safe and will allow us to use anticoagulation in our most vulnerable patients,” he said.

Dr. Ruff presented the full results from the AZALEA trial at the American Heart Association scientific sessions.

He noted that AFib is one of the most common medical conditions in the world and that it confers an increased risk of stroke. Anticoagulants reduce this risk very effectively, and while the NOACS, such as apixaban and rivaroxaban, are safer than warfarin, significant bleeding still occurs, and “shockingly,” he said, between 30% and 60% of patients are not prescribed an anticoagulant or discontinue treatment because of bleeding concerns.

“Clearly, we need safer anticoagulants to protect these patients. Factor XI inhibitors, of which abelacimab is one, have emerged as the most promising agents, as they are thought to provide precision anticoagulation,” Dr. Ruff said.

He explained that factor XI appears to be involved in the formation of thrombus, which blocks arteries and causes strokes and myocardial infarction (thrombosis), but not in the healing process of blood vessels after injury (hemostasis). So, it is believed that inhibiting factor XI should reduce thrombotic events without causing excess bleeding.

AZALEA, which is the largest and longest trial of a factor XI inhibitor to date, enrolled 1,287 adults with AF who were at moderate to high risk of stroke.

They were randomly assigned to receive one of three treatments: oral rivaroxaban 20 mg daily; abelacimab 90 mg; or abelacimab 150 mg. Abelacimab was given monthly by injection.

Both doses of abelacimab inhibited factor XI almost completely; 97% inhibition was achieved with the 90-mg dose, and 99% inhibition was achieved with the 150-mg dose.

Results showed that after a median follow-up of 1.8 years, there was a clear reduction in all bleeding endpoints with both doses of abelacimab, compared with rivaroxaban.

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

Further details from the phase 2b AZALEA trial with the factor XI inhibitor abelacimab (Anthos) show significant reductions in major and clinically relevant nonmajor bleeding, compared with rivaroxaban, for patients with atrial fibrillation (AFib); the risk of stroke was moderate to high.

The trial was stopped earlier this year because of an “overwhelming” reduction in bleeding with abelacimab in comparison to rivaroxaban. Abelacimab is a monoclonal antibody given by subcutaneous injection once a month.

“Details of the bleeding results have now shown that the 150-mg dose of abelacimab, which is the dose being carried forward to phase 3 trials, was associated with a 67% reduction in major or clinically relevant nonmajor bleeding, the primary endpoint of the study.”

In addition, major bleeding was reduced by 74%, and major gastrointestinal bleeding was reduced by 93%.

“We are seeing really profound reductions in bleeding with this agent vs. a NOAC [novel oral anticoagulant],” lead AZALEA investigator Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, said in an interview.

“Major bleeding – effectively the type of bleeding that results in hospitalization – is reduced by more than two-thirds, and major GI bleeding – which is the most common type of bleeding experienced by AF patients on anticoagulants – is almost eliminated. This gives us real hope that we have finally found an anticoagulant that is remarkably safe and will allow us to use anticoagulation in our most vulnerable patients,” he said.

Dr. Ruff presented the full results from the AZALEA trial at the American Heart Association scientific sessions.

He noted that AFib is one of the most common medical conditions in the world and that it confers an increased risk of stroke. Anticoagulants reduce this risk very effectively, and while the NOACS, such as apixaban and rivaroxaban, are safer than warfarin, significant bleeding still occurs, and “shockingly,” he said, between 30% and 60% of patients are not prescribed an anticoagulant or discontinue treatment because of bleeding concerns.

“Clearly, we need safer anticoagulants to protect these patients. Factor XI inhibitors, of which abelacimab is one, have emerged as the most promising agents, as they are thought to provide precision anticoagulation,” Dr. Ruff said.

He explained that factor XI appears to be involved in the formation of thrombus, which blocks arteries and causes strokes and myocardial infarction (thrombosis), but not in the healing process of blood vessels after injury (hemostasis). So, it is believed that inhibiting factor XI should reduce thrombotic events without causing excess bleeding.

AZALEA, which is the largest and longest trial of a factor XI inhibitor to date, enrolled 1,287 adults with AF who were at moderate to high risk of stroke.

They were randomly assigned to receive one of three treatments: oral rivaroxaban 20 mg daily; abelacimab 90 mg; or abelacimab 150 mg. Abelacimab was given monthly by injection.

Both doses of abelacimab inhibited factor XI almost completely; 97% inhibition was achieved with the 90-mg dose, and 99% inhibition was achieved with the 150-mg dose.

Results showed that after a median follow-up of 1.8 years, there was a clear reduction in all bleeding endpoints with both doses of abelacimab, compared with rivaroxaban.

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

Further details from the phase 2b AZALEA trial with the factor XI inhibitor abelacimab (Anthos) show significant reductions in major and clinically relevant nonmajor bleeding, compared with rivaroxaban, for patients with atrial fibrillation (AFib); the risk of stroke was moderate to high.

The trial was stopped earlier this year because of an “overwhelming” reduction in bleeding with abelacimab in comparison to rivaroxaban. Abelacimab is a monoclonal antibody given by subcutaneous injection once a month.

“Details of the bleeding results have now shown that the 150-mg dose of abelacimab, which is the dose being carried forward to phase 3 trials, was associated with a 67% reduction in major or clinically relevant nonmajor bleeding, the primary endpoint of the study.”

In addition, major bleeding was reduced by 74%, and major gastrointestinal bleeding was reduced by 93%.

“We are seeing really profound reductions in bleeding with this agent vs. a NOAC [novel oral anticoagulant],” lead AZALEA investigator Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, said in an interview.

“Major bleeding – effectively the type of bleeding that results in hospitalization – is reduced by more than two-thirds, and major GI bleeding – which is the most common type of bleeding experienced by AF patients on anticoagulants – is almost eliminated. This gives us real hope that we have finally found an anticoagulant that is remarkably safe and will allow us to use anticoagulation in our most vulnerable patients,” he said.

Dr. Ruff presented the full results from the AZALEA trial at the American Heart Association scientific sessions.

He noted that AFib is one of the most common medical conditions in the world and that it confers an increased risk of stroke. Anticoagulants reduce this risk very effectively, and while the NOACS, such as apixaban and rivaroxaban, are safer than warfarin, significant bleeding still occurs, and “shockingly,” he said, between 30% and 60% of patients are not prescribed an anticoagulant or discontinue treatment because of bleeding concerns.

“Clearly, we need safer anticoagulants to protect these patients. Factor XI inhibitors, of which abelacimab is one, have emerged as the most promising agents, as they are thought to provide precision anticoagulation,” Dr. Ruff said.

He explained that factor XI appears to be involved in the formation of thrombus, which blocks arteries and causes strokes and myocardial infarction (thrombosis), but not in the healing process of blood vessels after injury (hemostasis). So, it is believed that inhibiting factor XI should reduce thrombotic events without causing excess bleeding.

AZALEA, which is the largest and longest trial of a factor XI inhibitor to date, enrolled 1,287 adults with AF who were at moderate to high risk of stroke.

They were randomly assigned to receive one of three treatments: oral rivaroxaban 20 mg daily; abelacimab 90 mg; or abelacimab 150 mg. Abelacimab was given monthly by injection.

Both doses of abelacimab inhibited factor XI almost completely; 97% inhibition was achieved with the 90-mg dose, and 99% inhibition was achieved with the 150-mg dose.

Results showed that after a median follow-up of 1.8 years, there was a clear reduction in all bleeding endpoints with both doses of abelacimab, compared with rivaroxaban.

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

PHILADELPHIA – As an initial treatment strategy for treatment of atrial fibrillation (AF) in patients with obesity, dual energy cardioversion is substantially more reliable and just as safe as conventional single energy cardioversion, a multicenter randomized trial shows.

When treated with dual direct current cardioversion (DCCV), only 2% of patients with obesity failed to cardiovert on the first shock versus 14% (P = .002) of those treated with a conventional single DCCV, reported Joshua D. Aymond, MD, a fellow in electrophysiology at Ochsner Health, New Orleans.

Of the 14 patients in the single DCCV arm who did not convert on the first shock, 12 cardioverted when switched to dual energy. The remaining two cardioverted on the second dual shock.

In the dual DCCV group, of the two patients who did not cardiovert on the first dual shock, one did on the second. The other also cardioverted on a second shock, but this second shock was not delivered for 2 weeks, during which time the patient received a course of amiodarone-based anti-arrhythmic therapy.

No disadvantages seen with dual energy

The greater efficacy of a first shock with dual DCCV was achieved with no apparent disadvantages. There were no differences in post-procedure chest discomfort and no procedure-related adverse events in either arm, Dr. Aymond said.

The rising prevalence of obesity in the United States has created the need for a more effective first-line strategy for AF, noted Dr. Aymond, who presented the results of this study at the annual scientific sessions of the American Heart Association.

Cardioversion, which he characterized as the treatment of choice for AF, “fails to restore sinus rhythm in 20% to 35% of obese patients versus less than 10% of non-obese patients,” he said. The higher failure rate in patients with obesity is becoming a more common clinical issue not only due to the rising rates of obesity but a corresponding rise in AF, which is a related phenomenon.

“The risk of atrial fibrillation is increased by 50% relative to those who are not obese,” Dr. Aymond explained.

In this study, 200 patients at three participating centers were randomized to single DCCV or double DCCV after exclusions that included ventricular tachycardia and respiratory instability. The baseline characteristics were comparable. All 101 patients in the single DCCV group and 99 patients in the dual DCCV group were available for the intention-to-treat analysis.

200 vs. 400 joules delivered across the heart

In the study protocol, patients were fitted with four chest pads, two located adjacent but above the heart and two adjacent but below the heart. For single DCCV, 200 joules of energy were delivered from the upper right pad to the lower left pad across the heart. For dual DCCV, another 200 joules were delivered simultaneously from the upper left to the lower right across the heart. The total dose in the dual DCCV group was 400 joules.

The primary outcome was restoration of sinus rhythm of any duration immediately after DCCV. Safety, including clinical events, was a secondary outcome. Only the patients were blinded to the energy they received.

On univariate analysis, the odds ratio for successful cardioversion with dual DCCV was nearly eightfold higher (OR 7.8; P = .008) than single DCCV. On a simple multivariable analysis, when the researchers controlled for just age, sex, and body mass index, the odds ratio rose (OR 8.5; P = .007).

On a comprehensive multivariable analysis adding control for such characteristics as left ventricular ejection fraction (LVEF), obstructive sleep apnea, and antiarrhythmic drugs, the advantage of dual DCCV climbed above 12-fold (OR 12.6; P = .03).

The study is addressing a relevant and persistent question, said the AHA-invited discussant Jose A. Joglar, MD, program director, Clinical Cardiac Electrophysiology Fellowship, University of Texas Southwestern Medical Center, Dallas.

Dr. Joglar pointed out that alternatives to single DCCV for patients more difficult to cardiovert have been “sought for decades.” He noted that a variety of techniques, including dual DCCV, have been evaluated in small studies and case reports.

Alternatives for obese outlined

Several have shown promise, Dr. Joglar said. As one of several examples, he cited a 20-patient study that randomized patients to adhesive patches, like those employed in the Aymond trial, or handheld paddles. Both patches and paddles were applied with manual pressure while a 200-joule shock was delivered. The proportion of patients who cardioverted on the first shock was almost two times higher in the group after the first shock with the paddles (50% vs. 27%; P = .01). Dr. Joglar said the study supports the principle that 200 joules delivered by adhesive patches is inadequate for treatment of AF in many patients with obesity.

Dr. Joglar also cited studies suggesting that single DCCV delivered with higher energy than 200 joules appears to improve cardioversion success rates, but he indicated that this study with dual DCCV in the front-line setting provides evidence for another alternative.

“This is the first such trial with dual defibrillators as an initial strategy,” he said, calling the groups well matched and the superiority of dual DCCV “impressive.” He cautioned that the study size was well powered for the endpoint but perhaps small for evaluating relative safety.

Yet, “the study adds credibility and confidence for the use of dual DCCV, especially in difficult or refractory patients,” he said. He is less certain that it establishes dual DCCV as a standard first-line therapy in all patients with obesity. This would require additional studies to compare it to other types of strategies such as those he mentioned.

As an option for improving cardioversion in first-line treatment, dual DCCV “can be added to a list of other techniques, such as manual pressure or a higher initial dose with single DCCV,” he said.

Dr. Aymond and Dr. Joglar report no potential conflicts of interest.

PHILADELPHIA – As an initial treatment strategy for treatment of atrial fibrillation (AF) in patients with obesity, dual energy cardioversion is substantially more reliable and just as safe as conventional single energy cardioversion, a multicenter randomized trial shows.

When treated with dual direct current cardioversion (DCCV), only 2% of patients with obesity failed to cardiovert on the first shock versus 14% (P = .002) of those treated with a conventional single DCCV, reported Joshua D. Aymond, MD, a fellow in electrophysiology at Ochsner Health, New Orleans.

Of the 14 patients in the single DCCV arm who did not convert on the first shock, 12 cardioverted when switched to dual energy. The remaining two cardioverted on the second dual shock.

In the dual DCCV group, of the two patients who did not cardiovert on the first dual shock, one did on the second. The other also cardioverted on a second shock, but this second shock was not delivered for 2 weeks, during which time the patient received a course of amiodarone-based anti-arrhythmic therapy.

No disadvantages seen with dual energy

The greater efficacy of a first shock with dual DCCV was achieved with no apparent disadvantages. There were no differences in post-procedure chest discomfort and no procedure-related adverse events in either arm, Dr. Aymond said.

The rising prevalence of obesity in the United States has created the need for a more effective first-line strategy for AF, noted Dr. Aymond, who presented the results of this study at the annual scientific sessions of the American Heart Association.

Cardioversion, which he characterized as the treatment of choice for AF, “fails to restore sinus rhythm in 20% to 35% of obese patients versus less than 10% of non-obese patients,” he said. The higher failure rate in patients with obesity is becoming a more common clinical issue not only due to the rising rates of obesity but a corresponding rise in AF, which is a related phenomenon.

“The risk of atrial fibrillation is increased by 50% relative to those who are not obese,” Dr. Aymond explained.

In this study, 200 patients at three participating centers were randomized to single DCCV or double DCCV after exclusions that included ventricular tachycardia and respiratory instability. The baseline characteristics were comparable. All 101 patients in the single DCCV group and 99 patients in the dual DCCV group were available for the intention-to-treat analysis.

200 vs. 400 joules delivered across the heart

In the study protocol, patients were fitted with four chest pads, two located adjacent but above the heart and two adjacent but below the heart. For single DCCV, 200 joules of energy were delivered from the upper right pad to the lower left pad across the heart. For dual DCCV, another 200 joules were delivered simultaneously from the upper left to the lower right across the heart. The total dose in the dual DCCV group was 400 joules.

The primary outcome was restoration of sinus rhythm of any duration immediately after DCCV. Safety, including clinical events, was a secondary outcome. Only the patients were blinded to the energy they received.

On univariate analysis, the odds ratio for successful cardioversion with dual DCCV was nearly eightfold higher (OR 7.8; P = .008) than single DCCV. On a simple multivariable analysis, when the researchers controlled for just age, sex, and body mass index, the odds ratio rose (OR 8.5; P = .007).

On a comprehensive multivariable analysis adding control for such characteristics as left ventricular ejection fraction (LVEF), obstructive sleep apnea, and antiarrhythmic drugs, the advantage of dual DCCV climbed above 12-fold (OR 12.6; P = .03).

The study is addressing a relevant and persistent question, said the AHA-invited discussant Jose A. Joglar, MD, program director, Clinical Cardiac Electrophysiology Fellowship, University of Texas Southwestern Medical Center, Dallas.

Dr. Joglar pointed out that alternatives to single DCCV for patients more difficult to cardiovert have been “sought for decades.” He noted that a variety of techniques, including dual DCCV, have been evaluated in small studies and case reports.

Alternatives for obese outlined

Several have shown promise, Dr. Joglar said. As one of several examples, he cited a 20-patient study that randomized patients to adhesive patches, like those employed in the Aymond trial, or handheld paddles. Both patches and paddles were applied with manual pressure while a 200-joule shock was delivered. The proportion of patients who cardioverted on the first shock was almost two times higher in the group after the first shock with the paddles (50% vs. 27%; P = .01). Dr. Joglar said the study supports the principle that 200 joules delivered by adhesive patches is inadequate for treatment of AF in many patients with obesity.

Dr. Joglar also cited studies suggesting that single DCCV delivered with higher energy than 200 joules appears to improve cardioversion success rates, but he indicated that this study with dual DCCV in the front-line setting provides evidence for another alternative.

“This is the first such trial with dual defibrillators as an initial strategy,” he said, calling the groups well matched and the superiority of dual DCCV “impressive.” He cautioned that the study size was well powered for the endpoint but perhaps small for evaluating relative safety.

Yet, “the study adds credibility and confidence for the use of dual DCCV, especially in difficult or refractory patients,” he said. He is less certain that it establishes dual DCCV as a standard first-line therapy in all patients with obesity. This would require additional studies to compare it to other types of strategies such as those he mentioned.

As an option for improving cardioversion in first-line treatment, dual DCCV “can be added to a list of other techniques, such as manual pressure or a higher initial dose with single DCCV,” he said.

Dr. Aymond and Dr. Joglar report no potential conflicts of interest.

PHILADELPHIA – As an initial treatment strategy for treatment of atrial fibrillation (AF) in patients with obesity, dual energy cardioversion is substantially more reliable and just as safe as conventional single energy cardioversion, a multicenter randomized trial shows.

When treated with dual direct current cardioversion (DCCV), only 2% of patients with obesity failed to cardiovert on the first shock versus 14% (P = .002) of those treated with a conventional single DCCV, reported Joshua D. Aymond, MD, a fellow in electrophysiology at Ochsner Health, New Orleans.

Of the 14 patients in the single DCCV arm who did not convert on the first shock, 12 cardioverted when switched to dual energy. The remaining two cardioverted on the second dual shock.

In the dual DCCV group, of the two patients who did not cardiovert on the first dual shock, one did on the second. The other also cardioverted on a second shock, but this second shock was not delivered for 2 weeks, during which time the patient received a course of amiodarone-based anti-arrhythmic therapy.

No disadvantages seen with dual energy

The greater efficacy of a first shock with dual DCCV was achieved with no apparent disadvantages. There were no differences in post-procedure chest discomfort and no procedure-related adverse events in either arm, Dr. Aymond said.

The rising prevalence of obesity in the United States has created the need for a more effective first-line strategy for AF, noted Dr. Aymond, who presented the results of this study at the annual scientific sessions of the American Heart Association.

Cardioversion, which he characterized as the treatment of choice for AF, “fails to restore sinus rhythm in 20% to 35% of obese patients versus less than 10% of non-obese patients,” he said. The higher failure rate in patients with obesity is becoming a more common clinical issue not only due to the rising rates of obesity but a corresponding rise in AF, which is a related phenomenon.

“The risk of atrial fibrillation is increased by 50% relative to those who are not obese,” Dr. Aymond explained.

In this study, 200 patients at three participating centers were randomized to single DCCV or double DCCV after exclusions that included ventricular tachycardia and respiratory instability. The baseline characteristics were comparable. All 101 patients in the single DCCV group and 99 patients in the dual DCCV group were available for the intention-to-treat analysis.

200 vs. 400 joules delivered across the heart

In the study protocol, patients were fitted with four chest pads, two located adjacent but above the heart and two adjacent but below the heart. For single DCCV, 200 joules of energy were delivered from the upper right pad to the lower left pad across the heart. For dual DCCV, another 200 joules were delivered simultaneously from the upper left to the lower right across the heart. The total dose in the dual DCCV group was 400 joules.

The primary outcome was restoration of sinus rhythm of any duration immediately after DCCV. Safety, including clinical events, was a secondary outcome. Only the patients were blinded to the energy they received.

On univariate analysis, the odds ratio for successful cardioversion with dual DCCV was nearly eightfold higher (OR 7.8; P = .008) than single DCCV. On a simple multivariable analysis, when the researchers controlled for just age, sex, and body mass index, the odds ratio rose (OR 8.5; P = .007).

On a comprehensive multivariable analysis adding control for such characteristics as left ventricular ejection fraction (LVEF), obstructive sleep apnea, and antiarrhythmic drugs, the advantage of dual DCCV climbed above 12-fold (OR 12.6; P = .03).

The study is addressing a relevant and persistent question, said the AHA-invited discussant Jose A. Joglar, MD, program director, Clinical Cardiac Electrophysiology Fellowship, University of Texas Southwestern Medical Center, Dallas.

Dr. Joglar pointed out that alternatives to single DCCV for patients more difficult to cardiovert have been “sought for decades.” He noted that a variety of techniques, including dual DCCV, have been evaluated in small studies and case reports.

Alternatives for obese outlined

Several have shown promise, Dr. Joglar said. As one of several examples, he cited a 20-patient study that randomized patients to adhesive patches, like those employed in the Aymond trial, or handheld paddles. Both patches and paddles were applied with manual pressure while a 200-joule shock was delivered. The proportion of patients who cardioverted on the first shock was almost two times higher in the group after the first shock with the paddles (50% vs. 27%; P = .01). Dr. Joglar said the study supports the principle that 200 joules delivered by adhesive patches is inadequate for treatment of AF in many patients with obesity.

Dr. Joglar also cited studies suggesting that single DCCV delivered with higher energy than 200 joules appears to improve cardioversion success rates, but he indicated that this study with dual DCCV in the front-line setting provides evidence for another alternative.

“This is the first such trial with dual defibrillators as an initial strategy,” he said, calling the groups well matched and the superiority of dual DCCV “impressive.” He cautioned that the study size was well powered for the endpoint but perhaps small for evaluating relative safety.

Yet, “the study adds credibility and confidence for the use of dual DCCV, especially in difficult or refractory patients,” he said. He is less certain that it establishes dual DCCV as a standard first-line therapy in all patients with obesity. This would require additional studies to compare it to other types of strategies such as those he mentioned.

As an option for improving cardioversion in first-line treatment, dual DCCV “can be added to a list of other techniques, such as manual pressure or a higher initial dose with single DCCV,” he said.

Dr. Aymond and Dr. Joglar report no potential conflicts of interest.

Results of a trial using an intensive, 4-year program aimed at blood pressure lowering showed that intervention reduced not only blood pressure, but also significantly reduced the risk of total dementia over that period.

All-cause dementia, the primary outcome, was significantly reduced by 15% in the intervention group, compared with usual care, and cognitive impairment no dementia (CIND), a secondary outcome, was also significantly reduced by 16%.

“Blood pressure reduction is effective in reducing the risk of dementia in patients with hypertension,” concluded Jiang He, MD, PhD, professor of epidemiology and medicine and director of Tulane University’s Translational Science Institute, New Orleans. “This proven, effective intervention should be widely scaled up to reduce the global burden of dementia.”

He presented these results from the China Rural Hypertension Control Project (CRHCP) at the annual scientific sessions of the American Heart Association.

Target organ damage

Keith Ferdinand, MD, also from Tulane University, commented on the findings during a press conference at the meeting, noting that the result “opens our opportunity to recognize that the target organ damage of hypertension also now includes dementia.”

The researchers were able to “rigorously lower blood pressure from 157 to 127.6 in the intervention, 155 to 147 in the controls – 22 mg Hg – and if you look at the P values for all the various outcomes, they were very robust,” Dr. Ferdinand said.

Another interesting feature about the strategy used in this trial is that “this was true team-based care,” he pointed out. The trained interventionists in the study, called village doctors, collaborated with primary care physicians and initiated medications. “They stayed on a simple treatment protocol, and they were able to assist patients to ensure they had free medications, health coaching for lifestyle, home blood pressure measurement, and ensuring adherence.”

So, Dr. Ferdinand added, “one of the questions is whether this is a model we can use in other places around the globe, in places with low resources, and in the United States in disadvantaged populations.”

Public health priority

It’s estimated that the global number of those living with dementia will increase from 57.4 million in 2019 to 152.8 million by 2050, Dr. He said. “In the absence of curative treatment, the primary prevention of dementia through risk factor reduction, such as blood pressure lowering, becomes a public health priority.”

Previous randomized trials have lacked sample size and duration but have reported a nonsignificant reduction in dementia associated with antihypertensive treatment in patients with hypertension or a history of stroke, Dr. He noted.

This new trial aimed to test the effectiveness of intensive BP intervention to reduce the risk of all-cause dementia and cognitive impairment over a 48-month intervention period versus usual care.

It was an open-label, blinded-endpoint, cluster-randomized trial, and included 33,995 individual patients from 325 villages in China, aged 40 years and older, with untreated hypertension. The villages were randomly assigned to an intervention group or usual care, stratified by province, county, and township.

Patients were eligible if they had mean untreated systolic BP greater than 140 mm Hg and/or diastolic BP greater than 90 mm Hg or mean treated systolic BP of greater than 130 and/or diastolic greater than 80 mm Hg. Patients with a history of cardiovascular disease, chronic kidney disease, or diabetes and a mean systolic BP greater than 130 mm Hg and/or diastolic BP greater than 80 mm Hg from six measures on two different days were also eligible.

All were enrolled in the China New Rural Cooperative Medical Scheme, which covers 99% of rural residents for health care services, Dr. He noted.

The intervention was a simple stepped-care protocol for hypertension treatment, aimed at achieving a target systolic BP of less than 130 mm Hg and diastolic of less than 80 mm Hg.

Village doctors started and titrated antihypertensive treatment based on a protocol and were able to deliver discounted and free medications to patients. They also did health coaching on lifestyle modification and adherence to medication, and instructed patients on home BP monitoring.

Patients were provided training, supervision, and consultation by primary care physicians and hypertension specialists.

At the month 48 follow-up visit, the participants were assessed by neurologists who were blinded to randomization assignments. Neurologists did a variety of tests and assessments including collecting data on the patient’s medical and psychiatric history and risk factors for dementia, as well as neurologic assessment using the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Quick Dementia Rating System.

The primary outcome was all-cause dementia, defined according to recommendations from the National Institute on Aging–Alzheimer’s Association work groups on diagnostic guidelines for Alzheimer’s disease.

Secondary outcomes included CIND, a composite outcome of dementia or CIND, and a composite of dementia or deaths.

The final diagnosis of all-cause dementia or CIND was made by an expert adjudication panel blinded to the intervention assignment.

At 48 months, 91.3% of patients completed the follow-up for clinical outcomes. Participants were an average of 63 years of age, 61% were female, and 23% had less than a primary school education, Dr. He noted.

The net group differences in systolic and diastolic BP reduction were 22 and 9.3 mm Hg, respectively (P < .0001).

Significant differences were also seen between the groups in the primary outcome of all-cause dementia, as well as secondary outcomes of CIND, dementia or cognitive impairment, or dementia or deaths.

Serious adverse events were more common in the usual care group, and there was no difference between groups in the occurrence of falls or syncope.

The effect was consistent across subgroups, Dr. He said, including age, sex, education, cigarette smoking, body mass index, systolic BP, and fasting plasma glucose at baseline.

First definitive evidence

Invited discussant for the trial, Daniel W. Jones, MD, University of Mississippi Medical Center, Jackson, and past president of the AHA, pointed out that previous results from CRHCP on cardiovascular outcomes, reported earlier in 2023 in The Lancet, showed that, similar to results of the large SPRINT trial, lowering systolic BP to a goal of less than 130 mm Hg reduced a composite endpoint of MI, stroke, heart failure requiring hospitalization, and cardiovascular disease death over the 36-month follow-up.

The SPRINT findings also suggested a possible reduction in dementia, Dr. Jones said.

Now, in these new CRHCP results, “there was a clear benefit for intensive BP control in reducing risk for dementia and cognitive dysfunction,” he said. “This is, importantly, the first definitive evidence of dementia risk reduction demonstrated in a randomized controlled clinical trial. This outcome supports observational data that shows a strong relationship between BP and dementia.”

Since it is the first of its kind though, replication of the results will be important, he noted.

The study also showed that the intervention, using minimally trained village doctors, sustained BP control for 48 months. “This model could be used in any setting with modifications, including in the United States,” Dr. Jones said.

The study was supported by the Ministry of Science and Technology of China; U.S. investigators did not receive financial support from this study. The researchers and Dr. Jones disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Results of a trial using an intensive, 4-year program aimed at blood pressure lowering showed that intervention reduced not only blood pressure, but also significantly reduced the risk of total dementia over that period.

All-cause dementia, the primary outcome, was significantly reduced by 15% in the intervention group, compared with usual care, and cognitive impairment no dementia (CIND), a secondary outcome, was also significantly reduced by 16%.

“Blood pressure reduction is effective in reducing the risk of dementia in patients with hypertension,” concluded Jiang He, MD, PhD, professor of epidemiology and medicine and director of Tulane University’s Translational Science Institute, New Orleans. “This proven, effective intervention should be widely scaled up to reduce the global burden of dementia.”

He presented these results from the China Rural Hypertension Control Project (CRHCP) at the annual scientific sessions of the American Heart Association.

Target organ damage

Keith Ferdinand, MD, also from Tulane University, commented on the findings during a press conference at the meeting, noting that the result “opens our opportunity to recognize that the target organ damage of hypertension also now includes dementia.”

The researchers were able to “rigorously lower blood pressure from 157 to 127.6 in the intervention, 155 to 147 in the controls – 22 mg Hg – and if you look at the P values for all the various outcomes, they were very robust,” Dr. Ferdinand said.

Another interesting feature about the strategy used in this trial is that “this was true team-based care,” he pointed out. The trained interventionists in the study, called village doctors, collaborated with primary care physicians and initiated medications. “They stayed on a simple treatment protocol, and they were able to assist patients to ensure they had free medications, health coaching for lifestyle, home blood pressure measurement, and ensuring adherence.”

So, Dr. Ferdinand added, “one of the questions is whether this is a model we can use in other places around the globe, in places with low resources, and in the United States in disadvantaged populations.”

Public health priority

It’s estimated that the global number of those living with dementia will increase from 57.4 million in 2019 to 152.8 million by 2050, Dr. He said. “In the absence of curative treatment, the primary prevention of dementia through risk factor reduction, such as blood pressure lowering, becomes a public health priority.”

Previous randomized trials have lacked sample size and duration but have reported a nonsignificant reduction in dementia associated with antihypertensive treatment in patients with hypertension or a history of stroke, Dr. He noted.

This new trial aimed to test the effectiveness of intensive BP intervention to reduce the risk of all-cause dementia and cognitive impairment over a 48-month intervention period versus usual care.

It was an open-label, blinded-endpoint, cluster-randomized trial, and included 33,995 individual patients from 325 villages in China, aged 40 years and older, with untreated hypertension. The villages were randomly assigned to an intervention group or usual care, stratified by province, county, and township.

Patients were eligible if they had mean untreated systolic BP greater than 140 mm Hg and/or diastolic BP greater than 90 mm Hg or mean treated systolic BP of greater than 130 and/or diastolic greater than 80 mm Hg. Patients with a history of cardiovascular disease, chronic kidney disease, or diabetes and a mean systolic BP greater than 130 mm Hg and/or diastolic BP greater than 80 mm Hg from six measures on two different days were also eligible.

All were enrolled in the China New Rural Cooperative Medical Scheme, which covers 99% of rural residents for health care services, Dr. He noted.

The intervention was a simple stepped-care protocol for hypertension treatment, aimed at achieving a target systolic BP of less than 130 mm Hg and diastolic of less than 80 mm Hg.

Village doctors started and titrated antihypertensive treatment based on a protocol and were able to deliver discounted and free medications to patients. They also did health coaching on lifestyle modification and adherence to medication, and instructed patients on home BP monitoring.

Patients were provided training, supervision, and consultation by primary care physicians and hypertension specialists.

At the month 48 follow-up visit, the participants were assessed by neurologists who were blinded to randomization assignments. Neurologists did a variety of tests and assessments including collecting data on the patient’s medical and psychiatric history and risk factors for dementia, as well as neurologic assessment using the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Quick Dementia Rating System.

The primary outcome was all-cause dementia, defined according to recommendations from the National Institute on Aging–Alzheimer’s Association work groups on diagnostic guidelines for Alzheimer’s disease.

Secondary outcomes included CIND, a composite outcome of dementia or CIND, and a composite of dementia or deaths.

The final diagnosis of all-cause dementia or CIND was made by an expert adjudication panel blinded to the intervention assignment.

At 48 months, 91.3% of patients completed the follow-up for clinical outcomes. Participants were an average of 63 years of age, 61% were female, and 23% had less than a primary school education, Dr. He noted.

The net group differences in systolic and diastolic BP reduction were 22 and 9.3 mm Hg, respectively (P < .0001).

Significant differences were also seen between the groups in the primary outcome of all-cause dementia, as well as secondary outcomes of CIND, dementia or cognitive impairment, or dementia or deaths.

Serious adverse events were more common in the usual care group, and there was no difference between groups in the occurrence of falls or syncope.

The effect was consistent across subgroups, Dr. He said, including age, sex, education, cigarette smoking, body mass index, systolic BP, and fasting plasma glucose at baseline.

First definitive evidence

Invited discussant for the trial, Daniel W. Jones, MD, University of Mississippi Medical Center, Jackson, and past president of the AHA, pointed out that previous results from CRHCP on cardiovascular outcomes, reported earlier in 2023 in The Lancet, showed that, similar to results of the large SPRINT trial, lowering systolic BP to a goal of less than 130 mm Hg reduced a composite endpoint of MI, stroke, heart failure requiring hospitalization, and cardiovascular disease death over the 36-month follow-up.

The SPRINT findings also suggested a possible reduction in dementia, Dr. Jones said.

Now, in these new CRHCP results, “there was a clear benefit for intensive BP control in reducing risk for dementia and cognitive dysfunction,” he said. “This is, importantly, the first definitive evidence of dementia risk reduction demonstrated in a randomized controlled clinical trial. This outcome supports observational data that shows a strong relationship between BP and dementia.”

Since it is the first of its kind though, replication of the results will be important, he noted.

The study also showed that the intervention, using minimally trained village doctors, sustained BP control for 48 months. “This model could be used in any setting with modifications, including in the United States,” Dr. Jones said.

The study was supported by the Ministry of Science and Technology of China; U.S. investigators did not receive financial support from this study. The researchers and Dr. Jones disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Results of a trial using an intensive, 4-year program aimed at blood pressure lowering showed that intervention reduced not only blood pressure, but also significantly reduced the risk of total dementia over that period.

All-cause dementia, the primary outcome, was significantly reduced by 15% in the intervention group, compared with usual care, and cognitive impairment no dementia (CIND), a secondary outcome, was also significantly reduced by 16%.

“Blood pressure reduction is effective in reducing the risk of dementia in patients with hypertension,” concluded Jiang He, MD, PhD, professor of epidemiology and medicine and director of Tulane University’s Translational Science Institute, New Orleans. “This proven, effective intervention should be widely scaled up to reduce the global burden of dementia.”

He presented these results from the China Rural Hypertension Control Project (CRHCP) at the annual scientific sessions of the American Heart Association.

Target organ damage

Keith Ferdinand, MD, also from Tulane University, commented on the findings during a press conference at the meeting, noting that the result “opens our opportunity to recognize that the target organ damage of hypertension also now includes dementia.”

The researchers were able to “rigorously lower blood pressure from 157 to 127.6 in the intervention, 155 to 147 in the controls – 22 mg Hg – and if you look at the P values for all the various outcomes, they were very robust,” Dr. Ferdinand said.

Another interesting feature about the strategy used in this trial is that “this was true team-based care,” he pointed out. The trained interventionists in the study, called village doctors, collaborated with primary care physicians and initiated medications. “They stayed on a simple treatment protocol, and they were able to assist patients to ensure they had free medications, health coaching for lifestyle, home blood pressure measurement, and ensuring adherence.”

So, Dr. Ferdinand added, “one of the questions is whether this is a model we can use in other places around the globe, in places with low resources, and in the United States in disadvantaged populations.”

Public health priority

It’s estimated that the global number of those living with dementia will increase from 57.4 million in 2019 to 152.8 million by 2050, Dr. He said. “In the absence of curative treatment, the primary prevention of dementia through risk factor reduction, such as blood pressure lowering, becomes a public health priority.”

Previous randomized trials have lacked sample size and duration but have reported a nonsignificant reduction in dementia associated with antihypertensive treatment in patients with hypertension or a history of stroke, Dr. He noted.

This new trial aimed to test the effectiveness of intensive BP intervention to reduce the risk of all-cause dementia and cognitive impairment over a 48-month intervention period versus usual care.

It was an open-label, blinded-endpoint, cluster-randomized trial, and included 33,995 individual patients from 325 villages in China, aged 40 years and older, with untreated hypertension. The villages were randomly assigned to an intervention group or usual care, stratified by province, county, and township.

Patients were eligible if they had mean untreated systolic BP greater than 140 mm Hg and/or diastolic BP greater than 90 mm Hg or mean treated systolic BP of greater than 130 and/or diastolic greater than 80 mm Hg. Patients with a history of cardiovascular disease, chronic kidney disease, or diabetes and a mean systolic BP greater than 130 mm Hg and/or diastolic BP greater than 80 mm Hg from six measures on two different days were also eligible.

All were enrolled in the China New Rural Cooperative Medical Scheme, which covers 99% of rural residents for health care services, Dr. He noted.

The intervention was a simple stepped-care protocol for hypertension treatment, aimed at achieving a target systolic BP of less than 130 mm Hg and diastolic of less than 80 mm Hg.

Village doctors started and titrated antihypertensive treatment based on a protocol and were able to deliver discounted and free medications to patients. They also did health coaching on lifestyle modification and adherence to medication, and instructed patients on home BP monitoring.

Patients were provided training, supervision, and consultation by primary care physicians and hypertension specialists.

At the month 48 follow-up visit, the participants were assessed by neurologists who were blinded to randomization assignments. Neurologists did a variety of tests and assessments including collecting data on the patient’s medical and psychiatric history and risk factors for dementia, as well as neurologic assessment using the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Quick Dementia Rating System.

The primary outcome was all-cause dementia, defined according to recommendations from the National Institute on Aging–Alzheimer’s Association work groups on diagnostic guidelines for Alzheimer’s disease.

Secondary outcomes included CIND, a composite outcome of dementia or CIND, and a composite of dementia or deaths.

The final diagnosis of all-cause dementia or CIND was made by an expert adjudication panel blinded to the intervention assignment.

At 48 months, 91.3% of patients completed the follow-up for clinical outcomes. Participants were an average of 63 years of age, 61% were female, and 23% had less than a primary school education, Dr. He noted.

The net group differences in systolic and diastolic BP reduction were 22 and 9.3 mm Hg, respectively (P < .0001).

Significant differences were also seen between the groups in the primary outcome of all-cause dementia, as well as secondary outcomes of CIND, dementia or cognitive impairment, or dementia or deaths.

Serious adverse events were more common in the usual care group, and there was no difference between groups in the occurrence of falls or syncope.

The effect was consistent across subgroups, Dr. He said, including age, sex, education, cigarette smoking, body mass index, systolic BP, and fasting plasma glucose at baseline.

First definitive evidence

Invited discussant for the trial, Daniel W. Jones, MD, University of Mississippi Medical Center, Jackson, and past president of the AHA, pointed out that previous results from CRHCP on cardiovascular outcomes, reported earlier in 2023 in The Lancet, showed that, similar to results of the large SPRINT trial, lowering systolic BP to a goal of less than 130 mm Hg reduced a composite endpoint of MI, stroke, heart failure requiring hospitalization, and cardiovascular disease death over the 36-month follow-up.

The SPRINT findings also suggested a possible reduction in dementia, Dr. Jones said.

Now, in these new CRHCP results, “there was a clear benefit for intensive BP control in reducing risk for dementia and cognitive dysfunction,” he said. “This is, importantly, the first definitive evidence of dementia risk reduction demonstrated in a randomized controlled clinical trial. This outcome supports observational data that shows a strong relationship between BP and dementia.”

Since it is the first of its kind though, replication of the results will be important, he noted.

The study also showed that the intervention, using minimally trained village doctors, sustained BP control for 48 months. “This model could be used in any setting with modifications, including in the United States,” Dr. Jones said.

The study was supported by the Ministry of Science and Technology of China; U.S. investigators did not receive financial support from this study. The researchers and Dr. Jones disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Dr. Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.
 

Lp(a) strongly associated with CV risk

Similar to LDL cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Dr. Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Dr. Nissen, who presented these results at the annual scientific sessions of the American Heart Association. They were also published online in JAMA.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the United States and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure greater than 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min per 1.73 m²), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and 6 in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.
 

Safety profile is placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Dr. Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Dr. Nissen said they are too modest to expect a meaningful clinical benefit.
 

Lp(a) not responsive to lifestyle changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Dr. Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Dr. Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the University of California, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering Lp(a), it appears to be getting rid of it,” she said.

Dr. O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. Dr. O’Donoghue cited, as an example, a gene-editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair of the department of preventive medicine, Northwestern Medicine, Chicago.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Dr. Lloyd-Jones predicted that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Dr. Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Dr. Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Dr. Watson reported financial relationships with Amgen, Boehringer Ingelheim, Lilly, and Novartis. Dr. Lloyd-Jones disclosed no relevant financial relationships.

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

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Dr. Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.
 

Lp(a) strongly associated with CV risk

Similar to LDL cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Dr. Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Dr. Nissen, who presented these results at the annual scientific sessions of the American Heart Association. They were also published online in JAMA.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the United States and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure greater than 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min per 1.73 m²), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and 6 in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.
 

Safety profile is placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Dr. Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Dr. Nissen said they are too modest to expect a meaningful clinical benefit.
 

Lp(a) not responsive to lifestyle changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Dr. Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Dr. Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the University of California, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering Lp(a), it appears to be getting rid of it,” she said.

Dr. O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. Dr. O’Donoghue cited, as an example, a gene-editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair of the department of preventive medicine, Northwestern Medicine, Chicago.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Dr. Lloyd-Jones predicted that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Dr. Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Dr. Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Dr. Watson reported financial relationships with Amgen, Boehringer Ingelheim, Lilly, and Novartis. Dr. Lloyd-Jones disclosed no relevant financial relationships.

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

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Dr. Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.
 

Lp(a) strongly associated with CV risk

Similar to LDL cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Dr. Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Dr. Nissen, who presented these results at the annual scientific sessions of the American Heart Association. They were also published online in JAMA.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the United States and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure greater than 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min per 1.73 m²), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and 6 in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.
 

Safety profile is placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Dr. Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Dr. Nissen said they are too modest to expect a meaningful clinical benefit.
 

Lp(a) not responsive to lifestyle changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Dr. Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Dr. Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the University of California, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering Lp(a), it appears to be getting rid of it,” she said.

Dr. O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. Dr. O’Donoghue cited, as an example, a gene-editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair of the department of preventive medicine, Northwestern Medicine, Chicago.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Dr. Lloyd-Jones predicted that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Dr. Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Dr. Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Dr. Watson reported financial relationships with Amgen, Boehringer Ingelheim, Lilly, and Novartis. Dr. Lloyd-Jones disclosed no relevant financial relationships.

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

PHILADELPHIA – Aspirin may not be necessary or beneficial in patients with advanced heart failure who get a left ventricular assist device (LVAD), particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.

“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.

ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
 

Unexpected findings

“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”

Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.

The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.

In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.

“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
 

Shift of focus to therapy

The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.

“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”

But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”

Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.

“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”

Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.

PHILADELPHIA – Aspirin may not be necessary or beneficial in patients with advanced heart failure who get a left ventricular assist device (LVAD), particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.

“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.

ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
 

Unexpected findings

“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”

Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.

The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.

In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.

“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
 

Shift of focus to therapy

The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.

“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”

But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”

Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.

“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”

Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.

PHILADELPHIA – Aspirin may not be necessary or beneficial in patients with advanced heart failure who get a left ventricular assist device (LVAD), particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.

“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.

ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
 

Unexpected findings

“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”

Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.

The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.

In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.

“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
 

Shift of focus to therapy

The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.

“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”

But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”

Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.

“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”

Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.

PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.

In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that patients randomly assigned to dapagliflozin 10 mg along with the standard of care had improved outcomes based on a composite of seven primary endpoints, which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.

Richard M. Kirkner/MDedge News

“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).

Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
 

Lower-risk patients 

DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.

Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.

• The hierarchical seven primary endpoints were:
• Death, with cardiovascular death ranked first followed by noncardiovascular death
• Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
• Nonfatal MI
• Atrial fibrillation/flutter event
• New diagnosis of type 2 diabetes
• New York Heart Association functional class at the last visit
• Drop in body weight of at least 5% at the last visit

The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.

When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.

For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.

However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.  

The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.

He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.

“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
 

Not a ringing endorsement

But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.

Richard M. Kirkner/MDedge News

“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”

However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.

In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”

The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.

“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.

But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.

The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
 

PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.

In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that patients randomly assigned to dapagliflozin 10 mg along with the standard of care had improved outcomes based on a composite of seven primary endpoints, which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.

Richard M. Kirkner/MDedge News

“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).

Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
 

Lower-risk patients 

DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.

Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.

• The hierarchical seven primary endpoints were:
• Death, with cardiovascular death ranked first followed by noncardiovascular death
• Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
• Nonfatal MI
• Atrial fibrillation/flutter event
• New diagnosis of type 2 diabetes
• New York Heart Association functional class at the last visit
• Drop in body weight of at least 5% at the last visit

The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.

When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.

For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.

However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.  

The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.

He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.

“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
 

Not a ringing endorsement

But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.

Richard M. Kirkner/MDedge News

“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”

However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.

In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”

The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.

“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.

But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.

The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
 

PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.

In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that patients randomly assigned to dapagliflozin 10 mg along with the standard of care had improved outcomes based on a composite of seven primary endpoints, which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.

Richard M. Kirkner/MDedge News

“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).

Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
 

Lower-risk patients 

DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.

Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.

• The hierarchical seven primary endpoints were:
• Death, with cardiovascular death ranked first followed by noncardiovascular death
• Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
• Nonfatal MI
• Atrial fibrillation/flutter event
• New diagnosis of type 2 diabetes
• New York Heart Association functional class at the last visit
• Drop in body weight of at least 5% at the last visit

The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.

When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.

For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.

However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.  

The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.

He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.

“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
 

Not a ringing endorsement

But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.

Richard M. Kirkner/MDedge News

“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”

However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.

In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”

The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.

“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.

But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.

The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.