Cardiology

NEW ORLEANS – EHR-embedded alerts that a patient with heart failure with reduced ejection fraction (HFrEF) is a great candidate for treatment with a mineralocorticoid receptor antagonist (MRA) more than doubled prescribing of this “pillar” class for HFrEF, compared with control practices that used usual care and no alerts.

That’s according to results of BETTER CARE-HF, a single-center, randomized trial with more than 2,000 patients and involving 180 cardiologists.

“EHR-embedded tools cans be a rapid, low-cost, and high-impact method to increase prescription of life-saving therapies across large populations,” said Amrita Mukhopadhyay, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

Her study targeted underprescribing of an MRA – spironolactone or eplerenone (Inspra) – because of its “vastly underprescribed” status in U.S. practice, where roughly two-thirds of patients with HFrEF do not receive an MRA despite clear recommendations from several medical groups that it is an essential part of treatment for most patients with HFrEF. Dr. Mukhopadhyay estimated that more comprehensive prescribing of MRAs to U.S. patients with HFrEF could prevent more than 20,000 deaths annually.

She also explained that the EHR-embedded alert was carefully devised, through interviews with cardiologists and pilot testing, to optimize the nudge so that it was less intrusive but effective for capturing attention and initiating action.

‘Clinically relevant, impressive results’

“This is a really important study, because despite overwhelming evidence for more than a decade favoring MRA use for patients with HFrEF there is an incredibly large treatment gap. MRAs can reduce all-cause death in people with HFrEF by 25%-30%, as well as reduce hospitalizations for heart failure, at a cost of less than $50 a year,” commented Gregg C. Fonarow, MD, interim chief of cardiology at the University of California, Los Angeles. The study showed “very clinically relevant, impressive results” for individualized, patient-specific alerts to prescribe an MRA and order the laboratory tests, particularly for serum potassium levels, needed to safely start the treatment, Dr. Fonarow said in an interview.

The BETTER CARE-HF study ran at more than 60 practices in the New York City region operated by the NYU Langone Health system, which sponsored the study. The trial randomized 180 cardiologists from these practices in a cluster format to one of three study arms: Sixty cardiologists received the EHR-embedded alerts for their relevant patients (755 patients) when the patient was in the physician’s office; another 60 cardiologists received a less tailored, monthly message that flagged all patients with HFrEF in a cardiologist’s practice who remained untreated candidates for MRA intervention (812 patients); and a third arm of 60 cardiologists and their HFrEF patients served as controls where the clinicians received no alert or message (644 patients).

The study included 2,211 patients with HFrEF and not on MRA treatment at baseline who were all identified as good candidates for starting treatment with the class, with no contraindications, no preexisting hyperkalemia, and no advanced-stage renal dysfunction.

The study’s primary outcome was the percentage of patients in each subgroup who received a new prescription for an MRA. This occurred in 29.6% of the patients whose physicians received an alert, in 15.6% of the patients whose physicians received a monthly message, and in 11.7% of patients in the control practices. Statistical analyses showed that the alerts led to a significant 2.53-fold increase in MRA prescribing, while the messages linked with a significant 67% increase in prescribing, compared with the control practices, reported Dr. Mukhopadhyay, a health services researcher at NYU Langone Health in New York. Simultaneously with her report, the results also appeared in the Journal of the American College of Cardiology.

The findings also showed that the alert and message had no significant impact on the prescribing of any other medication classes for HFrEF, compared with the controls. And the alert intervention had minimal adverse effects. While patients in the alert arm showed a significant, 45% relative increase in the incidence of hyperkalemia episodes, compared with control patients (because of a 4.5% absolute increase in hyperkalemia events), the rate of “significant” hyperkalemia with a value of at least 5.5 mmol/L, occurred in 5.0% of patients in the alert group and 5.1% of patients in the control arm.

Potassium testing poses another barrier

Even though the alerts substantially improved MRA prescribing, 70% of patients deemed MRA eligible in the alert subgroup still failed to receive a prescription. One additional barrier specific to MRA prescribing is the need it triggers for serial laboratory testing to monitor serum potassium levels. “Potassium testing generates additional work outside the index visit, which along with the risk for hyperkalemia exists as a barrier,” commented Lee R. Goldberg, MD, a heart failure specialist and professor at the University of Pennsylvania in Philadelphia. “This may be the next aspect to focus on to improve MRA uptake,” he said as a designated discussant for the report.

Mitchel L. Zoler/MDedge News

“It’s not enough to just prompt medication treatment. We also need to prompt appropriate laboratory testing,” noted Dr. Fonarow.

He also said that the approach tested by Dr. Mukhopadhyay could now be expanded to outpatient cardiologists. “The onus is on everyone involved in caring for patients with HFrEF failure to explain why maximum effort is not being made to deploy” all of the guideline-directed medical therapies for the disorder.

EHR alerts “are one way to bridge the prescribing gap, but we need multiple approaches so that all eligible patients receive guideline-directed medical therapy,” Dr. Fonarow said.

BETTER CARE-HF received no commercial funding, and Dr. Mukhopadhyay had no disclosures. Dr. Fonarow has been a consultant to AstraZeneca, Amgen, Cytokinetics, Lilly, Merck, Novartis, and Pfizer. Dr. Goldberg has received personal fees from Abbott, VisCardia, and Zoll/Respircardia.

NEW ORLEANS – EHR-embedded alerts that a patient with heart failure with reduced ejection fraction (HFrEF) is a great candidate for treatment with a mineralocorticoid receptor antagonist (MRA) more than doubled prescribing of this “pillar” class for HFrEF, compared with control practices that used usual care and no alerts.

That’s according to results of BETTER CARE-HF, a single-center, randomized trial with more than 2,000 patients and involving 180 cardiologists.

“EHR-embedded tools cans be a rapid, low-cost, and high-impact method to increase prescription of life-saving therapies across large populations,” said Amrita Mukhopadhyay, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

Her study targeted underprescribing of an MRA – spironolactone or eplerenone (Inspra) – because of its “vastly underprescribed” status in U.S. practice, where roughly two-thirds of patients with HFrEF do not receive an MRA despite clear recommendations from several medical groups that it is an essential part of treatment for most patients with HFrEF. Dr. Mukhopadhyay estimated that more comprehensive prescribing of MRAs to U.S. patients with HFrEF could prevent more than 20,000 deaths annually.

She also explained that the EHR-embedded alert was carefully devised, through interviews with cardiologists and pilot testing, to optimize the nudge so that it was less intrusive but effective for capturing attention and initiating action.

‘Clinically relevant, impressive results’

“This is a really important study, because despite overwhelming evidence for more than a decade favoring MRA use for patients with HFrEF there is an incredibly large treatment gap. MRAs can reduce all-cause death in people with HFrEF by 25%-30%, as well as reduce hospitalizations for heart failure, at a cost of less than $50 a year,” commented Gregg C. Fonarow, MD, interim chief of cardiology at the University of California, Los Angeles. The study showed “very clinically relevant, impressive results” for individualized, patient-specific alerts to prescribe an MRA and order the laboratory tests, particularly for serum potassium levels, needed to safely start the treatment, Dr. Fonarow said in an interview.

The BETTER CARE-HF study ran at more than 60 practices in the New York City region operated by the NYU Langone Health system, which sponsored the study. The trial randomized 180 cardiologists from these practices in a cluster format to one of three study arms: Sixty cardiologists received the EHR-embedded alerts for their relevant patients (755 patients) when the patient was in the physician’s office; another 60 cardiologists received a less tailored, monthly message that flagged all patients with HFrEF in a cardiologist’s practice who remained untreated candidates for MRA intervention (812 patients); and a third arm of 60 cardiologists and their HFrEF patients served as controls where the clinicians received no alert or message (644 patients).

The study included 2,211 patients with HFrEF and not on MRA treatment at baseline who were all identified as good candidates for starting treatment with the class, with no contraindications, no preexisting hyperkalemia, and no advanced-stage renal dysfunction.

The study’s primary outcome was the percentage of patients in each subgroup who received a new prescription for an MRA. This occurred in 29.6% of the patients whose physicians received an alert, in 15.6% of the patients whose physicians received a monthly message, and in 11.7% of patients in the control practices. Statistical analyses showed that the alerts led to a significant 2.53-fold increase in MRA prescribing, while the messages linked with a significant 67% increase in prescribing, compared with the control practices, reported Dr. Mukhopadhyay, a health services researcher at NYU Langone Health in New York. Simultaneously with her report, the results also appeared in the Journal of the American College of Cardiology.

The findings also showed that the alert and message had no significant impact on the prescribing of any other medication classes for HFrEF, compared with the controls. And the alert intervention had minimal adverse effects. While patients in the alert arm showed a significant, 45% relative increase in the incidence of hyperkalemia episodes, compared with control patients (because of a 4.5% absolute increase in hyperkalemia events), the rate of “significant” hyperkalemia with a value of at least 5.5 mmol/L, occurred in 5.0% of patients in the alert group and 5.1% of patients in the control arm.

Potassium testing poses another barrier

Even though the alerts substantially improved MRA prescribing, 70% of patients deemed MRA eligible in the alert subgroup still failed to receive a prescription. One additional barrier specific to MRA prescribing is the need it triggers for serial laboratory testing to monitor serum potassium levels. “Potassium testing generates additional work outside the index visit, which along with the risk for hyperkalemia exists as a barrier,” commented Lee R. Goldberg, MD, a heart failure specialist and professor at the University of Pennsylvania in Philadelphia. “This may be the next aspect to focus on to improve MRA uptake,” he said as a designated discussant for the report.

Mitchel L. Zoler/MDedge News

“It’s not enough to just prompt medication treatment. We also need to prompt appropriate laboratory testing,” noted Dr. Fonarow.

He also said that the approach tested by Dr. Mukhopadhyay could now be expanded to outpatient cardiologists. “The onus is on everyone involved in caring for patients with HFrEF failure to explain why maximum effort is not being made to deploy” all of the guideline-directed medical therapies for the disorder.

EHR alerts “are one way to bridge the prescribing gap, but we need multiple approaches so that all eligible patients receive guideline-directed medical therapy,” Dr. Fonarow said.

BETTER CARE-HF received no commercial funding, and Dr. Mukhopadhyay had no disclosures. Dr. Fonarow has been a consultant to AstraZeneca, Amgen, Cytokinetics, Lilly, Merck, Novartis, and Pfizer. Dr. Goldberg has received personal fees from Abbott, VisCardia, and Zoll/Respircardia.

NEW ORLEANS – EHR-embedded alerts that a patient with heart failure with reduced ejection fraction (HFrEF) is a great candidate for treatment with a mineralocorticoid receptor antagonist (MRA) more than doubled prescribing of this “pillar” class for HFrEF, compared with control practices that used usual care and no alerts.

That’s according to results of BETTER CARE-HF, a single-center, randomized trial with more than 2,000 patients and involving 180 cardiologists.

“EHR-embedded tools cans be a rapid, low-cost, and high-impact method to increase prescription of life-saving therapies across large populations,” said Amrita Mukhopadhyay, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

Her study targeted underprescribing of an MRA – spironolactone or eplerenone (Inspra) – because of its “vastly underprescribed” status in U.S. practice, where roughly two-thirds of patients with HFrEF do not receive an MRA despite clear recommendations from several medical groups that it is an essential part of treatment for most patients with HFrEF. Dr. Mukhopadhyay estimated that more comprehensive prescribing of MRAs to U.S. patients with HFrEF could prevent more than 20,000 deaths annually.

She also explained that the EHR-embedded alert was carefully devised, through interviews with cardiologists and pilot testing, to optimize the nudge so that it was less intrusive but effective for capturing attention and initiating action.

‘Clinically relevant, impressive results’

“This is a really important study, because despite overwhelming evidence for more than a decade favoring MRA use for patients with HFrEF there is an incredibly large treatment gap. MRAs can reduce all-cause death in people with HFrEF by 25%-30%, as well as reduce hospitalizations for heart failure, at a cost of less than $50 a year,” commented Gregg C. Fonarow, MD, interim chief of cardiology at the University of California, Los Angeles. The study showed “very clinically relevant, impressive results” for individualized, patient-specific alerts to prescribe an MRA and order the laboratory tests, particularly for serum potassium levels, needed to safely start the treatment, Dr. Fonarow said in an interview.

The BETTER CARE-HF study ran at more than 60 practices in the New York City region operated by the NYU Langone Health system, which sponsored the study. The trial randomized 180 cardiologists from these practices in a cluster format to one of three study arms: Sixty cardiologists received the EHR-embedded alerts for their relevant patients (755 patients) when the patient was in the physician’s office; another 60 cardiologists received a less tailored, monthly message that flagged all patients with HFrEF in a cardiologist’s practice who remained untreated candidates for MRA intervention (812 patients); and a third arm of 60 cardiologists and their HFrEF patients served as controls where the clinicians received no alert or message (644 patients).

The study included 2,211 patients with HFrEF and not on MRA treatment at baseline who were all identified as good candidates for starting treatment with the class, with no contraindications, no preexisting hyperkalemia, and no advanced-stage renal dysfunction.

The study’s primary outcome was the percentage of patients in each subgroup who received a new prescription for an MRA. This occurred in 29.6% of the patients whose physicians received an alert, in 15.6% of the patients whose physicians received a monthly message, and in 11.7% of patients in the control practices. Statistical analyses showed that the alerts led to a significant 2.53-fold increase in MRA prescribing, while the messages linked with a significant 67% increase in prescribing, compared with the control practices, reported Dr. Mukhopadhyay, a health services researcher at NYU Langone Health in New York. Simultaneously with her report, the results also appeared in the Journal of the American College of Cardiology.

The findings also showed that the alert and message had no significant impact on the prescribing of any other medication classes for HFrEF, compared with the controls. And the alert intervention had minimal adverse effects. While patients in the alert arm showed a significant, 45% relative increase in the incidence of hyperkalemia episodes, compared with control patients (because of a 4.5% absolute increase in hyperkalemia events), the rate of “significant” hyperkalemia with a value of at least 5.5 mmol/L, occurred in 5.0% of patients in the alert group and 5.1% of patients in the control arm.

Potassium testing poses another barrier

Even though the alerts substantially improved MRA prescribing, 70% of patients deemed MRA eligible in the alert subgroup still failed to receive a prescription. One additional barrier specific to MRA prescribing is the need it triggers for serial laboratory testing to monitor serum potassium levels. “Potassium testing generates additional work outside the index visit, which along with the risk for hyperkalemia exists as a barrier,” commented Lee R. Goldberg, MD, a heart failure specialist and professor at the University of Pennsylvania in Philadelphia. “This may be the next aspect to focus on to improve MRA uptake,” he said as a designated discussant for the report.

Mitchel L. Zoler/MDedge News

“It’s not enough to just prompt medication treatment. We also need to prompt appropriate laboratory testing,” noted Dr. Fonarow.

He also said that the approach tested by Dr. Mukhopadhyay could now be expanded to outpatient cardiologists. “The onus is on everyone involved in caring for patients with HFrEF failure to explain why maximum effort is not being made to deploy” all of the guideline-directed medical therapies for the disorder.

EHR alerts “are one way to bridge the prescribing gap, but we need multiple approaches so that all eligible patients receive guideline-directed medical therapy,” Dr. Fonarow said.

BETTER CARE-HF received no commercial funding, and Dr. Mukhopadhyay had no disclosures. Dr. Fonarow has been a consultant to AstraZeneca, Amgen, Cytokinetics, Lilly, Merck, Novartis, and Pfizer. Dr. Goldberg has received personal fees from Abbott, VisCardia, and Zoll/Respircardia.

Immediate complete revascularization during the index procedure might become the new treatment paradigm in patients with an acute coronary syndrome (ACS) and multivessel disease, based on results of the BIOVASC trial.

In the trial, in patients presenting with ACS and multivessel disease, immediate complete revascularization was noninferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.

The BIOVASC trial was presented on March 5 by Roberto Diletti, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published online in The Lancet.

“We did not detect an early safety signal against an immediate complete revascularization strategy,” the authors state in the Lancet paper, adding: “Treating physicians should not be concerned about potential risks associated with immediate treatment of nonculprit lesions.”

They note, “This strategy might be particularly effective in patients with only two-vessel disease and reasonably simple lesions, with a high likelihood of procedural success without excessive use of radiation, contrast dye, or other resources.”

The trial also showed a shorter hospital stay with an immediate complete revascularization strategy.

“Immediate complete revascularization might have potential health economic benefits because of the lower rate of myocardial infarction, including spontaneous myocardial infarction, and unplanned revascularizations, and the shorter overall hospital stay,” the researchers conclude.

Introducing his presentation, Dr. Diletti explained that multiple studies have established the clinical benefit of complete coronary revascularization as compared with exclusive reperfusion of the culprit lesion, but the optimal timing for nonculprit lesion revascularization remains unclear.

The BIOVASC trial, conducted in Belgium, Italy, the Netherlands, and Spain, involved 1,525 patients with ST-segment elevation MI (STEMI) or non-STEMI ACS and multivessel coronary artery disease with a clearly identifiable culprit lesion.

They were randomly assigned to undergo immediate complete revascularization (percutaneous coronary intervention [PCI] of the culprit lesion first, followed by other nonculprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularization (PCI of only the culprit lesion during the index procedure and PCI of all nonculprit lesions deemed to be clinically significant within 6 weeks after the index procedure).

The primary outcome was the composite of all-cause mortality, MI, any unplanned ischemia-driven revascularization, or cerebrovascular events at 1 year after the index procedure.

The trial had a noninferiority design, with noninferiority of immediate to staged complete revascularization considered to be met if the upper boundary of the 95% confidence interval of the hazard ratio for the primary outcome did not exceed 1.39.

Among the trial population, 40% of patients had STEMI, 52% had non-STEMI, and 8% had unstable angina.

In the immediate complete revascularization group, 16 patients did not receive complete revascularization during the index procedure primarily because of prolonged procedure time, procedural complexity, or excessive contrast dye use. 

In the staged group, 30% of patients underwent all subsequent procedures during the index hospitalization.

Results showed that the primary composite outcome at 1 year occurred in 7.6% of the immediate revascularization group and in 9.4% of the staged group, meeting the noninferiority criteria (HR, 0.78; 95% CI, 0.55-1.11; P for noninferiority = .0011).

Superiority of the immediate over the staged complete revascularization strategy was not met at 1-year follow-up (P for superiority = .17).

However, in the prespecified analysis of clinical events at 30 days after the index procedure, immediate complete revascularization was superior to staged revascularization in terms of the composite primary outcome (2.2% vs. 5.8%; HR, 0.38; P for superiority = .0007).

One-year results showed no difference in all-cause death between the two groups, but the immediate complete revascularization group appeared to have a reduction in MI (1.9% vs. 4.5%)  and fewer unplanned ischemia-driven revascularizations (4.2% vs. 6.7%).

The difference in MI was mainly driven by spontaneous MIs (not procedure related) that predominantly occurred in the time window between the index procedure and the planned date for the staged intervention, and an originally nonculprit lesion was identified as the cause for these events in almost all cases.

Subgroup analysis showed similar results across the patient population, including age, sex, and STEMI vs. non-STEMI presentation.

High rate of MI in staged group

Discussant of the study at the ACC session, Dipti Itchhaporia, MD, University of California, Irvine, said this was a “very important trial.”  

She expressed surprise over the “remarkably high rate” of MI in the staged procedure group and asked Dr. Diletti why that might have occurred.

He responded that the operator may have misjudged the culprit lesion or that patients with ACS may have multiple unstable plaques and “treating the culprit lesion alone does not do the job.”

He added: “We need to look at the data more thoroughly to better understand this, but in both scenarios, immediate complete revascularization would prevent these events.” 

Dr. Itchhaporia also pointed out a low rate of functional imaging used in the study.  

Dr. Diletti replied that this reflected current European practice, but he acknowledged that, “in my opinion this reduces our ability to detect the culprit lesion.”

Commenting at an ACC press conference, David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., said the trial poses the question  “Can we fix it all at once?” and the results suggest “Yes, we can.”

He said this approach had the advantage of removing any uncertainly as to which was the culprit lesion. “We just fix everything – leave no blockage behind.”

But he pointed out that for  some patients this may not be appropriate, such as those with compromised renal function, in whom excessive amounts of contrast material should be avoided.

CABG still needs to be considered

In a comment accompanying the Lancet publication, Tobias Pustjens, MD, Pieter Vriesendorp, MD, and Arnoud W.J. van’t Hof, MD, Cardiovascular Research Institute Maastricht (the Netherlands), note that more than half of the patients presenting with an ACS have multivessel coronary disease. 

They say the trial results suggest that “pursuing an immediate complete revascularisation strategy, especially in times of reduced hospital capacity and staff scarcity, not only benefits the individual patient in clinical outcomes but can also safely reduce the pressure on health care systems.”

But they also point out that the possibility of coronary artery bypass grafting (CABG) should not be omitted, and that CABG is still the treatment of choice in patients with diabetes or complex coronary artery disease.

They conclude: “The results of the BIOVASC study move clinical practice forward from culprit-only to an immediate, complete revascularisation strategy. … However, further fine tuning of this treatment strategy to substantiate a role for intracoronary physiology assessment, intracoronary imaging, and guidance of the heart team decision is needed.”

The BIOVASC trial was supported by an unrestricted research grant from Biotronik AG. Dr. Diletti has received institutional research grants from Biotronik, Medtronic, ACIST Medical Systems, and Boston Scientific. Dr. van’t Hof has received institutional research grants from Biotronik.

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

Immediate complete revascularization during the index procedure might become the new treatment paradigm in patients with an acute coronary syndrome (ACS) and multivessel disease, based on results of the BIOVASC trial.

In the trial, in patients presenting with ACS and multivessel disease, immediate complete revascularization was noninferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.

The BIOVASC trial was presented on March 5 by Roberto Diletti, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published online in The Lancet.

“We did not detect an early safety signal against an immediate complete revascularization strategy,” the authors state in the Lancet paper, adding: “Treating physicians should not be concerned about potential risks associated with immediate treatment of nonculprit lesions.”

They note, “This strategy might be particularly effective in patients with only two-vessel disease and reasonably simple lesions, with a high likelihood of procedural success without excessive use of radiation, contrast dye, or other resources.”

The trial also showed a shorter hospital stay with an immediate complete revascularization strategy.

“Immediate complete revascularization might have potential health economic benefits because of the lower rate of myocardial infarction, including spontaneous myocardial infarction, and unplanned revascularizations, and the shorter overall hospital stay,” the researchers conclude.

Introducing his presentation, Dr. Diletti explained that multiple studies have established the clinical benefit of complete coronary revascularization as compared with exclusive reperfusion of the culprit lesion, but the optimal timing for nonculprit lesion revascularization remains unclear.

The BIOVASC trial, conducted in Belgium, Italy, the Netherlands, and Spain, involved 1,525 patients with ST-segment elevation MI (STEMI) or non-STEMI ACS and multivessel coronary artery disease with a clearly identifiable culprit lesion.

They were randomly assigned to undergo immediate complete revascularization (percutaneous coronary intervention [PCI] of the culprit lesion first, followed by other nonculprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularization (PCI of only the culprit lesion during the index procedure and PCI of all nonculprit lesions deemed to be clinically significant within 6 weeks after the index procedure).

The primary outcome was the composite of all-cause mortality, MI, any unplanned ischemia-driven revascularization, or cerebrovascular events at 1 year after the index procedure.

The trial had a noninferiority design, with noninferiority of immediate to staged complete revascularization considered to be met if the upper boundary of the 95% confidence interval of the hazard ratio for the primary outcome did not exceed 1.39.

Among the trial population, 40% of patients had STEMI, 52% had non-STEMI, and 8% had unstable angina.

In the immediate complete revascularization group, 16 patients did not receive complete revascularization during the index procedure primarily because of prolonged procedure time, procedural complexity, or excessive contrast dye use. 

In the staged group, 30% of patients underwent all subsequent procedures during the index hospitalization.

Results showed that the primary composite outcome at 1 year occurred in 7.6% of the immediate revascularization group and in 9.4% of the staged group, meeting the noninferiority criteria (HR, 0.78; 95% CI, 0.55-1.11; P for noninferiority = .0011).

Superiority of the immediate over the staged complete revascularization strategy was not met at 1-year follow-up (P for superiority = .17).

However, in the prespecified analysis of clinical events at 30 days after the index procedure, immediate complete revascularization was superior to staged revascularization in terms of the composite primary outcome (2.2% vs. 5.8%; HR, 0.38; P for superiority = .0007).

One-year results showed no difference in all-cause death between the two groups, but the immediate complete revascularization group appeared to have a reduction in MI (1.9% vs. 4.5%)  and fewer unplanned ischemia-driven revascularizations (4.2% vs. 6.7%).

The difference in MI was mainly driven by spontaneous MIs (not procedure related) that predominantly occurred in the time window between the index procedure and the planned date for the staged intervention, and an originally nonculprit lesion was identified as the cause for these events in almost all cases.

Subgroup analysis showed similar results across the patient population, including age, sex, and STEMI vs. non-STEMI presentation.

High rate of MI in staged group

Discussant of the study at the ACC session, Dipti Itchhaporia, MD, University of California, Irvine, said this was a “very important trial.”  

She expressed surprise over the “remarkably high rate” of MI in the staged procedure group and asked Dr. Diletti why that might have occurred.

He responded that the operator may have misjudged the culprit lesion or that patients with ACS may have multiple unstable plaques and “treating the culprit lesion alone does not do the job.”

He added: “We need to look at the data more thoroughly to better understand this, but in both scenarios, immediate complete revascularization would prevent these events.” 

Dr. Itchhaporia also pointed out a low rate of functional imaging used in the study.  

Dr. Diletti replied that this reflected current European practice, but he acknowledged that, “in my opinion this reduces our ability to detect the culprit lesion.”

Commenting at an ACC press conference, David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., said the trial poses the question  “Can we fix it all at once?” and the results suggest “Yes, we can.”

He said this approach had the advantage of removing any uncertainly as to which was the culprit lesion. “We just fix everything – leave no blockage behind.”

But he pointed out that for  some patients this may not be appropriate, such as those with compromised renal function, in whom excessive amounts of contrast material should be avoided.

CABG still needs to be considered

In a comment accompanying the Lancet publication, Tobias Pustjens, MD, Pieter Vriesendorp, MD, and Arnoud W.J. van’t Hof, MD, Cardiovascular Research Institute Maastricht (the Netherlands), note that more than half of the patients presenting with an ACS have multivessel coronary disease. 

They say the trial results suggest that “pursuing an immediate complete revascularisation strategy, especially in times of reduced hospital capacity and staff scarcity, not only benefits the individual patient in clinical outcomes but can also safely reduce the pressure on health care systems.”

But they also point out that the possibility of coronary artery bypass grafting (CABG) should not be omitted, and that CABG is still the treatment of choice in patients with diabetes or complex coronary artery disease.

They conclude: “The results of the BIOVASC study move clinical practice forward from culprit-only to an immediate, complete revascularisation strategy. … However, further fine tuning of this treatment strategy to substantiate a role for intracoronary physiology assessment, intracoronary imaging, and guidance of the heart team decision is needed.”

The BIOVASC trial was supported by an unrestricted research grant from Biotronik AG. Dr. Diletti has received institutional research grants from Biotronik, Medtronic, ACIST Medical Systems, and Boston Scientific. Dr. van’t Hof has received institutional research grants from Biotronik.

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

Immediate complete revascularization during the index procedure might become the new treatment paradigm in patients with an acute coronary syndrome (ACS) and multivessel disease, based on results of the BIOVASC trial.

In the trial, in patients presenting with ACS and multivessel disease, immediate complete revascularization was noninferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.

The BIOVASC trial was presented on March 5 by Roberto Diletti, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published online in The Lancet.

“We did not detect an early safety signal against an immediate complete revascularization strategy,” the authors state in the Lancet paper, adding: “Treating physicians should not be concerned about potential risks associated with immediate treatment of nonculprit lesions.”

They note, “This strategy might be particularly effective in patients with only two-vessel disease and reasonably simple lesions, with a high likelihood of procedural success without excessive use of radiation, contrast dye, or other resources.”

The trial also showed a shorter hospital stay with an immediate complete revascularization strategy.

“Immediate complete revascularization might have potential health economic benefits because of the lower rate of myocardial infarction, including spontaneous myocardial infarction, and unplanned revascularizations, and the shorter overall hospital stay,” the researchers conclude.

Introducing his presentation, Dr. Diletti explained that multiple studies have established the clinical benefit of complete coronary revascularization as compared with exclusive reperfusion of the culprit lesion, but the optimal timing for nonculprit lesion revascularization remains unclear.

The BIOVASC trial, conducted in Belgium, Italy, the Netherlands, and Spain, involved 1,525 patients with ST-segment elevation MI (STEMI) or non-STEMI ACS and multivessel coronary artery disease with a clearly identifiable culprit lesion.

They were randomly assigned to undergo immediate complete revascularization (percutaneous coronary intervention [PCI] of the culprit lesion first, followed by other nonculprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularization (PCI of only the culprit lesion during the index procedure and PCI of all nonculprit lesions deemed to be clinically significant within 6 weeks after the index procedure).

The primary outcome was the composite of all-cause mortality, MI, any unplanned ischemia-driven revascularization, or cerebrovascular events at 1 year after the index procedure.

The trial had a noninferiority design, with noninferiority of immediate to staged complete revascularization considered to be met if the upper boundary of the 95% confidence interval of the hazard ratio for the primary outcome did not exceed 1.39.

Among the trial population, 40% of patients had STEMI, 52% had non-STEMI, and 8% had unstable angina.

In the immediate complete revascularization group, 16 patients did not receive complete revascularization during the index procedure primarily because of prolonged procedure time, procedural complexity, or excessive contrast dye use. 

In the staged group, 30% of patients underwent all subsequent procedures during the index hospitalization.

Results showed that the primary composite outcome at 1 year occurred in 7.6% of the immediate revascularization group and in 9.4% of the staged group, meeting the noninferiority criteria (HR, 0.78; 95% CI, 0.55-1.11; P for noninferiority = .0011).

Superiority of the immediate over the staged complete revascularization strategy was not met at 1-year follow-up (P for superiority = .17).

However, in the prespecified analysis of clinical events at 30 days after the index procedure, immediate complete revascularization was superior to staged revascularization in terms of the composite primary outcome (2.2% vs. 5.8%; HR, 0.38; P for superiority = .0007).

One-year results showed no difference in all-cause death between the two groups, but the immediate complete revascularization group appeared to have a reduction in MI (1.9% vs. 4.5%)  and fewer unplanned ischemia-driven revascularizations (4.2% vs. 6.7%).

The difference in MI was mainly driven by spontaneous MIs (not procedure related) that predominantly occurred in the time window between the index procedure and the planned date for the staged intervention, and an originally nonculprit lesion was identified as the cause for these events in almost all cases.

Subgroup analysis showed similar results across the patient population, including age, sex, and STEMI vs. non-STEMI presentation.

High rate of MI in staged group

Discussant of the study at the ACC session, Dipti Itchhaporia, MD, University of California, Irvine, said this was a “very important trial.”  

She expressed surprise over the “remarkably high rate” of MI in the staged procedure group and asked Dr. Diletti why that might have occurred.

He responded that the operator may have misjudged the culprit lesion or that patients with ACS may have multiple unstable plaques and “treating the culprit lesion alone does not do the job.”

He added: “We need to look at the data more thoroughly to better understand this, but in both scenarios, immediate complete revascularization would prevent these events.” 

Dr. Itchhaporia also pointed out a low rate of functional imaging used in the study.  

Dr. Diletti replied that this reflected current European practice, but he acknowledged that, “in my opinion this reduces our ability to detect the culprit lesion.”

Commenting at an ACC press conference, David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., said the trial poses the question  “Can we fix it all at once?” and the results suggest “Yes, we can.”

He said this approach had the advantage of removing any uncertainly as to which was the culprit lesion. “We just fix everything – leave no blockage behind.”

But he pointed out that for  some patients this may not be appropriate, such as those with compromised renal function, in whom excessive amounts of contrast material should be avoided.

CABG still needs to be considered

In a comment accompanying the Lancet publication, Tobias Pustjens, MD, Pieter Vriesendorp, MD, and Arnoud W.J. van’t Hof, MD, Cardiovascular Research Institute Maastricht (the Netherlands), note that more than half of the patients presenting with an ACS have multivessel coronary disease. 

They say the trial results suggest that “pursuing an immediate complete revascularisation strategy, especially in times of reduced hospital capacity and staff scarcity, not only benefits the individual patient in clinical outcomes but can also safely reduce the pressure on health care systems.”

But they also point out that the possibility of coronary artery bypass grafting (CABG) should not be omitted, and that CABG is still the treatment of choice in patients with diabetes or complex coronary artery disease.

They conclude: “The results of the BIOVASC study move clinical practice forward from culprit-only to an immediate, complete revascularisation strategy. … However, further fine tuning of this treatment strategy to substantiate a role for intracoronary physiology assessment, intracoronary imaging, and guidance of the heart team decision is needed.”

The BIOVASC trial was supported by an unrestricted research grant from Biotronik AG. Dr. Diletti has received institutional research grants from Biotronik, Medtronic, ACIST Medical Systems, and Boston Scientific. Dr. van’t Hof has received institutional research grants from Biotronik.

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

NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.

“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.

“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
 

A basis for an ‘important discussion’ with patients

“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.

“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”

Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.

STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.

Their cumulative, median anthracycline dose was 300 mg/m², which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.

Tripled incidence of cardiac dysfunction in placebo patients

The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.

The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.

The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.

Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.

“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
 

The importance of a clinically meaningful effect

The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m², and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.

In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.

Mitchel L. Zoler/MDedge News

Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.

STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.

NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.

“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.

“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
 

A basis for an ‘important discussion’ with patients

“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.

“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”

Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.

STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.

Their cumulative, median anthracycline dose was 300 mg/m², which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.

Tripled incidence of cardiac dysfunction in placebo patients

The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.

The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.

The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.

Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.

“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
 

The importance of a clinically meaningful effect

The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m², and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.

In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.

Mitchel L. Zoler/MDedge News

Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.

STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.

NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.

“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.

“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
 

A basis for an ‘important discussion’ with patients

“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.

“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”

Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.

STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.

Their cumulative, median anthracycline dose was 300 mg/m², which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.

Tripled incidence of cardiac dysfunction in placebo patients

The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.

The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.

The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.

Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.

“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
 

The importance of a clinically meaningful effect

The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m², and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.

In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.

Mitchel L. Zoler/MDedge News

Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.

STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.

A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.

The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.

The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.

Mitchel L. Zoler/MDedge News

“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.

Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.

Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.

Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.

He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
 

CLEAR Outcomes

The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.

The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).

The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.

After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).

The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.

The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).

Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.

Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.

Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.

Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).

Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.

In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.

“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.

“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
 

‘Compelling findings’

Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.

She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.

She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.” 

Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis. 

She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”

In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”

He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.

Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown. 

On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”

“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”

In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.

But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”

In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.

“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”

The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.

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

A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.

The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.

The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.

Mitchel L. Zoler/MDedge News

“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.

Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.

Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.

Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.

He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
 

CLEAR Outcomes

The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.

The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).

The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.

After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).

The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.

The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).

Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.

Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.

Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.

Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).

Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.

In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.

“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.

“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
 

‘Compelling findings’

Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.

She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.

She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.” 

Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis. 

She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”

In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”

He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.

Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown. 

On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”

“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”

In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.

But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”

In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.

“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”

The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.

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

A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.

The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.

The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.

Mitchel L. Zoler/MDedge News

“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.

Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.

Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.

Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.

He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
 

CLEAR Outcomes

The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.

The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).

The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.

After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).

The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.

The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).

Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.

Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.

Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.

Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).

Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.

In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.

“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.

“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
 

‘Compelling findings’

Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.

She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.

She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.” 

Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis. 

She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”

In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”

He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.

Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown. 

On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”

“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”

In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.

But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”

In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.

“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”

The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.

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

NEW ORLEANS – In the first pivotal randomized, controlled trial of a transcatheter device for the repair of severe tricuspid regurgitation, a large reduction in valve dysfunction was associated with substantial improvement in quality of life (QOL) persisting out of 1 year of follow-up, according to results of the TRILUMINATE trial.

Based on the low procedural risks of the repair, the principal investigator, Paul Sorajja, MD, called the results “very clinically meaningful” as he presented the results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Conducted at 65 centers in the United States, Canada, and North America, TRILUMINATE evaluated a transcatheter end-to-end (TEER) repair performed with the TriClip G4 Delivery System (Abbott). The study included two cohorts, both of which will be followed for 5 years. One included patients with very severe tricuspid regurgitation enrolled in a single arm. Data on this cohort is expected later in 2023.

In the randomized portion of the study, 350 patients enrolled with severe tricuspid regurgitation underwent TEER with a clipping device and then were followed on the guideline-directed therapy (GDMT) for heart failure they were receiving at baseline. The control group was managed on GDMT alone.

The primary composite endpoint at 1 year was a composite of death from any cause and/or tricuspid valve surgery, hospitalization for heart failure, and quality of life as measured with the Kansas City Cardiomyopathy questionnaire (KCCQ).
 

Benefit driven by quality of life

For the primary endpoint, the win ratio, a statistical calculation of those who did relative to those who did not benefit, was 1.48, signifying a 48% advantage (P = .02). This was driven almost entirely by the KCCQ endpoint. There was no significant difference death and/or tricuspid valve surgery, which occurred in about 10% of both groups (P = .75) or heart failure hospitalization, which was occurred in slightly more patients randomized to repair (14.9% vs. 12.1%; P = .41).

For KCCQ, the mean increase at 1 year was 12.3 points in the repair group versus 0.6 points (P < .001) in the control group. With an increase of 5-10 points typically considered to be clinically meaningful, the advantage of repair over GDMT at the threshold of 15 points or greater was highly statistically significant (49.7% vs. 26.4%; P < .0001).

This advantage was attributed to control of regurgitation. The proportion achieving moderate or less regurgitation sustained at 1 year was 87% in the repair group versus 4.8% in the GDMT group (P < .0001).

When assessed independent of treatment, KCCQ benefits at 1 year increased in a stepwise fashion as severity of regurgitation was reduced, climbing from 2 points if there was no improvement to 6 points with one grade in improvement and then to 18 points with at least a two-grade improvement.

For regurgitation, “the repair was extremely effective,” said Dr. Sorajja of Allina Health Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis. He added that the degree of regurgitation control in the TRILUMINATE trial “is the highest ever reported.” With previous trials with other transcatheter devices in development, the improvement so far has been on the order of 70%-80%.

For enrollment in TRILUMINATE, patients were required to have at least an intermediate risk of morbidity or mortality from tricuspid valve surgery. Exclusion criteria included a left ventricular ejection fraction (LVEF) less than 20% and severe pulmonary hypertension.

More than 70% of patients had the highest (torrential) or second highest (massive) category of regurgitation on a five-level scale by echocardiography. Almost all the remaining were at the third level (severe).

Of those enrolled, the average age was roughly 78 years. About 55% were women. Nearly 60% were in New York Heart Association class III or IV heart failure and most had significant comorbidities, including hypertension (> 80%), atrial fibrillation (about 90%), and renal disease (35%). Patients with diabetes (16%), chronic obstructive pulmonary disease (10%), and liver disease (7.5%) were represented in lower numbers.
 

Surgery is not necessarily an option

All enrolled patients were considered to be at intermediate or greater risk for mortality with surgical replacement of the tricuspid valve, but Dr. Sorajja pointed out that surgery, which involves valve replacement, is not necessarily an alternative to valve repair. Even in fit patients, the high morbidity, mortality, and extended hospital stay associated with surgical valve replacement makes this procedure unattractive.

In this trial, most patients who underwent the transcatheter procedure were discharged within a day. The safety was excellent, Dr. Sorajja said. Only three patients (1.7%) had a major adverse event. This included two cases of new-onset renal failure and one cardiovascular death. There were no cases of endocarditis requiring surgery or any other type of nonelective cardiovascular surgery, including for any device-related issue.

In the sick population enrolled, Dr. Sorajja characterized the number of adverse events over 1 year as “very low.”

Ted Bosworth/MDedge News

These results are important, according to Kendra Grubb, MD, surgical director of the Structural Heart and Valve Center, Emory University, Atlanta. While she expressed surprise that there was no signal of benefit on hard endpoints at 1 year, she emphasized that “these patients feel terrible,” and they are frustrating to manage because surgery is often contraindicated or impractical.

“Finally, we have something for this group,” she said, noting that the mortality from valve replacement surgery even among patients who are fit enough for surgery to be considered is about 10%.

Ajay Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, was more circumspect. He agreed that the improvement in QOL was encouraging, but cautioned that QOL is a particularly soft outcome in a nonrandomized trial in which patients may feel better just knowing that there regurgitation has been controlled. He found the lack of benefit on hard outcomes not just surprising but “disappointing.”

Still, he agreed the improvement in QOL is potentially meaningful for a procedure that appears to be relatively safe.

Dr. Sorajja reported financial relationships with Boston Scientific, Edwards Lifesciences, Foldax. 4C Medical, Gore Medtronic, Phillips, Siemens, Shifamed, Vdyne, xDot, and Abbott Structural, which provided funding for this trial. Dr. Grubb reported financial relationships with Abbott Vascular, Ancora Heart, Bioventrix, Boston Scientific, Edwards Lifesciences, 4C Medical, JenaValve, and Medtronic. Dr. Kirtane reported financial relationships with Abbott Vascular, Amgen, Boston Scientific, Chiesi, Medtronic, Opsens, Phillips, ReCor, Regeneron, and Zoll.

NEW ORLEANS – In the first pivotal randomized, controlled trial of a transcatheter device for the repair of severe tricuspid regurgitation, a large reduction in valve dysfunction was associated with substantial improvement in quality of life (QOL) persisting out of 1 year of follow-up, according to results of the TRILUMINATE trial.

Based on the low procedural risks of the repair, the principal investigator, Paul Sorajja, MD, called the results “very clinically meaningful” as he presented the results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Conducted at 65 centers in the United States, Canada, and North America, TRILUMINATE evaluated a transcatheter end-to-end (TEER) repair performed with the TriClip G4 Delivery System (Abbott). The study included two cohorts, both of which will be followed for 5 years. One included patients with very severe tricuspid regurgitation enrolled in a single arm. Data on this cohort is expected later in 2023.

In the randomized portion of the study, 350 patients enrolled with severe tricuspid regurgitation underwent TEER with a clipping device and then were followed on the guideline-directed therapy (GDMT) for heart failure they were receiving at baseline. The control group was managed on GDMT alone.

The primary composite endpoint at 1 year was a composite of death from any cause and/or tricuspid valve surgery, hospitalization for heart failure, and quality of life as measured with the Kansas City Cardiomyopathy questionnaire (KCCQ).
 

Benefit driven by quality of life

For the primary endpoint, the win ratio, a statistical calculation of those who did relative to those who did not benefit, was 1.48, signifying a 48% advantage (P = .02). This was driven almost entirely by the KCCQ endpoint. There was no significant difference death and/or tricuspid valve surgery, which occurred in about 10% of both groups (P = .75) or heart failure hospitalization, which was occurred in slightly more patients randomized to repair (14.9% vs. 12.1%; P = .41).

For KCCQ, the mean increase at 1 year was 12.3 points in the repair group versus 0.6 points (P < .001) in the control group. With an increase of 5-10 points typically considered to be clinically meaningful, the advantage of repair over GDMT at the threshold of 15 points or greater was highly statistically significant (49.7% vs. 26.4%; P < .0001).

This advantage was attributed to control of regurgitation. The proportion achieving moderate or less regurgitation sustained at 1 year was 87% in the repair group versus 4.8% in the GDMT group (P < .0001).

When assessed independent of treatment, KCCQ benefits at 1 year increased in a stepwise fashion as severity of regurgitation was reduced, climbing from 2 points if there was no improvement to 6 points with one grade in improvement and then to 18 points with at least a two-grade improvement.

For regurgitation, “the repair was extremely effective,” said Dr. Sorajja of Allina Health Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis. He added that the degree of regurgitation control in the TRILUMINATE trial “is the highest ever reported.” With previous trials with other transcatheter devices in development, the improvement so far has been on the order of 70%-80%.

For enrollment in TRILUMINATE, patients were required to have at least an intermediate risk of morbidity or mortality from tricuspid valve surgery. Exclusion criteria included a left ventricular ejection fraction (LVEF) less than 20% and severe pulmonary hypertension.

More than 70% of patients had the highest (torrential) or second highest (massive) category of regurgitation on a five-level scale by echocardiography. Almost all the remaining were at the third level (severe).

Of those enrolled, the average age was roughly 78 years. About 55% were women. Nearly 60% were in New York Heart Association class III or IV heart failure and most had significant comorbidities, including hypertension (> 80%), atrial fibrillation (about 90%), and renal disease (35%). Patients with diabetes (16%), chronic obstructive pulmonary disease (10%), and liver disease (7.5%) were represented in lower numbers.
 

Surgery is not necessarily an option

All enrolled patients were considered to be at intermediate or greater risk for mortality with surgical replacement of the tricuspid valve, but Dr. Sorajja pointed out that surgery, which involves valve replacement, is not necessarily an alternative to valve repair. Even in fit patients, the high morbidity, mortality, and extended hospital stay associated with surgical valve replacement makes this procedure unattractive.

In this trial, most patients who underwent the transcatheter procedure were discharged within a day. The safety was excellent, Dr. Sorajja said. Only three patients (1.7%) had a major adverse event. This included two cases of new-onset renal failure and one cardiovascular death. There were no cases of endocarditis requiring surgery or any other type of nonelective cardiovascular surgery, including for any device-related issue.

In the sick population enrolled, Dr. Sorajja characterized the number of adverse events over 1 year as “very low.”

Ted Bosworth/MDedge News

These results are important, according to Kendra Grubb, MD, surgical director of the Structural Heart and Valve Center, Emory University, Atlanta. While she expressed surprise that there was no signal of benefit on hard endpoints at 1 year, she emphasized that “these patients feel terrible,” and they are frustrating to manage because surgery is often contraindicated or impractical.

“Finally, we have something for this group,” she said, noting that the mortality from valve replacement surgery even among patients who are fit enough for surgery to be considered is about 10%.

Ajay Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, was more circumspect. He agreed that the improvement in QOL was encouraging, but cautioned that QOL is a particularly soft outcome in a nonrandomized trial in which patients may feel better just knowing that there regurgitation has been controlled. He found the lack of benefit on hard outcomes not just surprising but “disappointing.”

Still, he agreed the improvement in QOL is potentially meaningful for a procedure that appears to be relatively safe.

Dr. Sorajja reported financial relationships with Boston Scientific, Edwards Lifesciences, Foldax. 4C Medical, Gore Medtronic, Phillips, Siemens, Shifamed, Vdyne, xDot, and Abbott Structural, which provided funding for this trial. Dr. Grubb reported financial relationships with Abbott Vascular, Ancora Heart, Bioventrix, Boston Scientific, Edwards Lifesciences, 4C Medical, JenaValve, and Medtronic. Dr. Kirtane reported financial relationships with Abbott Vascular, Amgen, Boston Scientific, Chiesi, Medtronic, Opsens, Phillips, ReCor, Regeneron, and Zoll.

NEW ORLEANS – In the first pivotal randomized, controlled trial of a transcatheter device for the repair of severe tricuspid regurgitation, a large reduction in valve dysfunction was associated with substantial improvement in quality of life (QOL) persisting out of 1 year of follow-up, according to results of the TRILUMINATE trial.

Based on the low procedural risks of the repair, the principal investigator, Paul Sorajja, MD, called the results “very clinically meaningful” as he presented the results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Conducted at 65 centers in the United States, Canada, and North America, TRILUMINATE evaluated a transcatheter end-to-end (TEER) repair performed with the TriClip G4 Delivery System (Abbott). The study included two cohorts, both of which will be followed for 5 years. One included patients with very severe tricuspid regurgitation enrolled in a single arm. Data on this cohort is expected later in 2023.

In the randomized portion of the study, 350 patients enrolled with severe tricuspid regurgitation underwent TEER with a clipping device and then were followed on the guideline-directed therapy (GDMT) for heart failure they were receiving at baseline. The control group was managed on GDMT alone.

The primary composite endpoint at 1 year was a composite of death from any cause and/or tricuspid valve surgery, hospitalization for heart failure, and quality of life as measured with the Kansas City Cardiomyopathy questionnaire (KCCQ).
 

Benefit driven by quality of life

For the primary endpoint, the win ratio, a statistical calculation of those who did relative to those who did not benefit, was 1.48, signifying a 48% advantage (P = .02). This was driven almost entirely by the KCCQ endpoint. There was no significant difference death and/or tricuspid valve surgery, which occurred in about 10% of both groups (P = .75) or heart failure hospitalization, which was occurred in slightly more patients randomized to repair (14.9% vs. 12.1%; P = .41).

For KCCQ, the mean increase at 1 year was 12.3 points in the repair group versus 0.6 points (P < .001) in the control group. With an increase of 5-10 points typically considered to be clinically meaningful, the advantage of repair over GDMT at the threshold of 15 points or greater was highly statistically significant (49.7% vs. 26.4%; P < .0001).

This advantage was attributed to control of regurgitation. The proportion achieving moderate or less regurgitation sustained at 1 year was 87% in the repair group versus 4.8% in the GDMT group (P < .0001).

When assessed independent of treatment, KCCQ benefits at 1 year increased in a stepwise fashion as severity of regurgitation was reduced, climbing from 2 points if there was no improvement to 6 points with one grade in improvement and then to 18 points with at least a two-grade improvement.

For regurgitation, “the repair was extremely effective,” said Dr. Sorajja of Allina Health Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis. He added that the degree of regurgitation control in the TRILUMINATE trial “is the highest ever reported.” With previous trials with other transcatheter devices in development, the improvement so far has been on the order of 70%-80%.

For enrollment in TRILUMINATE, patients were required to have at least an intermediate risk of morbidity or mortality from tricuspid valve surgery. Exclusion criteria included a left ventricular ejection fraction (LVEF) less than 20% and severe pulmonary hypertension.

More than 70% of patients had the highest (torrential) or second highest (massive) category of regurgitation on a five-level scale by echocardiography. Almost all the remaining were at the third level (severe).

Of those enrolled, the average age was roughly 78 years. About 55% were women. Nearly 60% were in New York Heart Association class III or IV heart failure and most had significant comorbidities, including hypertension (> 80%), atrial fibrillation (about 90%), and renal disease (35%). Patients with diabetes (16%), chronic obstructive pulmonary disease (10%), and liver disease (7.5%) were represented in lower numbers.
 

Surgery is not necessarily an option

All enrolled patients were considered to be at intermediate or greater risk for mortality with surgical replacement of the tricuspid valve, but Dr. Sorajja pointed out that surgery, which involves valve replacement, is not necessarily an alternative to valve repair. Even in fit patients, the high morbidity, mortality, and extended hospital stay associated with surgical valve replacement makes this procedure unattractive.

In this trial, most patients who underwent the transcatheter procedure were discharged within a day. The safety was excellent, Dr. Sorajja said. Only three patients (1.7%) had a major adverse event. This included two cases of new-onset renal failure and one cardiovascular death. There were no cases of endocarditis requiring surgery or any other type of nonelective cardiovascular surgery, including for any device-related issue.

In the sick population enrolled, Dr. Sorajja characterized the number of adverse events over 1 year as “very low.”

Ted Bosworth/MDedge News

These results are important, according to Kendra Grubb, MD, surgical director of the Structural Heart and Valve Center, Emory University, Atlanta. While she expressed surprise that there was no signal of benefit on hard endpoints at 1 year, she emphasized that “these patients feel terrible,” and they are frustrating to manage because surgery is often contraindicated or impractical.

“Finally, we have something for this group,” she said, noting that the mortality from valve replacement surgery even among patients who are fit enough for surgery to be considered is about 10%.

Ajay Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, was more circumspect. He agreed that the improvement in QOL was encouraging, but cautioned that QOL is a particularly soft outcome in a nonrandomized trial in which patients may feel better just knowing that there regurgitation has been controlled. He found the lack of benefit on hard outcomes not just surprising but “disappointing.”

Still, he agreed the improvement in QOL is potentially meaningful for a procedure that appears to be relatively safe.

Dr. Sorajja reported financial relationships with Boston Scientific, Edwards Lifesciences, Foldax. 4C Medical, Gore Medtronic, Phillips, Siemens, Shifamed, Vdyne, xDot, and Abbott Structural, which provided funding for this trial. Dr. Grubb reported financial relationships with Abbott Vascular, Ancora Heart, Bioventrix, Boston Scientific, Edwards Lifesciences, 4C Medical, JenaValve, and Medtronic. Dr. Kirtane reported financial relationships with Abbott Vascular, Amgen, Boston Scientific, Chiesi, Medtronic, Opsens, Phillips, ReCor, Regeneron, and Zoll.

The amount of medical knowledge is said to double every 73 days, making it much tougher for physicians to identify innovative findings and newer guidelines for helping patients. Yet not keeping up with the latest information can put doctors at risk. 

“Most doctors are feeling lost about keeping up to date,” said John P.A. Ioannidis, MD, professor of medicine at Stanford (Calif.) University School of Medicine. “The vast majority of new studies are either wrong or not useful, but physicians cannot sort out which are those studies.”

The sheer number of new studies may even force some doctors to retreat from areas where they have not kept up, said Stephen A. Martin, MD, professor of family medicine and community health at the University of Massachusetts, Worcester. “When doctors don’t feel they can stay current, they may refer more cases to specialists or narrow their focus,” he said.
 

Some specialties have a greater challenge than others

Dr. Martin said the deluge of studies heavily impacts generalists because they have a wider field of information to keep up with. However, certain specialties like oncology are particularly flooded with new findings.

Specialties with the greatest number of published studies are reportedly oncology, cardiology, and neurology. A 2021 study found that the number of articles with the word “stroke” in them increased five times from 2000 to 2020. And investigative treatments targeting cancer nearly quadrupled just between 2010 and 2020.

What’s more, physicians spend a great deal of time sifting through studies that are ultimately useless. In a survey of internists by Univadis, which is part of WebMD/Medscape, 82% said that fewer than half of the studies they read actually had an impact on how they practice medicine.

“You often have to dig into an article and learn more about a finding before you now whether it’s useful,” Dr. Martin said. “And in the end, relatively few new findings are truly novel ones that are useful for patient care.”
 

So what can a physician do? First, find out what you don’t know

Looking for new findings needs to be carried out systematically, according to William B. Cutrer, MD, MEd, a pediatric intensivist who is associate dean for undergraduate medical education at Vanderbilt University School of Medicine, Nashville, Tenn.

“Before you start, you have to know what you don’t know, and that’s often not so easy,” he said. “You may get a spark about what you don’t know in an encounter with a patient or colleague or through patient outcomes data,” he said. 

Dr. Martin, on the other hand, advocates a broad approach that involves finding out at least a little about everything in one’s field. “If you have a good base, you’re not starting from zero when you encounter a new clinical situation,” he said.

“The idea is that you don’t need to memorize most things, but you do need to know how to access them,” Dr. Martin said. “I memorize the things I do all the time, such as dosing or indicated testing, but I look up things that I don’t see that often and ones that have some complexity.”
 

Updating the old ways

For generations, doctors have stayed current by going to meetings, conversing with colleagues, and reading journals, but many physicians have updated these methods through various resources on the internet.

For example, meetings went virtual during the pandemic, and now that face-to-face meetings are back, many of them retain a virtual option, said Kevin Campbell, MD, a cardiologist at Health First Medical Group, Melbourne, Fla. “I typically go to one or two conferences a year, but I also learn a lot digitally,” he said. 

As to journal reading, “assessing an article is an essential skill,” Dr. Cutrer said. “It’s important to quickly decide whether a journal article is worth reading or not. One answer to this problem is to consult summaries of important articles. But summaries are sometimes unhelpful, and it is hard to know which articles are significant. Therefore, doctors have been reaching out to others who can research the articles for them.”   

For many years, some physicians have pooled their resources in journal clubs. “You get a chance to cross-cultivate your skills with others,” Dr. Ioannidis said. “But you need someone who is well informed and dedicated to run the journal club, using evidence-based principles.”

Dr. Cutrer said physicians like to cast their net wide because they are understandably wary of changing their practice based on one study. “Unless there is one large study that is really well designed, doctors will need two or more findings to be convinced,” he said. This requires having the ability to match studies across many journals.
 

Using research summaries

In the past two decades, physicians have gained access to countless summaries of journal articles prepared by armies of clinical experts working for review services such as the New England Journal of Medicine’s “Journal Watch,” Annals of Internal Medicine’s “In the Clinic,” and BMJ’s “State of the Arts.”

In addition to summarizing findings from a wide variety of journals in plain language, reviewers may compare them to similar studies and assess the validity of the finding by assigning a level of evidence.

Some commercial ventures provide similar services. Betsy Jones, executive vice president of clinical decisions at EBSCO, said the DynaMed service is now available through an app on the physician’s smartphone or through the electronic health record.

Physicians like this approach. Many specialists have noted that reading full-length articles was not an efficient use of their time, while even more said that reviews are efficient.
 

Exchanging information online

Physicians are increasingly keeping current by using the internet, especially on social media, Dr. Cutrer said. “Young doctors in particular are more likely to keep up digitally,” he said.

Internet-based information has become so widespread that disparities in health care from region to region have somewhat abated, according to Stuart J. Fischer, MD, an orthopedic surgeon at Summit Orthopaedics and Sports Medicine, New Jersey. “One positive outcome of this plethora of information today is that geographic disparities in clinical practice are not as great as they used to be,” he said.  

Rather than chatting up colleagues in the hallway, many physicians have come to rely on internet-based discussion boards. 
 

Blogs, podcasts, and Twitter

Blogs and podcasts, often focused on a specialty, can be a great way for physicians to keep up, said UMass Chan professor Dr. Martin. “Podcasts in particular have enhanced the ability to stay current,” he said. “You want to find someone you trust.”

Internal medicine podcasts include Annals on Call, where doctors discuss articles in the Annals of Internal Medicine, and the Curbsiders, where two internists interview a guest expert.

Orthopedic surgeons can visit podcasts like Nailed it, Orthobullets, the Ortho Show, and Inside Orthopedics. Neurologists can consult Brainwaves, Neurology Podcast, Practical Neurology Podcast, and Clinical Neurology with KD. And pediatricians can drop in on Talking Pediatrics, The Cribsiders, and PedsCases.

Meanwhile, Twitter has become a particularly effective way to broadcast new findings, speeding up the transition from the bench to the bedside, said Dr. Campbell, the Florida cardiologist. 

“I visit cardio-specific resources on Twitter,” he said. “They can be real-time video chats or posted messages. They spur discussion like a journal club. Colleagues present cases and drop in and out of the discussion.”

Others are not as enthusiastic. Although Stanford’s Dr. Ioannidis is in the heart of the Silicon Valley, he is leery of some of the new digital methods. “I don’t use Twitter,” he says. “You just add more people to the process, which could only make things more confusing. I want to be able to think a lot about it.”
 

Cutting-edge knowledge at the point of care

Consulting the literature often takes place at the point of care, when a particular patient requires treatment. This can be done by using clinical decision support (CDS) and by using clinical practice guidelines (CPGs), which are typically developed by panels of doctors at specialty societies.

“It used to be that the doctor was expected to know everything,” said Ms. Jones at DynaMed. “Today there is no way to keep up with it all. Doctors often need a quick memory jog.”

Ms. Jones said the CDS result always requires the doctor’s interpretation. “It is up to the doctor to decide whether a new finding is the best choice for his or her patient,” she said.

Dr. Martin recommends going easy on point-of-care resources. “They can be used for showing a patient a differential diagnosis list or checking the cost of a procedure, but they are harder to use for novel developments that require time and context to evaluate their impact,” he said.

CPGs, meanwhile, have a high profile in the research world. In a 2018 study, Dr. Ioannidis found that 8 of the 15 most-cited articles were CPGs, disease definitions, or disease statistics.

Dr. Fischer said CPGs are typically based on thorough reviews of the literature, but they do involve experts’ interpretation of the science. “It can be difficult to obtain specific answers to some medical questions, especially for problems with complex treatments or variations,” he said.

As a result, Dr. Fischer said doctors have to use their judgment in applying CPGs to a specific patient. “For example, the orthopedic surgeon would normally recommend a total hip replacement for patients with a bad hip, but it might not be appropriate for an overweight patient.”
 

Stay skeptical

There are many novel ways for physicians to keep current, including summaries of articles, discussion boards, blogs, podcasts, Twitter, clinical decision support, and clinical practice guidelines.

Even with all these new services, though, doctors need to retain a healthy amount of skepticism about new research findings, Dr. Ioannidis said. “Ask yourself questions such as: Does it deal with a real problem? Am I getting the real information? Is it relevant to real patients? Is it offering good value for money?”

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

The amount of medical knowledge is said to double every 73 days, making it much tougher for physicians to identify innovative findings and newer guidelines for helping patients. Yet not keeping up with the latest information can put doctors at risk. 

“Most doctors are feeling lost about keeping up to date,” said John P.A. Ioannidis, MD, professor of medicine at Stanford (Calif.) University School of Medicine. “The vast majority of new studies are either wrong or not useful, but physicians cannot sort out which are those studies.”

The sheer number of new studies may even force some doctors to retreat from areas where they have not kept up, said Stephen A. Martin, MD, professor of family medicine and community health at the University of Massachusetts, Worcester. “When doctors don’t feel they can stay current, they may refer more cases to specialists or narrow their focus,” he said.
 

Some specialties have a greater challenge than others

Dr. Martin said the deluge of studies heavily impacts generalists because they have a wider field of information to keep up with. However, certain specialties like oncology are particularly flooded with new findings.

Specialties with the greatest number of published studies are reportedly oncology, cardiology, and neurology. A 2021 study found that the number of articles with the word “stroke” in them increased five times from 2000 to 2020. And investigative treatments targeting cancer nearly quadrupled just between 2010 and 2020.

What’s more, physicians spend a great deal of time sifting through studies that are ultimately useless. In a survey of internists by Univadis, which is part of WebMD/Medscape, 82% said that fewer than half of the studies they read actually had an impact on how they practice medicine.

“You often have to dig into an article and learn more about a finding before you now whether it’s useful,” Dr. Martin said. “And in the end, relatively few new findings are truly novel ones that are useful for patient care.”
 

So what can a physician do? First, find out what you don’t know

Looking for new findings needs to be carried out systematically, according to William B. Cutrer, MD, MEd, a pediatric intensivist who is associate dean for undergraduate medical education at Vanderbilt University School of Medicine, Nashville, Tenn.

“Before you start, you have to know what you don’t know, and that’s often not so easy,” he said. “You may get a spark about what you don’t know in an encounter with a patient or colleague or through patient outcomes data,” he said. 

Dr. Martin, on the other hand, advocates a broad approach that involves finding out at least a little about everything in one’s field. “If you have a good base, you’re not starting from zero when you encounter a new clinical situation,” he said.

“The idea is that you don’t need to memorize most things, but you do need to know how to access them,” Dr. Martin said. “I memorize the things I do all the time, such as dosing or indicated testing, but I look up things that I don’t see that often and ones that have some complexity.”
 

Updating the old ways

For generations, doctors have stayed current by going to meetings, conversing with colleagues, and reading journals, but many physicians have updated these methods through various resources on the internet.

For example, meetings went virtual during the pandemic, and now that face-to-face meetings are back, many of them retain a virtual option, said Kevin Campbell, MD, a cardiologist at Health First Medical Group, Melbourne, Fla. “I typically go to one or two conferences a year, but I also learn a lot digitally,” he said. 

As to journal reading, “assessing an article is an essential skill,” Dr. Cutrer said. “It’s important to quickly decide whether a journal article is worth reading or not. One answer to this problem is to consult summaries of important articles. But summaries are sometimes unhelpful, and it is hard to know which articles are significant. Therefore, doctors have been reaching out to others who can research the articles for them.”   

For many years, some physicians have pooled their resources in journal clubs. “You get a chance to cross-cultivate your skills with others,” Dr. Ioannidis said. “But you need someone who is well informed and dedicated to run the journal club, using evidence-based principles.”

Dr. Cutrer said physicians like to cast their net wide because they are understandably wary of changing their practice based on one study. “Unless there is one large study that is really well designed, doctors will need two or more findings to be convinced,” he said. This requires having the ability to match studies across many journals.
 

Using research summaries

In the past two decades, physicians have gained access to countless summaries of journal articles prepared by armies of clinical experts working for review services such as the New England Journal of Medicine’s “Journal Watch,” Annals of Internal Medicine’s “In the Clinic,” and BMJ’s “State of the Arts.”

In addition to summarizing findings from a wide variety of journals in plain language, reviewers may compare them to similar studies and assess the validity of the finding by assigning a level of evidence.

Some commercial ventures provide similar services. Betsy Jones, executive vice president of clinical decisions at EBSCO, said the DynaMed service is now available through an app on the physician’s smartphone or through the electronic health record.

Physicians like this approach. Many specialists have noted that reading full-length articles was not an efficient use of their time, while even more said that reviews are efficient.
 

Exchanging information online

Physicians are increasingly keeping current by using the internet, especially on social media, Dr. Cutrer said. “Young doctors in particular are more likely to keep up digitally,” he said.

Internet-based information has become so widespread that disparities in health care from region to region have somewhat abated, according to Stuart J. Fischer, MD, an orthopedic surgeon at Summit Orthopaedics and Sports Medicine, New Jersey. “One positive outcome of this plethora of information today is that geographic disparities in clinical practice are not as great as they used to be,” he said.  

Rather than chatting up colleagues in the hallway, many physicians have come to rely on internet-based discussion boards. 
 

Blogs, podcasts, and Twitter

Blogs and podcasts, often focused on a specialty, can be a great way for physicians to keep up, said UMass Chan professor Dr. Martin. “Podcasts in particular have enhanced the ability to stay current,” he said. “You want to find someone you trust.”

Internal medicine podcasts include Annals on Call, where doctors discuss articles in the Annals of Internal Medicine, and the Curbsiders, where two internists interview a guest expert.

Orthopedic surgeons can visit podcasts like Nailed it, Orthobullets, the Ortho Show, and Inside Orthopedics. Neurologists can consult Brainwaves, Neurology Podcast, Practical Neurology Podcast, and Clinical Neurology with KD. And pediatricians can drop in on Talking Pediatrics, The Cribsiders, and PedsCases.

Meanwhile, Twitter has become a particularly effective way to broadcast new findings, speeding up the transition from the bench to the bedside, said Dr. Campbell, the Florida cardiologist. 

“I visit cardio-specific resources on Twitter,” he said. “They can be real-time video chats or posted messages. They spur discussion like a journal club. Colleagues present cases and drop in and out of the discussion.”

Others are not as enthusiastic. Although Stanford’s Dr. Ioannidis is in the heart of the Silicon Valley, he is leery of some of the new digital methods. “I don’t use Twitter,” he says. “You just add more people to the process, which could only make things more confusing. I want to be able to think a lot about it.”
 

Cutting-edge knowledge at the point of care

Consulting the literature often takes place at the point of care, when a particular patient requires treatment. This can be done by using clinical decision support (CDS) and by using clinical practice guidelines (CPGs), which are typically developed by panels of doctors at specialty societies.

“It used to be that the doctor was expected to know everything,” said Ms. Jones at DynaMed. “Today there is no way to keep up with it all. Doctors often need a quick memory jog.”

Ms. Jones said the CDS result always requires the doctor’s interpretation. “It is up to the doctor to decide whether a new finding is the best choice for his or her patient,” she said.

Dr. Martin recommends going easy on point-of-care resources. “They can be used for showing a patient a differential diagnosis list or checking the cost of a procedure, but they are harder to use for novel developments that require time and context to evaluate their impact,” he said.

CPGs, meanwhile, have a high profile in the research world. In a 2018 study, Dr. Ioannidis found that 8 of the 15 most-cited articles were CPGs, disease definitions, or disease statistics.

Dr. Fischer said CPGs are typically based on thorough reviews of the literature, but they do involve experts’ interpretation of the science. “It can be difficult to obtain specific answers to some medical questions, especially for problems with complex treatments or variations,” he said.

As a result, Dr. Fischer said doctors have to use their judgment in applying CPGs to a specific patient. “For example, the orthopedic surgeon would normally recommend a total hip replacement for patients with a bad hip, but it might not be appropriate for an overweight patient.”
 

Stay skeptical

There are many novel ways for physicians to keep current, including summaries of articles, discussion boards, blogs, podcasts, Twitter, clinical decision support, and clinical practice guidelines.

Even with all these new services, though, doctors need to retain a healthy amount of skepticism about new research findings, Dr. Ioannidis said. “Ask yourself questions such as: Does it deal with a real problem? Am I getting the real information? Is it relevant to real patients? Is it offering good value for money?”

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

The amount of medical knowledge is said to double every 73 days, making it much tougher for physicians to identify innovative findings and newer guidelines for helping patients. Yet not keeping up with the latest information can put doctors at risk. 

“Most doctors are feeling lost about keeping up to date,” said John P.A. Ioannidis, MD, professor of medicine at Stanford (Calif.) University School of Medicine. “The vast majority of new studies are either wrong or not useful, but physicians cannot sort out which are those studies.”

The sheer number of new studies may even force some doctors to retreat from areas where they have not kept up, said Stephen A. Martin, MD, professor of family medicine and community health at the University of Massachusetts, Worcester. “When doctors don’t feel they can stay current, they may refer more cases to specialists or narrow their focus,” he said.
 

Some specialties have a greater challenge than others

Dr. Martin said the deluge of studies heavily impacts generalists because they have a wider field of information to keep up with. However, certain specialties like oncology are particularly flooded with new findings.

Specialties with the greatest number of published studies are reportedly oncology, cardiology, and neurology. A 2021 study found that the number of articles with the word “stroke” in them increased five times from 2000 to 2020. And investigative treatments targeting cancer nearly quadrupled just between 2010 and 2020.

What’s more, physicians spend a great deal of time sifting through studies that are ultimately useless. In a survey of internists by Univadis, which is part of WebMD/Medscape, 82% said that fewer than half of the studies they read actually had an impact on how they practice medicine.

“You often have to dig into an article and learn more about a finding before you now whether it’s useful,” Dr. Martin said. “And in the end, relatively few new findings are truly novel ones that are useful for patient care.”
 

So what can a physician do? First, find out what you don’t know

Looking for new findings needs to be carried out systematically, according to William B. Cutrer, MD, MEd, a pediatric intensivist who is associate dean for undergraduate medical education at Vanderbilt University School of Medicine, Nashville, Tenn.

“Before you start, you have to know what you don’t know, and that’s often not so easy,” he said. “You may get a spark about what you don’t know in an encounter with a patient or colleague or through patient outcomes data,” he said. 

Dr. Martin, on the other hand, advocates a broad approach that involves finding out at least a little about everything in one’s field. “If you have a good base, you’re not starting from zero when you encounter a new clinical situation,” he said.

“The idea is that you don’t need to memorize most things, but you do need to know how to access them,” Dr. Martin said. “I memorize the things I do all the time, such as dosing or indicated testing, but I look up things that I don’t see that often and ones that have some complexity.”
 

Updating the old ways

For generations, doctors have stayed current by going to meetings, conversing with colleagues, and reading journals, but many physicians have updated these methods through various resources on the internet.

For example, meetings went virtual during the pandemic, and now that face-to-face meetings are back, many of them retain a virtual option, said Kevin Campbell, MD, a cardiologist at Health First Medical Group, Melbourne, Fla. “I typically go to one or two conferences a year, but I also learn a lot digitally,” he said. 

As to journal reading, “assessing an article is an essential skill,” Dr. Cutrer said. “It’s important to quickly decide whether a journal article is worth reading or not. One answer to this problem is to consult summaries of important articles. But summaries are sometimes unhelpful, and it is hard to know which articles are significant. Therefore, doctors have been reaching out to others who can research the articles for them.”   

For many years, some physicians have pooled their resources in journal clubs. “You get a chance to cross-cultivate your skills with others,” Dr. Ioannidis said. “But you need someone who is well informed and dedicated to run the journal club, using evidence-based principles.”

Dr. Cutrer said physicians like to cast their net wide because they are understandably wary of changing their practice based on one study. “Unless there is one large study that is really well designed, doctors will need two or more findings to be convinced,” he said. This requires having the ability to match studies across many journals.
 

Using research summaries

In the past two decades, physicians have gained access to countless summaries of journal articles prepared by armies of clinical experts working for review services such as the New England Journal of Medicine’s “Journal Watch,” Annals of Internal Medicine’s “In the Clinic,” and BMJ’s “State of the Arts.”

In addition to summarizing findings from a wide variety of journals in plain language, reviewers may compare them to similar studies and assess the validity of the finding by assigning a level of evidence.

Some commercial ventures provide similar services. Betsy Jones, executive vice president of clinical decisions at EBSCO, said the DynaMed service is now available through an app on the physician’s smartphone or through the electronic health record.

Physicians like this approach. Many specialists have noted that reading full-length articles was not an efficient use of their time, while even more said that reviews are efficient.
 

Exchanging information online

Physicians are increasingly keeping current by using the internet, especially on social media, Dr. Cutrer said. “Young doctors in particular are more likely to keep up digitally,” he said.

Internet-based information has become so widespread that disparities in health care from region to region have somewhat abated, according to Stuart J. Fischer, MD, an orthopedic surgeon at Summit Orthopaedics and Sports Medicine, New Jersey. “One positive outcome of this plethora of information today is that geographic disparities in clinical practice are not as great as they used to be,” he said.  

Rather than chatting up colleagues in the hallway, many physicians have come to rely on internet-based discussion boards. 
 

Blogs, podcasts, and Twitter

Blogs and podcasts, often focused on a specialty, can be a great way for physicians to keep up, said UMass Chan professor Dr. Martin. “Podcasts in particular have enhanced the ability to stay current,” he said. “You want to find someone you trust.”

Internal medicine podcasts include Annals on Call, where doctors discuss articles in the Annals of Internal Medicine, and the Curbsiders, where two internists interview a guest expert.

Orthopedic surgeons can visit podcasts like Nailed it, Orthobullets, the Ortho Show, and Inside Orthopedics. Neurologists can consult Brainwaves, Neurology Podcast, Practical Neurology Podcast, and Clinical Neurology with KD. And pediatricians can drop in on Talking Pediatrics, The Cribsiders, and PedsCases.

Meanwhile, Twitter has become a particularly effective way to broadcast new findings, speeding up the transition from the bench to the bedside, said Dr. Campbell, the Florida cardiologist. 

“I visit cardio-specific resources on Twitter,” he said. “They can be real-time video chats or posted messages. They spur discussion like a journal club. Colleagues present cases and drop in and out of the discussion.”

Others are not as enthusiastic. Although Stanford’s Dr. Ioannidis is in the heart of the Silicon Valley, he is leery of some of the new digital methods. “I don’t use Twitter,” he says. “You just add more people to the process, which could only make things more confusing. I want to be able to think a lot about it.”
 

Cutting-edge knowledge at the point of care

Consulting the literature often takes place at the point of care, when a particular patient requires treatment. This can be done by using clinical decision support (CDS) and by using clinical practice guidelines (CPGs), which are typically developed by panels of doctors at specialty societies.

“It used to be that the doctor was expected to know everything,” said Ms. Jones at DynaMed. “Today there is no way to keep up with it all. Doctors often need a quick memory jog.”

Ms. Jones said the CDS result always requires the doctor’s interpretation. “It is up to the doctor to decide whether a new finding is the best choice for his or her patient,” she said.

Dr. Martin recommends going easy on point-of-care resources. “They can be used for showing a patient a differential diagnosis list or checking the cost of a procedure, but they are harder to use for novel developments that require time and context to evaluate their impact,” he said.

CPGs, meanwhile, have a high profile in the research world. In a 2018 study, Dr. Ioannidis found that 8 of the 15 most-cited articles were CPGs, disease definitions, or disease statistics.

Dr. Fischer said CPGs are typically based on thorough reviews of the literature, but they do involve experts’ interpretation of the science. “It can be difficult to obtain specific answers to some medical questions, especially for problems with complex treatments or variations,” he said.

As a result, Dr. Fischer said doctors have to use their judgment in applying CPGs to a specific patient. “For example, the orthopedic surgeon would normally recommend a total hip replacement for patients with a bad hip, but it might not be appropriate for an overweight patient.”
 

Stay skeptical

There are many novel ways for physicians to keep current, including summaries of articles, discussion boards, blogs, podcasts, Twitter, clinical decision support, and clinical practice guidelines.

Even with all these new services, though, doctors need to retain a healthy amount of skepticism about new research findings, Dr. Ioannidis said. “Ask yourself questions such as: Does it deal with a real problem? Am I getting the real information? Is it relevant to real patients? Is it offering good value for money?”

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

Any amount of exercise in middle age is associated with better cognition in later life, new research suggests.

A prospective study of 1,400 participants showed that those who exercised to any extent in adulthood had significantly better cognitive scores later in life, compared with their peers who were physically inactive.

Maintaining an exercise routine throughout adulthood showed the strongest link to subsequent mental acuity.

Although these associations lessened when investigators controlled for childhood cognitive ability, socioeconomic background, and education, they remained statistically significant.

“Our findings support recommendations for greater participation in physical activity across adulthood,” lead investigator Sarah-Naomi James, PhD, research fellow at the Medical Research Council Unit for Lifelong Health and Ageing at the University College London, told this news organization.

“We provide evidence to encourage inactive adults to be active even to a small extent … at any point during adulthood,” which can improve cognition and memory later in life, Dr. James said.

The findings were published online in the Journal of Neurology, Neurosurgery & Psychiatry.
 

Exercise timing

Previous studies have established a link between fitness training and cognitive benefit later in life, but the researchers wanted to explore whether the timing or type of exercise influenced cognitive outcomes in later life.

The investigators asked more than 1,400 participants in the 1946 British birth cohort how much they had exercised at ages 36, 43, 60, and 69 years.

The questions changed slightly for each assessment period, but in general, participants were asked whether in the past month they had exercised or participated in such activities as badminton, swimming, fitness exercises, yoga, dancing, football, mountain climbing, jogging, or brisk walks for 30 minutes or more; and if so, how many times they participated per month.

Prior research showed that when the participants were aged 60 years, the most commonly reported activities were walking (71%), swimming (33%), floor exercises (24%), and cycling (15%).

When they turned 69, researchers tested participants’ cognitive performance using the Addenbrooke’s Cognitive Examination–III, which measures attention and orientation, verbal fluency, memory, language, and visuospatial function. In this study sample, 53% were women, and all were White.

Physical activity levels were classified as inactive, moderately active (one to four times per month), and most active (five or more times per month). In addition, they were summed across all five assessments to create a total score ranging from 0 (inactive at all ages) to 5 (active at all ages).

Overall, 11% of participants were physically inactive at all five time points; 17% were active at one time point; 20% were active at two and three time points; 17% were active at four time points; and 15% were active at all five time points.
 

‘Cradle to grave’ study?

Results showed that being physically active at all study time points was significantly associated with higher cognitive performance, verbal memory, and processing speed when participants were aged 69 (P < .01).

Those who exercised to any extent in adulthood – even just once a month during one of the time periods, fared better cognitively in later life, compared with physically inactive participants. (P < .01).

Study limitations cited include a lack of diversity among participants and a disproportionately high attrition rate among those who were socially disadvantaged.

“Our findings show that being active during every decade from their 30s on was associated with better cognition at around 70. Indeed, those who were active for longer had the highest cognitive function,” Dr. James said.

“However, it is also never too late to start. People in our study who only started being active in their 50s or 60s still had higher cognitive scores at age 70, compared to people of the same age who had never been active,” she added.

Dr. James intends to continue following the study sample to determine whether physical activity is linked to preserved cognitive aging “and buffers the effects of cognitive deterioration in the presence of disease markers that cause dementia, ultimately delaying dementia onset.

“We hope the cohort we study will be the first ‘cradle to grave’ study in the world, where we have followed people for their entire lives,” she said.
 

Encouraging finding

In a comment, Joel Hughes, PhD, professor of psychology and director of clinical training at Kent (Ohio) State University, said the study contributes to the idea that “accumulation of physical activity over one’s lifetime fits the data better than a ‘sensitive period’ – which suggests that it’s never too late to start exercising.”

Dr. Hughes, who was not involved in the research, noted that “exercise can improve cerebral blood flow and hemodynamic function, as well as greater activation of relevant brain regions such as the frontal lobes.”

While observing that the effects of exercise on cognition are likely complex from a mechanistic point of view, the finding that “exercise preserves or improves cognition later in life is encouraging,” he said.

The study received funding from the UK Medical Research Council and Alzheimer’s Research UK. The investigators and Dr. Hughes report no relevant financial relationships.

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

Any amount of exercise in middle age is associated with better cognition in later life, new research suggests.

A prospective study of 1,400 participants showed that those who exercised to any extent in adulthood had significantly better cognitive scores later in life, compared with their peers who were physically inactive.

Maintaining an exercise routine throughout adulthood showed the strongest link to subsequent mental acuity.

Although these associations lessened when investigators controlled for childhood cognitive ability, socioeconomic background, and education, they remained statistically significant.

“Our findings support recommendations for greater participation in physical activity across adulthood,” lead investigator Sarah-Naomi James, PhD, research fellow at the Medical Research Council Unit for Lifelong Health and Ageing at the University College London, told this news organization.

“We provide evidence to encourage inactive adults to be active even to a small extent … at any point during adulthood,” which can improve cognition and memory later in life, Dr. James said.

The findings were published online in the Journal of Neurology, Neurosurgery & Psychiatry.
 

Exercise timing

Previous studies have established a link between fitness training and cognitive benefit later in life, but the researchers wanted to explore whether the timing or type of exercise influenced cognitive outcomes in later life.

The investigators asked more than 1,400 participants in the 1946 British birth cohort how much they had exercised at ages 36, 43, 60, and 69 years.

The questions changed slightly for each assessment period, but in general, participants were asked whether in the past month they had exercised or participated in such activities as badminton, swimming, fitness exercises, yoga, dancing, football, mountain climbing, jogging, or brisk walks for 30 minutes or more; and if so, how many times they participated per month.

Prior research showed that when the participants were aged 60 years, the most commonly reported activities were walking (71%), swimming (33%), floor exercises (24%), and cycling (15%).

When they turned 69, researchers tested participants’ cognitive performance using the Addenbrooke’s Cognitive Examination–III, which measures attention and orientation, verbal fluency, memory, language, and visuospatial function. In this study sample, 53% were women, and all were White.

Physical activity levels were classified as inactive, moderately active (one to four times per month), and most active (five or more times per month). In addition, they were summed across all five assessments to create a total score ranging from 0 (inactive at all ages) to 5 (active at all ages).

Overall, 11% of participants were physically inactive at all five time points; 17% were active at one time point; 20% were active at two and three time points; 17% were active at four time points; and 15% were active at all five time points.
 

‘Cradle to grave’ study?

Results showed that being physically active at all study time points was significantly associated with higher cognitive performance, verbal memory, and processing speed when participants were aged 69 (P < .01).

Those who exercised to any extent in adulthood – even just once a month during one of the time periods, fared better cognitively in later life, compared with physically inactive participants. (P < .01).

Study limitations cited include a lack of diversity among participants and a disproportionately high attrition rate among those who were socially disadvantaged.

“Our findings show that being active during every decade from their 30s on was associated with better cognition at around 70. Indeed, those who were active for longer had the highest cognitive function,” Dr. James said.

“However, it is also never too late to start. People in our study who only started being active in their 50s or 60s still had higher cognitive scores at age 70, compared to people of the same age who had never been active,” she added.

Dr. James intends to continue following the study sample to determine whether physical activity is linked to preserved cognitive aging “and buffers the effects of cognitive deterioration in the presence of disease markers that cause dementia, ultimately delaying dementia onset.

“We hope the cohort we study will be the first ‘cradle to grave’ study in the world, where we have followed people for their entire lives,” she said.
 

Encouraging finding

In a comment, Joel Hughes, PhD, professor of psychology and director of clinical training at Kent (Ohio) State University, said the study contributes to the idea that “accumulation of physical activity over one’s lifetime fits the data better than a ‘sensitive period’ – which suggests that it’s never too late to start exercising.”

Dr. Hughes, who was not involved in the research, noted that “exercise can improve cerebral blood flow and hemodynamic function, as well as greater activation of relevant brain regions such as the frontal lobes.”

While observing that the effects of exercise on cognition are likely complex from a mechanistic point of view, the finding that “exercise preserves or improves cognition later in life is encouraging,” he said.

The study received funding from the UK Medical Research Council and Alzheimer’s Research UK. The investigators and Dr. Hughes report no relevant financial relationships.

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

Any amount of exercise in middle age is associated with better cognition in later life, new research suggests.

A prospective study of 1,400 participants showed that those who exercised to any extent in adulthood had significantly better cognitive scores later in life, compared with their peers who were physically inactive.

Maintaining an exercise routine throughout adulthood showed the strongest link to subsequent mental acuity.

Although these associations lessened when investigators controlled for childhood cognitive ability, socioeconomic background, and education, they remained statistically significant.

“Our findings support recommendations for greater participation in physical activity across adulthood,” lead investigator Sarah-Naomi James, PhD, research fellow at the Medical Research Council Unit for Lifelong Health and Ageing at the University College London, told this news organization.

“We provide evidence to encourage inactive adults to be active even to a small extent … at any point during adulthood,” which can improve cognition and memory later in life, Dr. James said.

The findings were published online in the Journal of Neurology, Neurosurgery & Psychiatry.
 

Exercise timing

Previous studies have established a link between fitness training and cognitive benefit later in life, but the researchers wanted to explore whether the timing or type of exercise influenced cognitive outcomes in later life.

The investigators asked more than 1,400 participants in the 1946 British birth cohort how much they had exercised at ages 36, 43, 60, and 69 years.

The questions changed slightly for each assessment period, but in general, participants were asked whether in the past month they had exercised or participated in such activities as badminton, swimming, fitness exercises, yoga, dancing, football, mountain climbing, jogging, or brisk walks for 30 minutes or more; and if so, how many times they participated per month.

Prior research showed that when the participants were aged 60 years, the most commonly reported activities were walking (71%), swimming (33%), floor exercises (24%), and cycling (15%).

When they turned 69, researchers tested participants’ cognitive performance using the Addenbrooke’s Cognitive Examination–III, which measures attention and orientation, verbal fluency, memory, language, and visuospatial function. In this study sample, 53% were women, and all were White.

Physical activity levels were classified as inactive, moderately active (one to four times per month), and most active (five or more times per month). In addition, they were summed across all five assessments to create a total score ranging from 0 (inactive at all ages) to 5 (active at all ages).

Overall, 11% of participants were physically inactive at all five time points; 17% were active at one time point; 20% were active at two and three time points; 17% were active at four time points; and 15% were active at all five time points.
 

‘Cradle to grave’ study?

Results showed that being physically active at all study time points was significantly associated with higher cognitive performance, verbal memory, and processing speed when participants were aged 69 (P < .01).

Those who exercised to any extent in adulthood – even just once a month during one of the time periods, fared better cognitively in later life, compared with physically inactive participants. (P < .01).

Study limitations cited include a lack of diversity among participants and a disproportionately high attrition rate among those who were socially disadvantaged.

“Our findings show that being active during every decade from their 30s on was associated with better cognition at around 70. Indeed, those who were active for longer had the highest cognitive function,” Dr. James said.

“However, it is also never too late to start. People in our study who only started being active in their 50s or 60s still had higher cognitive scores at age 70, compared to people of the same age who had never been active,” she added.

Dr. James intends to continue following the study sample to determine whether physical activity is linked to preserved cognitive aging “and buffers the effects of cognitive deterioration in the presence of disease markers that cause dementia, ultimately delaying dementia onset.

“We hope the cohort we study will be the first ‘cradle to grave’ study in the world, where we have followed people for their entire lives,” she said.
 

Encouraging finding

In a comment, Joel Hughes, PhD, professor of psychology and director of clinical training at Kent (Ohio) State University, said the study contributes to the idea that “accumulation of physical activity over one’s lifetime fits the data better than a ‘sensitive period’ – which suggests that it’s never too late to start exercising.”

Dr. Hughes, who was not involved in the research, noted that “exercise can improve cerebral blood flow and hemodynamic function, as well as greater activation of relevant brain regions such as the frontal lobes.”

While observing that the effects of exercise on cognition are likely complex from a mechanistic point of view, the finding that “exercise preserves or improves cognition later in life is encouraging,” he said.

The study received funding from the UK Medical Research Council and Alzheimer’s Research UK. The investigators and Dr. Hughes report no relevant financial relationships.

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

Older adults who added a quarter mile of steps to their day showed a reduction in risk of cardiovascular events by 14% within 4 years, according to a study in more than 400 individuals.

“Aging is such a dynamic process, but most studies of daily steps and step goals are conducted on younger populations,” lead author Erin E. Dooley, PhD, an epidemiologist at the University of Alabama at Birmingham, said in an interview.

American Heart Association

The impact of more modest step goals in older adults has not been well studied, Dr. Dooley said.

The population in the current study ranged from 71 to 92 years, with an average age of 78 years. The older age and relatively short follow-up period show the importance of steps and physical activity in older adults, she said.

Dr. Dooley presented the study at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

She and her colleagues analyzed a subsample of participants in Atherosclerosis Risk in Communities (ARIC) study, an ongoing study conducted by the National Heart, Lung, and Blood Institute. The study population included 452 adults for whom step data were available at visit 6 of the ARIC study between 2016 and 2017. Participants wore an accelerometer on the waist for at least 10 hours a day for at least 3 days. The mean age of the participants was 78.4 years, 59% were women, and 20% were Black.

Outcomes were measured through December 2019 and included fatal and nonfatal cardiovascular disease (CVD) events of coronary heart disease, stroke, and heart failure.

Overall, each additional 500 steps per day was linked to a 14% reduction in risk of a CVD event (hazard ratio, 0.86; 95% confidence interval, 0.76-0.98). The mean step count was 3,447 steps per day, and 34 participants (7.5%) experienced a CVD event over 1,269 person-years of follow-up.

The cumulative risk of CVD was significantly higher (11.5%) in the quartile of adults with the lowest step count (defined as fewer than 2,077 steps per day), compared with 3.5% in those with the highest step count (defined as at least 4,453 steps per day).

In addition, adults in the highest quartile of steps had a 77% reduced risk of a proximal CVD (within 3.5 years) event over the study period (HR, 0.23).

Kei Uesugi/Stone/Getty Images

Additional research is needed to explore whether increased steps prevent or delay CVD and whether low step counts may be a biomarker for underlying disease, the researchers noted in their abstract.

However, the results support the value of even a modest increase in activity to reduce CVD risk in older adults.

Small steps may get patients started

Dr. Dooley said she was surprised at the degree of benefits on heart health from 500 steps, and noted that the findings have clinical implications.

“Steps may be a more understandable metric for physical activity for patients than talking about moderate to vigorous intensity physical activity,” she said in an interview. “While we do not want to diminish the importance of higher intensity physical activity, encouraging small increases in the number of daily steps can also have great benefits for heart health.

“Steps are counted using a variety of devices and phones, so it may be helpful for patients to show clinicians their activity during well visits,” Dr. Dooley said. “Walking may also be more manageable for people as it is low impact. Achievable goals are also important. This study suggests that, for older adults, around 3,000 steps or more was associated with reduced CVD risk,” although the greatest benefits were seen with the most active group who averaged 4,500 or more steps per day.

More research is needed to show how steps may change over time, and how this relates to CVD and heart health,” she said. “At this time, we only had a single measure of physical activity.”

Study fills research gap for older adults

“Currently, the majority of the literature exploring a relationship between physical activity and the risk for developing cardiovascular disease has evaluated all adults together, not only those who are 70 year of age and older,” Monica C. Serra, PhD, of the University of Texas, San Antonio, said in an interview. “This study allows us to start to target specific cardiovascular recommendations for older adults.”.

“It is always exciting to see results from physical activity studies that continue to support prior evidence that even small amounts of physical activity are beneficial to cardiovascular health,” said Dr. Serra, who is also vice chair of the program committee for the meeting. “These results suggest that even if only small additions in physical activity are achievable, they may have cumulative benefits in reducing cardiovascular disease risk.” For clinicians, the results also provide targets that are easy for patients to understand, said Dr. Serra. Daily step counts allow clinicians to provide specific and measurable goals to help their older patients increase physical activity.

“Small additions in total daily step counts may have clinically meaningful benefits to heart health, so promoting their patients to make any slight changes that are able to be consistently incorporated into their schedule should be encouraged. This may be best monitored by encouraging the use of an activity tracker,” she said.

Although the current study adds to the literature with objective measures of physical activity utilizing accelerometers, these devices are not as sensitive at picking up activities such as bicycling or swimming, which may be more appropriate for some older adults with mobility limitations and chronic conditions, Dr. Serra said. Additional research is needed to assess the impact of other activities on CVD in the older population.

The meeting was sponsored by the American Heart Association. The study received no outside funding. Dr. Dooley and Dr. Serra had no financial conflicts to disclose.

Older adults who added a quarter mile of steps to their day showed a reduction in risk of cardiovascular events by 14% within 4 years, according to a study in more than 400 individuals.

“Aging is such a dynamic process, but most studies of daily steps and step goals are conducted on younger populations,” lead author Erin E. Dooley, PhD, an epidemiologist at the University of Alabama at Birmingham, said in an interview.

American Heart Association

The impact of more modest step goals in older adults has not been well studied, Dr. Dooley said.

The population in the current study ranged from 71 to 92 years, with an average age of 78 years. The older age and relatively short follow-up period show the importance of steps and physical activity in older adults, she said.

Dr. Dooley presented the study at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

She and her colleagues analyzed a subsample of participants in Atherosclerosis Risk in Communities (ARIC) study, an ongoing study conducted by the National Heart, Lung, and Blood Institute. The study population included 452 adults for whom step data were available at visit 6 of the ARIC study between 2016 and 2017. Participants wore an accelerometer on the waist for at least 10 hours a day for at least 3 days. The mean age of the participants was 78.4 years, 59% were women, and 20% were Black.

Outcomes were measured through December 2019 and included fatal and nonfatal cardiovascular disease (CVD) events of coronary heart disease, stroke, and heart failure.

Overall, each additional 500 steps per day was linked to a 14% reduction in risk of a CVD event (hazard ratio, 0.86; 95% confidence interval, 0.76-0.98). The mean step count was 3,447 steps per day, and 34 participants (7.5%) experienced a CVD event over 1,269 person-years of follow-up.

The cumulative risk of CVD was significantly higher (11.5%) in the quartile of adults with the lowest step count (defined as fewer than 2,077 steps per day), compared with 3.5% in those with the highest step count (defined as at least 4,453 steps per day).

In addition, adults in the highest quartile of steps had a 77% reduced risk of a proximal CVD (within 3.5 years) event over the study period (HR, 0.23).

Kei Uesugi/Stone/Getty Images

Additional research is needed to explore whether increased steps prevent or delay CVD and whether low step counts may be a biomarker for underlying disease, the researchers noted in their abstract.

However, the results support the value of even a modest increase in activity to reduce CVD risk in older adults.

Small steps may get patients started

Dr. Dooley said she was surprised at the degree of benefits on heart health from 500 steps, and noted that the findings have clinical implications.

“Steps may be a more understandable metric for physical activity for patients than talking about moderate to vigorous intensity physical activity,” she said in an interview. “While we do not want to diminish the importance of higher intensity physical activity, encouraging small increases in the number of daily steps can also have great benefits for heart health.

“Steps are counted using a variety of devices and phones, so it may be helpful for patients to show clinicians their activity during well visits,” Dr. Dooley said. “Walking may also be more manageable for people as it is low impact. Achievable goals are also important. This study suggests that, for older adults, around 3,000 steps or more was associated with reduced CVD risk,” although the greatest benefits were seen with the most active group who averaged 4,500 or more steps per day.

More research is needed to show how steps may change over time, and how this relates to CVD and heart health,” she said. “At this time, we only had a single measure of physical activity.”

Study fills research gap for older adults

“Currently, the majority of the literature exploring a relationship between physical activity and the risk for developing cardiovascular disease has evaluated all adults together, not only those who are 70 year of age and older,” Monica C. Serra, PhD, of the University of Texas, San Antonio, said in an interview. “This study allows us to start to target specific cardiovascular recommendations for older adults.”.

“It is always exciting to see results from physical activity studies that continue to support prior evidence that even small amounts of physical activity are beneficial to cardiovascular health,” said Dr. Serra, who is also vice chair of the program committee for the meeting. “These results suggest that even if only small additions in physical activity are achievable, they may have cumulative benefits in reducing cardiovascular disease risk.” For clinicians, the results also provide targets that are easy for patients to understand, said Dr. Serra. Daily step counts allow clinicians to provide specific and measurable goals to help their older patients increase physical activity.

“Small additions in total daily step counts may have clinically meaningful benefits to heart health, so promoting their patients to make any slight changes that are able to be consistently incorporated into their schedule should be encouraged. This may be best monitored by encouraging the use of an activity tracker,” she said.

Although the current study adds to the literature with objective measures of physical activity utilizing accelerometers, these devices are not as sensitive at picking up activities such as bicycling or swimming, which may be more appropriate for some older adults with mobility limitations and chronic conditions, Dr. Serra said. Additional research is needed to assess the impact of other activities on CVD in the older population.

The meeting was sponsored by the American Heart Association. The study received no outside funding. Dr. Dooley and Dr. Serra had no financial conflicts to disclose.

Older adults who added a quarter mile of steps to their day showed a reduction in risk of cardiovascular events by 14% within 4 years, according to a study in more than 400 individuals.

“Aging is such a dynamic process, but most studies of daily steps and step goals are conducted on younger populations,” lead author Erin E. Dooley, PhD, an epidemiologist at the University of Alabama at Birmingham, said in an interview.

American Heart Association

The impact of more modest step goals in older adults has not been well studied, Dr. Dooley said.

The population in the current study ranged from 71 to 92 years, with an average age of 78 years. The older age and relatively short follow-up period show the importance of steps and physical activity in older adults, she said.

Dr. Dooley presented the study at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

She and her colleagues analyzed a subsample of participants in Atherosclerosis Risk in Communities (ARIC) study, an ongoing study conducted by the National Heart, Lung, and Blood Institute. The study population included 452 adults for whom step data were available at visit 6 of the ARIC study between 2016 and 2017. Participants wore an accelerometer on the waist for at least 10 hours a day for at least 3 days. The mean age of the participants was 78.4 years, 59% were women, and 20% were Black.

Outcomes were measured through December 2019 and included fatal and nonfatal cardiovascular disease (CVD) events of coronary heart disease, stroke, and heart failure.

Overall, each additional 500 steps per day was linked to a 14% reduction in risk of a CVD event (hazard ratio, 0.86; 95% confidence interval, 0.76-0.98). The mean step count was 3,447 steps per day, and 34 participants (7.5%) experienced a CVD event over 1,269 person-years of follow-up.

The cumulative risk of CVD was significantly higher (11.5%) in the quartile of adults with the lowest step count (defined as fewer than 2,077 steps per day), compared with 3.5% in those with the highest step count (defined as at least 4,453 steps per day).

In addition, adults in the highest quartile of steps had a 77% reduced risk of a proximal CVD (within 3.5 years) event over the study period (HR, 0.23).

Kei Uesugi/Stone/Getty Images

Additional research is needed to explore whether increased steps prevent or delay CVD and whether low step counts may be a biomarker for underlying disease, the researchers noted in their abstract.

However, the results support the value of even a modest increase in activity to reduce CVD risk in older adults.

Small steps may get patients started

Dr. Dooley said she was surprised at the degree of benefits on heart health from 500 steps, and noted that the findings have clinical implications.

“Steps may be a more understandable metric for physical activity for patients than talking about moderate to vigorous intensity physical activity,” she said in an interview. “While we do not want to diminish the importance of higher intensity physical activity, encouraging small increases in the number of daily steps can also have great benefits for heart health.

“Steps are counted using a variety of devices and phones, so it may be helpful for patients to show clinicians their activity during well visits,” Dr. Dooley said. “Walking may also be more manageable for people as it is low impact. Achievable goals are also important. This study suggests that, for older adults, around 3,000 steps or more was associated with reduced CVD risk,” although the greatest benefits were seen with the most active group who averaged 4,500 or more steps per day.

More research is needed to show how steps may change over time, and how this relates to CVD and heart health,” she said. “At this time, we only had a single measure of physical activity.”

Study fills research gap for older adults

“Currently, the majority of the literature exploring a relationship between physical activity and the risk for developing cardiovascular disease has evaluated all adults together, not only those who are 70 year of age and older,” Monica C. Serra, PhD, of the University of Texas, San Antonio, said in an interview. “This study allows us to start to target specific cardiovascular recommendations for older adults.”.

“It is always exciting to see results from physical activity studies that continue to support prior evidence that even small amounts of physical activity are beneficial to cardiovascular health,” said Dr. Serra, who is also vice chair of the program committee for the meeting. “These results suggest that even if only small additions in physical activity are achievable, they may have cumulative benefits in reducing cardiovascular disease risk.” For clinicians, the results also provide targets that are easy for patients to understand, said Dr. Serra. Daily step counts allow clinicians to provide specific and measurable goals to help their older patients increase physical activity.

“Small additions in total daily step counts may have clinically meaningful benefits to heart health, so promoting their patients to make any slight changes that are able to be consistently incorporated into their schedule should be encouraged. This may be best monitored by encouraging the use of an activity tracker,” she said.

Although the current study adds to the literature with objective measures of physical activity utilizing accelerometers, these devices are not as sensitive at picking up activities such as bicycling or swimming, which may be more appropriate for some older adults with mobility limitations and chronic conditions, Dr. Serra said. Additional research is needed to assess the impact of other activities on CVD in the older population.

The meeting was sponsored by the American Heart Association. The study received no outside funding. Dr. Dooley and Dr. Serra had no financial conflicts to disclose.

The Food and Drug Administration has declined to approve omecamtiv mecarbil (Cytokinetics) for treatment of adults with chronic heart failure with reduced ejection fraction (HFrEF), citing a lack of evidence on efficacy.

Waldemarus/iStock/Getty Images Plus

Omecamtiv mecarbil is a first-in-class, selective cardiac myosin activator designed to improve cardiac performance.

Last December, a panel of FDA advisers recommended against approval of omecamtiv mecarbil for chronic HFrEF, as reported by this news organization.

The FDA Cardiovascular and Renal Drugs Advisory Committee voted 8 to 3 (with no abstentions) that the benefits of omecamtiv mecarbil do not outweigh the risks for HFrEF. The drug had a PDUFA date of February 28.

The committee’s decision was based on results from the phase 3 GALACTIC-HF trial, which enrolled 8,256 patients with HFrEF who were at risk of hospitalization and death, despite standard-of-care therapy.

As previously reported by this news organization, omecamtiv mecarbil produced a positive result for the study’s primary endpoint, with a 2.1% absolute reduction in the combined rate of cardiovascular (CV) death, first HF hospitalization, or first urgent visit for HF, compared with placebo during a median follow-up of about 22 months.

This represented an 8% relative risk reduction and broke down as a 0.6% absolute drop in CV death, compared with placebo, a 0.7% cut in HF hospitalization, and a 0.8% drop in urgent outpatient HF visits.

In a complete response letter, the FDA said GALACTIC-HF is “not sufficiently persuasive to establish substantial evidence of effectiveness for reducing the risk of heart failure events and cardiovascular death” in adults with HFrEF, Cytokinetics shared in a news release.

Further, the FDA said results from an additional clinical trial of omecamtiv mecarbil are required to establish substantial evidence of effectiveness for the treatment of HFrEF, with benefits that outweigh the risks, Cytokinetics said.

The company said it will request a meeting with the FDA to gain a better understanding of what may be required to support potential approval of omecamtiv mecarbil. However, the company also said it has “no plans” to conduct an additional clinical trial of omecamtiv mecarbil.

Instead, the company said its focus remains on the development of aficamten, the next-in-class cardiac myosin inhibitor, currently the subject of SEQUOIA-HCM, a phase 3 clinical trial in patients with obstructive hypertrophic cardiomyopathy.

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

The Food and Drug Administration has declined to approve omecamtiv mecarbil (Cytokinetics) for treatment of adults with chronic heart failure with reduced ejection fraction (HFrEF), citing a lack of evidence on efficacy.

Waldemarus/iStock/Getty Images Plus

Omecamtiv mecarbil is a first-in-class, selective cardiac myosin activator designed to improve cardiac performance.

Last December, a panel of FDA advisers recommended against approval of omecamtiv mecarbil for chronic HFrEF, as reported by this news organization.

The FDA Cardiovascular and Renal Drugs Advisory Committee voted 8 to 3 (with no abstentions) that the benefits of omecamtiv mecarbil do not outweigh the risks for HFrEF. The drug had a PDUFA date of February 28.

The committee’s decision was based on results from the phase 3 GALACTIC-HF trial, which enrolled 8,256 patients with HFrEF who were at risk of hospitalization and death, despite standard-of-care therapy.

As previously reported by this news organization, omecamtiv mecarbil produced a positive result for the study’s primary endpoint, with a 2.1% absolute reduction in the combined rate of cardiovascular (CV) death, first HF hospitalization, or first urgent visit for HF, compared with placebo during a median follow-up of about 22 months.

This represented an 8% relative risk reduction and broke down as a 0.6% absolute drop in CV death, compared with placebo, a 0.7% cut in HF hospitalization, and a 0.8% drop in urgent outpatient HF visits.

In a complete response letter, the FDA said GALACTIC-HF is “not sufficiently persuasive to establish substantial evidence of effectiveness for reducing the risk of heart failure events and cardiovascular death” in adults with HFrEF, Cytokinetics shared in a news release.

Further, the FDA said results from an additional clinical trial of omecamtiv mecarbil are required to establish substantial evidence of effectiveness for the treatment of HFrEF, with benefits that outweigh the risks, Cytokinetics said.

The company said it will request a meeting with the FDA to gain a better understanding of what may be required to support potential approval of omecamtiv mecarbil. However, the company also said it has “no plans” to conduct an additional clinical trial of omecamtiv mecarbil.

Instead, the company said its focus remains on the development of aficamten, the next-in-class cardiac myosin inhibitor, currently the subject of SEQUOIA-HCM, a phase 3 clinical trial in patients with obstructive hypertrophic cardiomyopathy.

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

The Food and Drug Administration has declined to approve omecamtiv mecarbil (Cytokinetics) for treatment of adults with chronic heart failure with reduced ejection fraction (HFrEF), citing a lack of evidence on efficacy.

Waldemarus/iStock/Getty Images Plus

Omecamtiv mecarbil is a first-in-class, selective cardiac myosin activator designed to improve cardiac performance.

Last December, a panel of FDA advisers recommended against approval of omecamtiv mecarbil for chronic HFrEF, as reported by this news organization.

The FDA Cardiovascular and Renal Drugs Advisory Committee voted 8 to 3 (with no abstentions) that the benefits of omecamtiv mecarbil do not outweigh the risks for HFrEF. The drug had a PDUFA date of February 28.

The committee’s decision was based on results from the phase 3 GALACTIC-HF trial, which enrolled 8,256 patients with HFrEF who were at risk of hospitalization and death, despite standard-of-care therapy.

As previously reported by this news organization, omecamtiv mecarbil produced a positive result for the study’s primary endpoint, with a 2.1% absolute reduction in the combined rate of cardiovascular (CV) death, first HF hospitalization, or first urgent visit for HF, compared with placebo during a median follow-up of about 22 months.

This represented an 8% relative risk reduction and broke down as a 0.6% absolute drop in CV death, compared with placebo, a 0.7% cut in HF hospitalization, and a 0.8% drop in urgent outpatient HF visits.

In a complete response letter, the FDA said GALACTIC-HF is “not sufficiently persuasive to establish substantial evidence of effectiveness for reducing the risk of heart failure events and cardiovascular death” in adults with HFrEF, Cytokinetics shared in a news release.

Further, the FDA said results from an additional clinical trial of omecamtiv mecarbil are required to establish substantial evidence of effectiveness for the treatment of HFrEF, with benefits that outweigh the risks, Cytokinetics said.

The company said it will request a meeting with the FDA to gain a better understanding of what may be required to support potential approval of omecamtiv mecarbil. However, the company also said it has “no plans” to conduct an additional clinical trial of omecamtiv mecarbil.

Instead, the company said its focus remains on the development of aficamten, the next-in-class cardiac myosin inhibitor, currently the subject of SEQUOIA-HCM, a phase 3 clinical trial in patients with obstructive hypertrophic cardiomyopathy.

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

A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).

In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD, compared with never-users, in a large population-based U.S. cohort. Less frequent use was not associated with increased odds for CAD.

In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD, compared with other people.

Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming joint scientific sessions of the American College of Cardiology and the World Heart Federation 2023.

“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use, was associated with CAD” in the large population-based cohort, said Dr. Paranjpe, a resident physician at Stanford (Calif.) University, during the press conference.

“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.

“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.

“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Dr. Paranjpe said in an interview.

“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell has also shown that cannabis causes vascular inflammation that may lead to CAD.

“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (i.e., stroke, heart attack) in patient[s] with existing CAD.”
 

ASCVD risk

Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “This adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).

“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 – people who think that they’re invincible,” Dr. Page, a professor at the University of Colorado at Denver, Aurora, who was not involved with this research, told this news organization in an interview.

“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.

“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults – because that’s where you’re seeing the highest amount of use.”
 

‘All of Us’ observational study

In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.

They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.

There were 39,678 never-users, 8,749 who used it once or twice, 2,075 who used it monthly, 2,720 who used it weekly, and 4,736 who used it daily.

Of these, 3,506 individuals had CAD, based on medical records.

Only daily users had a significantly higher risk for CAD, compared with never-users (odds ratio, 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.

The median age for daily users was 41, whereas the median age for never-users was 59.
 

GWAS analyses

The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.

“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Dr. Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”

The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.

The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.

Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04).

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

A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).

In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD, compared with never-users, in a large population-based U.S. cohort. Less frequent use was not associated with increased odds for CAD.

In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD, compared with other people.

Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming joint scientific sessions of the American College of Cardiology and the World Heart Federation 2023.

“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use, was associated with CAD” in the large population-based cohort, said Dr. Paranjpe, a resident physician at Stanford (Calif.) University, during the press conference.

“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.

“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.

“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Dr. Paranjpe said in an interview.

“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell has also shown that cannabis causes vascular inflammation that may lead to CAD.

“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (i.e., stroke, heart attack) in patient[s] with existing CAD.”
 

ASCVD risk

Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “This adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).

“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 – people who think that they’re invincible,” Dr. Page, a professor at the University of Colorado at Denver, Aurora, who was not involved with this research, told this news organization in an interview.

“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.

“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults – because that’s where you’re seeing the highest amount of use.”
 

‘All of Us’ observational study

In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.

They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.

There were 39,678 never-users, 8,749 who used it once or twice, 2,075 who used it monthly, 2,720 who used it weekly, and 4,736 who used it daily.

Of these, 3,506 individuals had CAD, based on medical records.

Only daily users had a significantly higher risk for CAD, compared with never-users (odds ratio, 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.

The median age for daily users was 41, whereas the median age for never-users was 59.
 

GWAS analyses

The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.

“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Dr. Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”

The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.

The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.

Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04).

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

A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).

In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD, compared with never-users, in a large population-based U.S. cohort. Less frequent use was not associated with increased odds for CAD.

In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD, compared with other people.

Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming joint scientific sessions of the American College of Cardiology and the World Heart Federation 2023.

“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use, was associated with CAD” in the large population-based cohort, said Dr. Paranjpe, a resident physician at Stanford (Calif.) University, during the press conference.

“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.

“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.

“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Dr. Paranjpe said in an interview.

“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell has also shown that cannabis causes vascular inflammation that may lead to CAD.

“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (i.e., stroke, heart attack) in patient[s] with existing CAD.”
 

ASCVD risk

Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “This adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).

“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 – people who think that they’re invincible,” Dr. Page, a professor at the University of Colorado at Denver, Aurora, who was not involved with this research, told this news organization in an interview.

“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.

“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults – because that’s where you’re seeing the highest amount of use.”
 

‘All of Us’ observational study

In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.

They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.

There were 39,678 never-users, 8,749 who used it once or twice, 2,075 who used it monthly, 2,720 who used it weekly, and 4,736 who used it daily.

Of these, 3,506 individuals had CAD, based on medical records.

Only daily users had a significantly higher risk for CAD, compared with never-users (odds ratio, 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.

The median age for daily users was 41, whereas the median age for never-users was 59.
 

GWAS analyses

The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.

“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Dr. Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”

The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.

The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.

Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04).

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