TBD Meeting (3243-22)

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

CHICAGO – Early ablation of atrial fibrillation (AFib) reduces the risk of progression, compared with antiarrhythmic therapies, according to results of a multicenter, randomized trial called PROGRESSIVE-AF.

Over 36 months of follow-up, the trial linked early ablation with a reduced risk of persistent AFib (1.9% vs. 7.4%), and in addition, those in the ablation group were less likely to have recurrent atrial tachyarrhythmias of any kind (56.5% vs. 77.2%), reported Jason G. Andrade, MD, at the American Heart Association scientific sessions.

Ted Bosworth/MDedge

Serving as a long-term extension of the EARLY-AF trial published almost 2 years ago, this trial expands evidence that progressive AFib can be attenuated, a concept that has been debated.

“Can early AFib ablation stop progression?” asked Carina Blomström-Lindqvist, MD, PhD. The invited discussant for the PROGRESSION-AF trial, Dr. Blomström-Lundqvist concluded, “here is another set of data that suggests it can.”

By another set of data, Dr. Blomström-Lindqvist was referring to a previously published multinational study called ATTEST In this study, which involved 29 sites worldwide and compared radiofrequency ablation to antiarrhythmic drug therapy, early ablation also produced a lower risk of persistent AFib at the end of 3 years (2.4% vs. 17.5%; P = .0009).

In the previously published open-label EARLY-AF trial, 303 patients with paroxysmal, untreated AFib were randomized to cryoballoon ablation or antiarrhythmic drugs. The primary endpoint was the first documented recurrence of an atrial tachyarrhythmia between 91 and 365 days. The lower rate following ablation (42.9% vs. 67.8%) represented a more than 50% reduction in risk (hazard ratio, 0.48; P < .001) relative to antiarrhythmic therapy.

In PROGRESSIVE-AF, the same 303 patients were monitored continuously for an additional 24 months with an implanted cardiac monitor programmed with an AFib-detection algorithm. The data from the monitor were obtained daily. Over the final 2 years of the study, office visits were conducted every 6 months.
 

Tachyarrhythmias represent primary endpoint

In addition to persistent AFib, defined as lasting ≥ 7 days or lasting 48 hours to 7 days but requiring cardioversion for termination, patients in PROGRESSIVE-AF were also monitored for recurrent atrial tachyarrhythmias, AFib burden, quality of life (QOL), and health care utilization, and safety.

The average age was roughly 58 years. Although more than one-third had hypertension, most had no other comorbidities. The authors emphasized that the study population overall was relatively young and healthy.

Those randomized to antiarrhythmic therapy in EARLY-AF/PROGRESSIVE-AF received commonly prescribed therapies titrated to maximally tolerated doses using standardized protocols. At the start of EARLY-AF, flecainide, taken by 65% of patients, was the most commonly used agent, followed by sotalol, propafenone, dronedarone, and amiodarone.

At the end of PROGRESSIVE-AF, the order of the most common therapies did not change relative to EARLY-AF, but only 49% of patients were taking flecainide and 31% were no longer taking any antiarrhythmic therapy.

At the end of 3 years of follow-up in EARLY-AF/PROGRESSIVE-AF, the difference in persistent AFib represented a 75% reduction in favor of early ablation (HR, 0.25; 95% confidence interval, 0.09-0.70).

In those treated with ablation relative to those treated with antiarrhythmic therapy, the lower rate of atrial tachyarrhythmia lasting more than 7 days (1.9% vs. 6.0%) represented a 70% risk reduction (HR, 0.30; 95% CI 0.10-0.93). The protection from cardioversion for atrial tachyarrhythmia lasting between 2 and 7 days in duration (0.6% vs. 4.7%) translated into an 86% relative reduction (HR, 0.14; 95% CI, 0.02-0.85).

The impact on QOL for those randomized to ablation, which was measured with both AFib-specific and generic measures, was meaningful to patients, according to Dr. Andrade, director of the Cardiac Electrophysiology Laboratory, Vancouver General Hospital.

For example, the mean difference in the AF Quality of Life Survey (AFEQT), was 8.0 at 1 year and 7.4 at 3 years in favor of ablation. A change of 5 points in this score is considered to be a clinically meaningful difference, according to Dr. Andrade.

Numerically, the relative risk of emergency room visits and cardioversion were lower in the ablation group, but the differences did not reach statistical significance. However, the lower hazard ratio for hospitalization was significant (HR, 0.31; 95% CI, 0.15-0.66), supporting a reduction in consumption of health care resources.
 

Ablation found safer than drugs

The rate of adverse events of any kind (11.0% vs. 23.5%) and serious adverse events (4.5% vs. 10.1%) were lower in the ablation group.

There were no differences in major adverse cardiovascular events observed in this period of follow-up, but Dr. Andrade pointed out that follow-up was not long enough to expect differences in these events.

Impressed by the magnitude of the reduction in persistent AFib in a population of relatively young and healthy patients considered to be at a low risk of AFib progression, Dr. Blomström-Lindqvist, a professor of cardiology at the Institution of Medical Science, Uppsala, Sweden, indicated that the data support early ablation as a means to reduce risk of this outcome.

However, she did caution that progressive AFib was observed in a relatively small proportion of patients managed with antiarrhythmic therapy at 3 years, an outcome relevant when discussing treatment options with patients.

The results were published in New England Journal of Medicine simultaneously with Dr. Andrade’s presentation.

Dr. Andrade reports financial relationships with Bayer, Bayliss, Biosense, Bristol-Myers Squibb, Medtronic and Servier. The trial, funded largely by the Canadian government and Canadian professional societies, received additional funding from Bayliss and Medtronic. Dr. Blomström-Lundqvist reports financial relationships with Bayer, Boston Scientific, Cathprint, Medtronic, and Sanofi.

CHICAGO – Early ablation of atrial fibrillation (AFib) reduces the risk of progression, compared with antiarrhythmic therapies, according to results of a multicenter, randomized trial called PROGRESSIVE-AF.

Over 36 months of follow-up, the trial linked early ablation with a reduced risk of persistent AFib (1.9% vs. 7.4%), and in addition, those in the ablation group were less likely to have recurrent atrial tachyarrhythmias of any kind (56.5% vs. 77.2%), reported Jason G. Andrade, MD, at the American Heart Association scientific sessions.

Ted Bosworth/MDedge

Serving as a long-term extension of the EARLY-AF trial published almost 2 years ago, this trial expands evidence that progressive AFib can be attenuated, a concept that has been debated.

“Can early AFib ablation stop progression?” asked Carina Blomström-Lindqvist, MD, PhD. The invited discussant for the PROGRESSION-AF trial, Dr. Blomström-Lundqvist concluded, “here is another set of data that suggests it can.”

By another set of data, Dr. Blomström-Lindqvist was referring to a previously published multinational study called ATTEST In this study, which involved 29 sites worldwide and compared radiofrequency ablation to antiarrhythmic drug therapy, early ablation also produced a lower risk of persistent AFib at the end of 3 years (2.4% vs. 17.5%; P = .0009).

In the previously published open-label EARLY-AF trial, 303 patients with paroxysmal, untreated AFib were randomized to cryoballoon ablation or antiarrhythmic drugs. The primary endpoint was the first documented recurrence of an atrial tachyarrhythmia between 91 and 365 days. The lower rate following ablation (42.9% vs. 67.8%) represented a more than 50% reduction in risk (hazard ratio, 0.48; P < .001) relative to antiarrhythmic therapy.

In PROGRESSIVE-AF, the same 303 patients were monitored continuously for an additional 24 months with an implanted cardiac monitor programmed with an AFib-detection algorithm. The data from the monitor were obtained daily. Over the final 2 years of the study, office visits were conducted every 6 months.
 

Tachyarrhythmias represent primary endpoint

In addition to persistent AFib, defined as lasting ≥ 7 days or lasting 48 hours to 7 days but requiring cardioversion for termination, patients in PROGRESSIVE-AF were also monitored for recurrent atrial tachyarrhythmias, AFib burden, quality of life (QOL), and health care utilization, and safety.

The average age was roughly 58 years. Although more than one-third had hypertension, most had no other comorbidities. The authors emphasized that the study population overall was relatively young and healthy.

Those randomized to antiarrhythmic therapy in EARLY-AF/PROGRESSIVE-AF received commonly prescribed therapies titrated to maximally tolerated doses using standardized protocols. At the start of EARLY-AF, flecainide, taken by 65% of patients, was the most commonly used agent, followed by sotalol, propafenone, dronedarone, and amiodarone.

At the end of PROGRESSIVE-AF, the order of the most common therapies did not change relative to EARLY-AF, but only 49% of patients were taking flecainide and 31% were no longer taking any antiarrhythmic therapy.

At the end of 3 years of follow-up in EARLY-AF/PROGRESSIVE-AF, the difference in persistent AFib represented a 75% reduction in favor of early ablation (HR, 0.25; 95% confidence interval, 0.09-0.70).

In those treated with ablation relative to those treated with antiarrhythmic therapy, the lower rate of atrial tachyarrhythmia lasting more than 7 days (1.9% vs. 6.0%) represented a 70% risk reduction (HR, 0.30; 95% CI 0.10-0.93). The protection from cardioversion for atrial tachyarrhythmia lasting between 2 and 7 days in duration (0.6% vs. 4.7%) translated into an 86% relative reduction (HR, 0.14; 95% CI, 0.02-0.85).

The impact on QOL for those randomized to ablation, which was measured with both AFib-specific and generic measures, was meaningful to patients, according to Dr. Andrade, director of the Cardiac Electrophysiology Laboratory, Vancouver General Hospital.

For example, the mean difference in the AF Quality of Life Survey (AFEQT), was 8.0 at 1 year and 7.4 at 3 years in favor of ablation. A change of 5 points in this score is considered to be a clinically meaningful difference, according to Dr. Andrade.

Numerically, the relative risk of emergency room visits and cardioversion were lower in the ablation group, but the differences did not reach statistical significance. However, the lower hazard ratio for hospitalization was significant (HR, 0.31; 95% CI, 0.15-0.66), supporting a reduction in consumption of health care resources.
 

Ablation found safer than drugs

The rate of adverse events of any kind (11.0% vs. 23.5%) and serious adverse events (4.5% vs. 10.1%) were lower in the ablation group.

There were no differences in major adverse cardiovascular events observed in this period of follow-up, but Dr. Andrade pointed out that follow-up was not long enough to expect differences in these events.

Impressed by the magnitude of the reduction in persistent AFib in a population of relatively young and healthy patients considered to be at a low risk of AFib progression, Dr. Blomström-Lindqvist, a professor of cardiology at the Institution of Medical Science, Uppsala, Sweden, indicated that the data support early ablation as a means to reduce risk of this outcome.

However, she did caution that progressive AFib was observed in a relatively small proportion of patients managed with antiarrhythmic therapy at 3 years, an outcome relevant when discussing treatment options with patients.

The results were published in New England Journal of Medicine simultaneously with Dr. Andrade’s presentation.

Dr. Andrade reports financial relationships with Bayer, Bayliss, Biosense, Bristol-Myers Squibb, Medtronic and Servier. The trial, funded largely by the Canadian government and Canadian professional societies, received additional funding from Bayliss and Medtronic. Dr. Blomström-Lundqvist reports financial relationships with Bayer, Boston Scientific, Cathprint, Medtronic, and Sanofi.

CHICAGO – Early ablation of atrial fibrillation (AFib) reduces the risk of progression, compared with antiarrhythmic therapies, according to results of a multicenter, randomized trial called PROGRESSIVE-AF.

Over 36 months of follow-up, the trial linked early ablation with a reduced risk of persistent AFib (1.9% vs. 7.4%), and in addition, those in the ablation group were less likely to have recurrent atrial tachyarrhythmias of any kind (56.5% vs. 77.2%), reported Jason G. Andrade, MD, at the American Heart Association scientific sessions.

Ted Bosworth/MDedge

Serving as a long-term extension of the EARLY-AF trial published almost 2 years ago, this trial expands evidence that progressive AFib can be attenuated, a concept that has been debated.

“Can early AFib ablation stop progression?” asked Carina Blomström-Lindqvist, MD, PhD. The invited discussant for the PROGRESSION-AF trial, Dr. Blomström-Lundqvist concluded, “here is another set of data that suggests it can.”

By another set of data, Dr. Blomström-Lindqvist was referring to a previously published multinational study called ATTEST In this study, which involved 29 sites worldwide and compared radiofrequency ablation to antiarrhythmic drug therapy, early ablation also produced a lower risk of persistent AFib at the end of 3 years (2.4% vs. 17.5%; P = .0009).

In the previously published open-label EARLY-AF trial, 303 patients with paroxysmal, untreated AFib were randomized to cryoballoon ablation or antiarrhythmic drugs. The primary endpoint was the first documented recurrence of an atrial tachyarrhythmia between 91 and 365 days. The lower rate following ablation (42.9% vs. 67.8%) represented a more than 50% reduction in risk (hazard ratio, 0.48; P < .001) relative to antiarrhythmic therapy.

In PROGRESSIVE-AF, the same 303 patients were monitored continuously for an additional 24 months with an implanted cardiac monitor programmed with an AFib-detection algorithm. The data from the monitor were obtained daily. Over the final 2 years of the study, office visits were conducted every 6 months.
 

Tachyarrhythmias represent primary endpoint

In addition to persistent AFib, defined as lasting ≥ 7 days or lasting 48 hours to 7 days but requiring cardioversion for termination, patients in PROGRESSIVE-AF were also monitored for recurrent atrial tachyarrhythmias, AFib burden, quality of life (QOL), and health care utilization, and safety.

The average age was roughly 58 years. Although more than one-third had hypertension, most had no other comorbidities. The authors emphasized that the study population overall was relatively young and healthy.

Those randomized to antiarrhythmic therapy in EARLY-AF/PROGRESSIVE-AF received commonly prescribed therapies titrated to maximally tolerated doses using standardized protocols. At the start of EARLY-AF, flecainide, taken by 65% of patients, was the most commonly used agent, followed by sotalol, propafenone, dronedarone, and amiodarone.

At the end of PROGRESSIVE-AF, the order of the most common therapies did not change relative to EARLY-AF, but only 49% of patients were taking flecainide and 31% were no longer taking any antiarrhythmic therapy.

At the end of 3 years of follow-up in EARLY-AF/PROGRESSIVE-AF, the difference in persistent AFib represented a 75% reduction in favor of early ablation (HR, 0.25; 95% confidence interval, 0.09-0.70).

In those treated with ablation relative to those treated with antiarrhythmic therapy, the lower rate of atrial tachyarrhythmia lasting more than 7 days (1.9% vs. 6.0%) represented a 70% risk reduction (HR, 0.30; 95% CI 0.10-0.93). The protection from cardioversion for atrial tachyarrhythmia lasting between 2 and 7 days in duration (0.6% vs. 4.7%) translated into an 86% relative reduction (HR, 0.14; 95% CI, 0.02-0.85).

The impact on QOL for those randomized to ablation, which was measured with both AFib-specific and generic measures, was meaningful to patients, according to Dr. Andrade, director of the Cardiac Electrophysiology Laboratory, Vancouver General Hospital.

For example, the mean difference in the AF Quality of Life Survey (AFEQT), was 8.0 at 1 year and 7.4 at 3 years in favor of ablation. A change of 5 points in this score is considered to be a clinically meaningful difference, according to Dr. Andrade.

Numerically, the relative risk of emergency room visits and cardioversion were lower in the ablation group, but the differences did not reach statistical significance. However, the lower hazard ratio for hospitalization was significant (HR, 0.31; 95% CI, 0.15-0.66), supporting a reduction in consumption of health care resources.
 

Ablation found safer than drugs

The rate of adverse events of any kind (11.0% vs. 23.5%) and serious adverse events (4.5% vs. 10.1%) were lower in the ablation group.

There were no differences in major adverse cardiovascular events observed in this period of follow-up, but Dr. Andrade pointed out that follow-up was not long enough to expect differences in these events.

Impressed by the magnitude of the reduction in persistent AFib in a population of relatively young and healthy patients considered to be at a low risk of AFib progression, Dr. Blomström-Lindqvist, a professor of cardiology at the Institution of Medical Science, Uppsala, Sweden, indicated that the data support early ablation as a means to reduce risk of this outcome.

However, she did caution that progressive AFib was observed in a relatively small proportion of patients managed with antiarrhythmic therapy at 3 years, an outcome relevant when discussing treatment options with patients.

The results were published in New England Journal of Medicine simultaneously with Dr. Andrade’s presentation.

Dr. Andrade reports financial relationships with Bayer, Bayliss, Biosense, Bristol-Myers Squibb, Medtronic and Servier. The trial, funded largely by the Canadian government and Canadian professional societies, received additional funding from Bayliss and Medtronic. Dr. Blomström-Lundqvist reports financial relationships with Bayer, Boston Scientific, Cathprint, Medtronic, and Sanofi.

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

CHICAGO – In patients with chronic limb-threatening ischemia (CLTI) and a usable saphenous vein segment, a surgical procedure leads to better outcomes than an endovascular approach, according results of the multinational randomized BEST-CLI trial.

In that study, conducted with two cohorts, the advantage of surgery was limited to the group with an available saphenous vein, but in this group the advantage over an endovascular approach was substantial, according to Alik Farber, MD, chief of vascular and endovascular surgery at Boston University.

Ted Bosworth/MDedge News

“Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI as part of fully informed, shared decision-making,” Dr. Farber stated in presenting the results at the annual scientific sessions of the American Heart Association.

The study pursued two hypotheses, which is why CLTI patients were divided into two cohorts. For cohort 1, which was limited to CLTI patients with an available saphenous vein, it was predicted that surgery would be better than an endovascular approach. For cohort 2, which enrolled patients who needed an alternative conduit, the hypothesis was that endovascular procedures would prove superior.

The study confirmed the first hypothesis, but there was no difference between the two approaches for the composite primary outcome of major adverse limb events (MALE) in the second cohort.
 

Saphenous vein availability determined cohort

Candidates for the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Patients with CLTI) trial had to have CLTI producing severe ischemia and to be judged by both surgeons and cardiovascular specialists to be candidates for both types of interventions. Eligible patients were then enrolled in cohort 1 if the saphenous vein was considered the best conduit on imaging. If not, they were enrolled in cohort 2.

Patients were randomized to undergo surgical or endovascular repair only after the cohort was assigned. The primary composite MALE endpoint consisted of an adjudicated first major reintervention, such as new bypass or thrombectomy, an above-the-ankle amputation, or death from any cause.

In cohort 1, the primary composite MALE endpoint was reached in 42.6% of those in surgical arm and 57.4% in the endovascular arm, translating into a 32% relative risk reduction (hazard ratio, 0.68; P < .001) in favor of surgery at the end of a median of 2.7 years of follow-up.

The main advantage was the difference in reinterventions. The lower rate in the surgical group (9.2% vs. 23.5%), translated into a 65% relative risk reduction for this endpoint (HR, 035; P < .001).

The reduction in above-ankle amputations in the surgical group (10.4% vs. 14.9%) was also significant (HR, 0.73; P = .04), but the reduction in all-cause mortality (33.0% vs. 37.6%) was not (HR, 0.98; P = .81).

BEST-CLI involved 150 sites in North America, Europe, and New Zealand. Cohort 1, which randomized 1,434 patients, was the larger of the two. In the second cohort, only 396 patients were randomized, which Dr. Farber said “might have been underpowered.”

The results were published in the New England Journal of Medicine simultaneously with presentation of the results at the meeting.

After a median follow-up of 1.6 years in cohort 2, the slightly lower proportion of patients who reached the composite MALE endpoint in the surgical group relative to the endovascular group (42.8% vs. 47.7%) did not translate into a significant advantage (HR, 0.79; P = .12).

For the individual components, the lower rate of reinterventions in the surgical arm (14.4% vs. 25.6%) did reach statistical significance (HR, 0.47; P = .002), but both amputation (14.9% vs. 14.1%) and all-cause death (26.3% vs. 24.1%) were numerically but not significantly higher in the surgical group.

The primary safety endpoint was major adverse cardiovascular events (MACE). This was not significantly different in either cohort. There were also no major differences between groups in the risk of perioperative complications.

Level 1 evidence provided for intervention choice

Overall, BEST-CLI showed that both surgical and endovascular revascularizations are effective and safe, according to Dr. Farber. As a result, he suggested that both can be considered even if a saphenous vein is available when specific patient characteristics make one more attractive than another.

Yet, in a general population with an available saphenous vein, these data provide “level 1 evidence” that a surgical approach should be the dominant choice, he added.

Ted Bosworth/MDedge News

A quality of life (QOL) substudy of BEST-CLI did not challenge this conclusion. Rather, the main finding was that restoring circulation by either approach has a major favorable impact on patient well-being, according to Matthew Menard, MD, codirector of endovascular surgery at Brigham and Women’s Hospital, Boston.

In this substudy, presented separately from the primary BEST-CLI results, that analysis confirmed that baseline QOL was extremely poor, whether measured with a disease specific instrument such as VascuQol, or generic instruments, such as SF-12.

Surgical or endovascular treatment produced clinically meaningful and sustained improvements in every QOL measure employed, according to Dr. Menard, and this was true in either cohort.
 

Results not necessarily relevant to all

These data are likely relevant to the patients evaluated, but “it is important to consider who made it into this trial,” according to Naomi M. Hamburg, MD, section chief of vascular biology at Boston University.

Ted Bosworth/MDedge News

Not least, patients had to be candidates for either surgical or endovascular repair to get into the study, omitting those patients not deemed by the investigators to be suited for either.

In addition, Dr. Hamburg pointed out that there was a low enrollment of Blacks (20%) and women (28%), two groups for whom CTLI is a common condition.

Lastly, Dr Hamburg questioned whether specific types of anatomy might be better suited to one procedure relative to another, a variable not considered in this study. Reassured by Dr. Farber that this will be explored in subsequent analyses of BEST-CLI data, Dr. Hamburg expressed interest in learning the results.

Dr. Hamburg was among those who spoke about the growing urgency to optimize strategies for early diagnosis and treatment of CTLI. She plugged the PAD National Action Plan as one of the efforts to thwart the coming wave of CTLI expected from the steep climb in the prevalence of diabetes in the United States.

Dr. Farber reported a financial relationship with Sanifit Therapeutics. The study was funded by the National Heart, Lung, and Blood Institute, but received additional support from multiple pharmaceutical companies. Dr. Menard reported a financial relationship with Janssen Pharmaceuticals. Dr. Hamburg reported financial relationships with Acceleron Pharma, Merck, NovoNordisk, and Sanifit.

CHICAGO – In patients with chronic limb-threatening ischemia (CLTI) and a usable saphenous vein segment, a surgical procedure leads to better outcomes than an endovascular approach, according results of the multinational randomized BEST-CLI trial.

In that study, conducted with two cohorts, the advantage of surgery was limited to the group with an available saphenous vein, but in this group the advantage over an endovascular approach was substantial, according to Alik Farber, MD, chief of vascular and endovascular surgery at Boston University.

Ted Bosworth/MDedge News

“Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI as part of fully informed, shared decision-making,” Dr. Farber stated in presenting the results at the annual scientific sessions of the American Heart Association.

The study pursued two hypotheses, which is why CLTI patients were divided into two cohorts. For cohort 1, which was limited to CLTI patients with an available saphenous vein, it was predicted that surgery would be better than an endovascular approach. For cohort 2, which enrolled patients who needed an alternative conduit, the hypothesis was that endovascular procedures would prove superior.

The study confirmed the first hypothesis, but there was no difference between the two approaches for the composite primary outcome of major adverse limb events (MALE) in the second cohort.
 

Saphenous vein availability determined cohort

Candidates for the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Patients with CLTI) trial had to have CLTI producing severe ischemia and to be judged by both surgeons and cardiovascular specialists to be candidates for both types of interventions. Eligible patients were then enrolled in cohort 1 if the saphenous vein was considered the best conduit on imaging. If not, they were enrolled in cohort 2.

Patients were randomized to undergo surgical or endovascular repair only after the cohort was assigned. The primary composite MALE endpoint consisted of an adjudicated first major reintervention, such as new bypass or thrombectomy, an above-the-ankle amputation, or death from any cause.

In cohort 1, the primary composite MALE endpoint was reached in 42.6% of those in surgical arm and 57.4% in the endovascular arm, translating into a 32% relative risk reduction (hazard ratio, 0.68; P < .001) in favor of surgery at the end of a median of 2.7 years of follow-up.

The main advantage was the difference in reinterventions. The lower rate in the surgical group (9.2% vs. 23.5%), translated into a 65% relative risk reduction for this endpoint (HR, 035; P < .001).

The reduction in above-ankle amputations in the surgical group (10.4% vs. 14.9%) was also significant (HR, 0.73; P = .04), but the reduction in all-cause mortality (33.0% vs. 37.6%) was not (HR, 0.98; P = .81).

BEST-CLI involved 150 sites in North America, Europe, and New Zealand. Cohort 1, which randomized 1,434 patients, was the larger of the two. In the second cohort, only 396 patients were randomized, which Dr. Farber said “might have been underpowered.”

The results were published in the New England Journal of Medicine simultaneously with presentation of the results at the meeting.

After a median follow-up of 1.6 years in cohort 2, the slightly lower proportion of patients who reached the composite MALE endpoint in the surgical group relative to the endovascular group (42.8% vs. 47.7%) did not translate into a significant advantage (HR, 0.79; P = .12).

For the individual components, the lower rate of reinterventions in the surgical arm (14.4% vs. 25.6%) did reach statistical significance (HR, 0.47; P = .002), but both amputation (14.9% vs. 14.1%) and all-cause death (26.3% vs. 24.1%) were numerically but not significantly higher in the surgical group.

The primary safety endpoint was major adverse cardiovascular events (MACE). This was not significantly different in either cohort. There were also no major differences between groups in the risk of perioperative complications.

Level 1 evidence provided for intervention choice

Overall, BEST-CLI showed that both surgical and endovascular revascularizations are effective and safe, according to Dr. Farber. As a result, he suggested that both can be considered even if a saphenous vein is available when specific patient characteristics make one more attractive than another.

Yet, in a general population with an available saphenous vein, these data provide “level 1 evidence” that a surgical approach should be the dominant choice, he added.

Ted Bosworth/MDedge News

A quality of life (QOL) substudy of BEST-CLI did not challenge this conclusion. Rather, the main finding was that restoring circulation by either approach has a major favorable impact on patient well-being, according to Matthew Menard, MD, codirector of endovascular surgery at Brigham and Women’s Hospital, Boston.

In this substudy, presented separately from the primary BEST-CLI results, that analysis confirmed that baseline QOL was extremely poor, whether measured with a disease specific instrument such as VascuQol, or generic instruments, such as SF-12.

Surgical or endovascular treatment produced clinically meaningful and sustained improvements in every QOL measure employed, according to Dr. Menard, and this was true in either cohort.
 

Results not necessarily relevant to all

These data are likely relevant to the patients evaluated, but “it is important to consider who made it into this trial,” according to Naomi M. Hamburg, MD, section chief of vascular biology at Boston University.

Ted Bosworth/MDedge News

Not least, patients had to be candidates for either surgical or endovascular repair to get into the study, omitting those patients not deemed by the investigators to be suited for either.

In addition, Dr. Hamburg pointed out that there was a low enrollment of Blacks (20%) and women (28%), two groups for whom CTLI is a common condition.

Lastly, Dr Hamburg questioned whether specific types of anatomy might be better suited to one procedure relative to another, a variable not considered in this study. Reassured by Dr. Farber that this will be explored in subsequent analyses of BEST-CLI data, Dr. Hamburg expressed interest in learning the results.

Dr. Hamburg was among those who spoke about the growing urgency to optimize strategies for early diagnosis and treatment of CTLI. She plugged the PAD National Action Plan as one of the efforts to thwart the coming wave of CTLI expected from the steep climb in the prevalence of diabetes in the United States.

Dr. Farber reported a financial relationship with Sanifit Therapeutics. The study was funded by the National Heart, Lung, and Blood Institute, but received additional support from multiple pharmaceutical companies. Dr. Menard reported a financial relationship with Janssen Pharmaceuticals. Dr. Hamburg reported financial relationships with Acceleron Pharma, Merck, NovoNordisk, and Sanifit.

CHICAGO – In patients with chronic limb-threatening ischemia (CLTI) and a usable saphenous vein segment, a surgical procedure leads to better outcomes than an endovascular approach, according results of the multinational randomized BEST-CLI trial.

In that study, conducted with two cohorts, the advantage of surgery was limited to the group with an available saphenous vein, but in this group the advantage over an endovascular approach was substantial, according to Alik Farber, MD, chief of vascular and endovascular surgery at Boston University.

Ted Bosworth/MDedge News

“Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI as part of fully informed, shared decision-making,” Dr. Farber stated in presenting the results at the annual scientific sessions of the American Heart Association.

The study pursued two hypotheses, which is why CLTI patients were divided into two cohorts. For cohort 1, which was limited to CLTI patients with an available saphenous vein, it was predicted that surgery would be better than an endovascular approach. For cohort 2, which enrolled patients who needed an alternative conduit, the hypothesis was that endovascular procedures would prove superior.

The study confirmed the first hypothesis, but there was no difference between the two approaches for the composite primary outcome of major adverse limb events (MALE) in the second cohort.
 

Saphenous vein availability determined cohort

Candidates for the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Patients with CLTI) trial had to have CLTI producing severe ischemia and to be judged by both surgeons and cardiovascular specialists to be candidates for both types of interventions. Eligible patients were then enrolled in cohort 1 if the saphenous vein was considered the best conduit on imaging. If not, they were enrolled in cohort 2.

Patients were randomized to undergo surgical or endovascular repair only after the cohort was assigned. The primary composite MALE endpoint consisted of an adjudicated first major reintervention, such as new bypass or thrombectomy, an above-the-ankle amputation, or death from any cause.

In cohort 1, the primary composite MALE endpoint was reached in 42.6% of those in surgical arm and 57.4% in the endovascular arm, translating into a 32% relative risk reduction (hazard ratio, 0.68; P < .001) in favor of surgery at the end of a median of 2.7 years of follow-up.

The main advantage was the difference in reinterventions. The lower rate in the surgical group (9.2% vs. 23.5%), translated into a 65% relative risk reduction for this endpoint (HR, 035; P < .001).

The reduction in above-ankle amputations in the surgical group (10.4% vs. 14.9%) was also significant (HR, 0.73; P = .04), but the reduction in all-cause mortality (33.0% vs. 37.6%) was not (HR, 0.98; P = .81).

BEST-CLI involved 150 sites in North America, Europe, and New Zealand. Cohort 1, which randomized 1,434 patients, was the larger of the two. In the second cohort, only 396 patients were randomized, which Dr. Farber said “might have been underpowered.”

The results were published in the New England Journal of Medicine simultaneously with presentation of the results at the meeting.

After a median follow-up of 1.6 years in cohort 2, the slightly lower proportion of patients who reached the composite MALE endpoint in the surgical group relative to the endovascular group (42.8% vs. 47.7%) did not translate into a significant advantage (HR, 0.79; P = .12).

For the individual components, the lower rate of reinterventions in the surgical arm (14.4% vs. 25.6%) did reach statistical significance (HR, 0.47; P = .002), but both amputation (14.9% vs. 14.1%) and all-cause death (26.3% vs. 24.1%) were numerically but not significantly higher in the surgical group.

The primary safety endpoint was major adverse cardiovascular events (MACE). This was not significantly different in either cohort. There were also no major differences between groups in the risk of perioperative complications.

Level 1 evidence provided for intervention choice

Overall, BEST-CLI showed that both surgical and endovascular revascularizations are effective and safe, according to Dr. Farber. As a result, he suggested that both can be considered even if a saphenous vein is available when specific patient characteristics make one more attractive than another.

Yet, in a general population with an available saphenous vein, these data provide “level 1 evidence” that a surgical approach should be the dominant choice, he added.

Ted Bosworth/MDedge News

A quality of life (QOL) substudy of BEST-CLI did not challenge this conclusion. Rather, the main finding was that restoring circulation by either approach has a major favorable impact on patient well-being, according to Matthew Menard, MD, codirector of endovascular surgery at Brigham and Women’s Hospital, Boston.

In this substudy, presented separately from the primary BEST-CLI results, that analysis confirmed that baseline QOL was extremely poor, whether measured with a disease specific instrument such as VascuQol, or generic instruments, such as SF-12.

Surgical or endovascular treatment produced clinically meaningful and sustained improvements in every QOL measure employed, according to Dr. Menard, and this was true in either cohort.
 

Results not necessarily relevant to all

These data are likely relevant to the patients evaluated, but “it is important to consider who made it into this trial,” according to Naomi M. Hamburg, MD, section chief of vascular biology at Boston University.

Ted Bosworth/MDedge News

Not least, patients had to be candidates for either surgical or endovascular repair to get into the study, omitting those patients not deemed by the investigators to be suited for either.

In addition, Dr. Hamburg pointed out that there was a low enrollment of Blacks (20%) and women (28%), two groups for whom CTLI is a common condition.

Lastly, Dr Hamburg questioned whether specific types of anatomy might be better suited to one procedure relative to another, a variable not considered in this study. Reassured by Dr. Farber that this will be explored in subsequent analyses of BEST-CLI data, Dr. Hamburg expressed interest in learning the results.

Dr. Hamburg was among those who spoke about the growing urgency to optimize strategies for early diagnosis and treatment of CTLI. She plugged the PAD National Action Plan as one of the efforts to thwart the coming wave of CTLI expected from the steep climb in the prevalence of diabetes in the United States.

Dr. Farber reported a financial relationship with Sanifit Therapeutics. The study was funded by the National Heart, Lung, and Blood Institute, but received additional support from multiple pharmaceutical companies. Dr. Menard reported a financial relationship with Janssen Pharmaceuticals. Dr. Hamburg reported financial relationships with Acceleron Pharma, Merck, NovoNordisk, and Sanifit.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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