MDedge Endocrinology

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.

The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology. 

MDedge News/Mitchel L. Zoler

“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).

The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.

Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.

“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.

The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.

“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said. 

Non-dippers

Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.

“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”

The study did find some differences in the blood pressure profile between the two dosing schedules.

“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said. 

“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.

The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.

TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.

The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.

The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).

What to recommend in clinical practice?

Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.

Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”

She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.

“The finding of no difference in event rate in the TIME study is therefore very intriguing.”

She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.  

“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.

Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”

The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions. 

And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”

The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.

“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.

On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”

Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”

One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.

“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.

Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.

“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.

Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”

The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.  

“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.  

“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”

Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.

“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”

She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”

The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.

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

BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.

The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology. 

MDedge News/Mitchel L. Zoler

“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).

The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.

Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.

“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.

The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.

“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said. 

Non-dippers

Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.

“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”

The study did find some differences in the blood pressure profile between the two dosing schedules.

“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said. 

“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.

The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.

TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.

The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.

The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).

What to recommend in clinical practice?

Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.

Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”

She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.

“The finding of no difference in event rate in the TIME study is therefore very intriguing.”

She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.  

“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.

Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”

The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions. 

And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”

The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.

“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.

On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”

Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”

One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.

“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.

Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.

“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.

Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”

The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.  

“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.  

“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”

Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.

“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”

She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”

The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.

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

BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.

The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology. 

MDedge News/Mitchel L. Zoler

“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).

The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.

Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.

“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.

The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.

“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said. 

Non-dippers

Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.

“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”

The study did find some differences in the blood pressure profile between the two dosing schedules.

“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said. 

“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.

The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.

TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.

The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.

The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).

What to recommend in clinical practice?

Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.

Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”

She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.

“The finding of no difference in event rate in the TIME study is therefore very intriguing.”

She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.  

“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.

Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”

The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions. 

And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”

The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.

“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.

On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”

Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”

One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.

“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.

Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.

“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.

Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”

The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.  

“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.  

“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”

Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.

“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”

She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”

The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.

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

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.