TBD Meeting (3243-21)

A pair of updated scoring models for estimating a patient’s risk for contrast-associated acute kidney injury during and immediately after percutaneous coronary intervention worked better than a widely used prior version in initial validation testing using data collected at a single U.S. tertiary-care hospital.

Mount Sinai Medical Center

While the two new risk scores looked promising, they need further, external validation with additional, diverse patient cohorts, Roxana Mehran, MD, cautioned at the American Heart Association scientific sessions.

“Don’t change anything until we externally validate this,” urged Dr. Mehran, professor and director of the Center for Interventional Cardiovascular Research and Clinical Trials at Icahn School of Medicine at Mount Sinai in New York. External validation of the two new risk scores is in progress with planned reporting of the results in 2022, she said in an interview.

One of the two new algorithms, which both predict a patient’s risk for developing acute kidney injury (AKI) as a result of receiving iodinated contrast media within 48 hours of a percutaneous coronary intervention (PCI), relies on eight easily available variables taken from a patient’s medical record just prior to undergoing PCI: age, type of coronary disease (ranging from asymptomatic or stable angina to ST-segment elevation MI), estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, hemoglobin, basal glucose, and heart failure.

This risk score accounted for 72% (a C-statistic of 0.72) of the observed AKI episodes during the derivation phase, which used data from 14,616 consecutive Mount Sinai patients who underwent PCI during January 2012–December 2017.

Internal validation using data from 5,606 consecutive Mount Sinai patients who underwent PCI during January 2018–December 2020 showed that the eight-item formula accounted for 84% of all incident AKI events occurring during or within 48 hours of a PCI procedure.
 

Accounting for periprocedural variables

A second risk score included the eight preprocedural variables plus four additional periprocedural variables: complex PCI anatomy, contrast volume during the procedure, development of a periprocedural bleed, and having slow or no reflow into affected coronaries (less than TIMI grade 3 flow) immediately after the procedure. The second model produced a C-statistic of 0.74 during derivation and accounted for 86% of incident AKI events in the validation analysis.

The data Dr. Mehran reported appeared in The Lancet .

She and her coauthors designed these two new algorithms to replace a “widely used” and externally validated risk score that Dr. Mehran and associates introduced in 2004. Despite its merits, the 17-year-old scoring formula has limitations including “low discrimination” with a C-statistic of 0.67, derivation from data that’s now 20 years old, and exclusion of patients with ST-elevation MIs, the authors said in the new report.

Dr. Mehran encouraged interventional cardiologists to use both new risk scores (once externally validated) when possible.

The eight-item preprocedural model “gives clinicians an idea about a patient’s risk [for incident AKI] before they go into the catheterization laboratory,” and then they can further refine the risk assessment during the procedure based on the four periprocedural risk factors, she explained. The goal is to target “tailored preventive strategies” to patients identified by the scoring algorithms as being at high risk for AKI.
 

A role for preventive measures

Preventive strategies to consider for higher-risk patients include limiting the administered volume of iodinated contrast media, increasing hydration, and avoiding nephrotoxic agents, Dr. Mehran said. The two new risk-assessment tools will “allow for better evaluation of PCI patients” when testing “innovative strategies and treatments” designed to help avoid contrast-associated AKI.

“The focus to date has been on measures to protect renal function from contrast media, based on indirect data,” Estelle C. Nijssen, MSc, and Joachim E. Wildberger, MD, wrote in an editorial that accompanied the published report. “The effect of prophylactic measures on longer-term averse outcomes is still unclear,” they noted. “Perhaps our focus should shift from contrast and renal function to the heart, the role of which has probably been undervalued in this setting,” wrote Ms. Nijssen, a researcher at Maastricht (The Netherlands) University, and Dr. Wildberger, professor and chairman of the department of radiology at Maastricht University.

The editorial’s authors noted that the two new risk scores have the advantage of relying on variables that are “readily available in clinical practice.” But they also noted several limitations, such as the model’s development from largely low-risk patients who had a low, roughly 30% prevalence of chronic kidney disease. During 9 full years studied, 2012-2020, the annual incidence of AKI showed a downward trend, with an incidence of just over 3% in 2020.

Dr. Mehran attributed this decline in AKI to “great work identifying high-risk patients” and using the prophylactic measures she cited. But even when occurring at relatively low incidence, “AKI is still an important complication that is associated with mortality post PCI,” she stressed.

Establishing a safe contrast dose

“The study is great, and helps reinforce the risk factors that are most important to consider when risk stratifying patients prior to PCI,” said Neal Yuan, MD, a cardiologist at the University of California, San Francisco, who has studied contrast-associated AKI in patients who undergo PCI. The report from Dr. Mehran also “confirms in a large cohort the association between contrast-associated AKI and death,” and describes “an easy method for calculating risk,” he said in an interview.

Dr. Yuan agreed on the need for external validation, and once adequately validated he called for incorporation of the risk score into EHRs. Another important issue for future study is “how much [AKI] risk is too much risk,” he said.

The risk factors identified in Dr. Mehran’s report “are some of the same ones identified in previous studies. Even though this was a more contemporary dataset, there is not a ton of new [findings]; it mainly strengthens findings from prior studies.”

Results published by Dr. Yuan and his associates in 2020 used data from more than 20,000 U.S. patients who underwent PCI to try to identify a generally safe upper limit for the dose of iodinated contrast.

The main purpose for performing AKI risk stratification on PCI patients is to “identify high-risk patients and use preventive strategies when treating these patients.” Current AKI preventive strategies “mainly fall into intravascular volume expansion, and reduced contrast.” What’s less clear is “how to operationalize reduced contrast,” he said.

The report by Dr. Yuan showed that “about 10% of PCI patients were at very high risk” for contrast-associated AKI “no matter what is done.” In contrast, about two-thirds of PCI patients “could receive lots of contrast and still be very unlikely to develop AKI,” Dr. Yuan said.

He voiced some skepticism about the willingness of many clinicians to routinely use a formal risk score to assess their patients scheduled for PCI.

Most operators “approximate AKI risk based on variables such as age and creatinine level, but few take time to put the variables into a calculator to get an exact risk number.” In a “small survey” he ran, he found that these rough approximations often ignore important risk factors like hemoglobin level. This inertia by clinicians against routinely using a risk score could be addressed, at least in part, by integrating the risk score into an EHR for automatic calculation, Dr. Yuan suggested.

Dr. Mehran noted that the risk score that she introduced in 2004 is used “in many EHRs to identify high-risk patients.”

The current study received no commercial or external funding. Dr. Mehran has been a consultant to Boston Scientific, Cine-Med Research, CIRM, and Janssen, and she holds equity in Applied Therapeutics, Elixir Medical, and STEL. Dr. Wildberger had no relevant disclosures. Ms. Nijssen and Dr. Yuan had no disclosures.

mzoler@mdedge.com

A pair of updated scoring models for estimating a patient’s risk for contrast-associated acute kidney injury during and immediately after percutaneous coronary intervention worked better than a widely used prior version in initial validation testing using data collected at a single U.S. tertiary-care hospital.

Mount Sinai Medical Center

While the two new risk scores looked promising, they need further, external validation with additional, diverse patient cohorts, Roxana Mehran, MD, cautioned at the American Heart Association scientific sessions.

“Don’t change anything until we externally validate this,” urged Dr. Mehran, professor and director of the Center for Interventional Cardiovascular Research and Clinical Trials at Icahn School of Medicine at Mount Sinai in New York. External validation of the two new risk scores is in progress with planned reporting of the results in 2022, she said in an interview.

One of the two new algorithms, which both predict a patient’s risk for developing acute kidney injury (AKI) as a result of receiving iodinated contrast media within 48 hours of a percutaneous coronary intervention (PCI), relies on eight easily available variables taken from a patient’s medical record just prior to undergoing PCI: age, type of coronary disease (ranging from asymptomatic or stable angina to ST-segment elevation MI), estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, hemoglobin, basal glucose, and heart failure.

This risk score accounted for 72% (a C-statistic of 0.72) of the observed AKI episodes during the derivation phase, which used data from 14,616 consecutive Mount Sinai patients who underwent PCI during January 2012–December 2017.

Internal validation using data from 5,606 consecutive Mount Sinai patients who underwent PCI during January 2018–December 2020 showed that the eight-item formula accounted for 84% of all incident AKI events occurring during or within 48 hours of a PCI procedure.
 

Accounting for periprocedural variables

A second risk score included the eight preprocedural variables plus four additional periprocedural variables: complex PCI anatomy, contrast volume during the procedure, development of a periprocedural bleed, and having slow or no reflow into affected coronaries (less than TIMI grade 3 flow) immediately after the procedure. The second model produced a C-statistic of 0.74 during derivation and accounted for 86% of incident AKI events in the validation analysis.

The data Dr. Mehran reported appeared in The Lancet .

She and her coauthors designed these two new algorithms to replace a “widely used” and externally validated risk score that Dr. Mehran and associates introduced in 2004. Despite its merits, the 17-year-old scoring formula has limitations including “low discrimination” with a C-statistic of 0.67, derivation from data that’s now 20 years old, and exclusion of patients with ST-elevation MIs, the authors said in the new report.

Dr. Mehran encouraged interventional cardiologists to use both new risk scores (once externally validated) when possible.

The eight-item preprocedural model “gives clinicians an idea about a patient’s risk [for incident AKI] before they go into the catheterization laboratory,” and then they can further refine the risk assessment during the procedure based on the four periprocedural risk factors, she explained. The goal is to target “tailored preventive strategies” to patients identified by the scoring algorithms as being at high risk for AKI.
 

A role for preventive measures

Preventive strategies to consider for higher-risk patients include limiting the administered volume of iodinated contrast media, increasing hydration, and avoiding nephrotoxic agents, Dr. Mehran said. The two new risk-assessment tools will “allow for better evaluation of PCI patients” when testing “innovative strategies and treatments” designed to help avoid contrast-associated AKI.

“The focus to date has been on measures to protect renal function from contrast media, based on indirect data,” Estelle C. Nijssen, MSc, and Joachim E. Wildberger, MD, wrote in an editorial that accompanied the published report. “The effect of prophylactic measures on longer-term averse outcomes is still unclear,” they noted. “Perhaps our focus should shift from contrast and renal function to the heart, the role of which has probably been undervalued in this setting,” wrote Ms. Nijssen, a researcher at Maastricht (The Netherlands) University, and Dr. Wildberger, professor and chairman of the department of radiology at Maastricht University.

The editorial’s authors noted that the two new risk scores have the advantage of relying on variables that are “readily available in clinical practice.” But they also noted several limitations, such as the model’s development from largely low-risk patients who had a low, roughly 30% prevalence of chronic kidney disease. During 9 full years studied, 2012-2020, the annual incidence of AKI showed a downward trend, with an incidence of just over 3% in 2020.

Dr. Mehran attributed this decline in AKI to “great work identifying high-risk patients” and using the prophylactic measures she cited. But even when occurring at relatively low incidence, “AKI is still an important complication that is associated with mortality post PCI,” she stressed.

Establishing a safe contrast dose

“The study is great, and helps reinforce the risk factors that are most important to consider when risk stratifying patients prior to PCI,” said Neal Yuan, MD, a cardiologist at the University of California, San Francisco, who has studied contrast-associated AKI in patients who undergo PCI. The report from Dr. Mehran also “confirms in a large cohort the association between contrast-associated AKI and death,” and describes “an easy method for calculating risk,” he said in an interview.

Dr. Yuan agreed on the need for external validation, and once adequately validated he called for incorporation of the risk score into EHRs. Another important issue for future study is “how much [AKI] risk is too much risk,” he said.

The risk factors identified in Dr. Mehran’s report “are some of the same ones identified in previous studies. Even though this was a more contemporary dataset, there is not a ton of new [findings]; it mainly strengthens findings from prior studies.”

Results published by Dr. Yuan and his associates in 2020 used data from more than 20,000 U.S. patients who underwent PCI to try to identify a generally safe upper limit for the dose of iodinated contrast.

The main purpose for performing AKI risk stratification on PCI patients is to “identify high-risk patients and use preventive strategies when treating these patients.” Current AKI preventive strategies “mainly fall into intravascular volume expansion, and reduced contrast.” What’s less clear is “how to operationalize reduced contrast,” he said.

The report by Dr. Yuan showed that “about 10% of PCI patients were at very high risk” for contrast-associated AKI “no matter what is done.” In contrast, about two-thirds of PCI patients “could receive lots of contrast and still be very unlikely to develop AKI,” Dr. Yuan said.

He voiced some skepticism about the willingness of many clinicians to routinely use a formal risk score to assess their patients scheduled for PCI.

Most operators “approximate AKI risk based on variables such as age and creatinine level, but few take time to put the variables into a calculator to get an exact risk number.” In a “small survey” he ran, he found that these rough approximations often ignore important risk factors like hemoglobin level. This inertia by clinicians against routinely using a risk score could be addressed, at least in part, by integrating the risk score into an EHR for automatic calculation, Dr. Yuan suggested.

Dr. Mehran noted that the risk score that she introduced in 2004 is used “in many EHRs to identify high-risk patients.”

The current study received no commercial or external funding. Dr. Mehran has been a consultant to Boston Scientific, Cine-Med Research, CIRM, and Janssen, and she holds equity in Applied Therapeutics, Elixir Medical, and STEL. Dr. Wildberger had no relevant disclosures. Ms. Nijssen and Dr. Yuan had no disclosures.

mzoler@mdedge.com

A pair of updated scoring models for estimating a patient’s risk for contrast-associated acute kidney injury during and immediately after percutaneous coronary intervention worked better than a widely used prior version in initial validation testing using data collected at a single U.S. tertiary-care hospital.

Mount Sinai Medical Center

While the two new risk scores looked promising, they need further, external validation with additional, diverse patient cohorts, Roxana Mehran, MD, cautioned at the American Heart Association scientific sessions.

“Don’t change anything until we externally validate this,” urged Dr. Mehran, professor and director of the Center for Interventional Cardiovascular Research and Clinical Trials at Icahn School of Medicine at Mount Sinai in New York. External validation of the two new risk scores is in progress with planned reporting of the results in 2022, she said in an interview.

One of the two new algorithms, which both predict a patient’s risk for developing acute kidney injury (AKI) as a result of receiving iodinated contrast media within 48 hours of a percutaneous coronary intervention (PCI), relies on eight easily available variables taken from a patient’s medical record just prior to undergoing PCI: age, type of coronary disease (ranging from asymptomatic or stable angina to ST-segment elevation MI), estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, hemoglobin, basal glucose, and heart failure.

This risk score accounted for 72% (a C-statistic of 0.72) of the observed AKI episodes during the derivation phase, which used data from 14,616 consecutive Mount Sinai patients who underwent PCI during January 2012–December 2017.

Internal validation using data from 5,606 consecutive Mount Sinai patients who underwent PCI during January 2018–December 2020 showed that the eight-item formula accounted for 84% of all incident AKI events occurring during or within 48 hours of a PCI procedure.
 

Accounting for periprocedural variables

A second risk score included the eight preprocedural variables plus four additional periprocedural variables: complex PCI anatomy, contrast volume during the procedure, development of a periprocedural bleed, and having slow or no reflow into affected coronaries (less than TIMI grade 3 flow) immediately after the procedure. The second model produced a C-statistic of 0.74 during derivation and accounted for 86% of incident AKI events in the validation analysis.

The data Dr. Mehran reported appeared in The Lancet .

She and her coauthors designed these two new algorithms to replace a “widely used” and externally validated risk score that Dr. Mehran and associates introduced in 2004. Despite its merits, the 17-year-old scoring formula has limitations including “low discrimination” with a C-statistic of 0.67, derivation from data that’s now 20 years old, and exclusion of patients with ST-elevation MIs, the authors said in the new report.

Dr. Mehran encouraged interventional cardiologists to use both new risk scores (once externally validated) when possible.

The eight-item preprocedural model “gives clinicians an idea about a patient’s risk [for incident AKI] before they go into the catheterization laboratory,” and then they can further refine the risk assessment during the procedure based on the four periprocedural risk factors, she explained. The goal is to target “tailored preventive strategies” to patients identified by the scoring algorithms as being at high risk for AKI.
 

A role for preventive measures

Preventive strategies to consider for higher-risk patients include limiting the administered volume of iodinated contrast media, increasing hydration, and avoiding nephrotoxic agents, Dr. Mehran said. The two new risk-assessment tools will “allow for better evaluation of PCI patients” when testing “innovative strategies and treatments” designed to help avoid contrast-associated AKI.

“The focus to date has been on measures to protect renal function from contrast media, based on indirect data,” Estelle C. Nijssen, MSc, and Joachim E. Wildberger, MD, wrote in an editorial that accompanied the published report. “The effect of prophylactic measures on longer-term averse outcomes is still unclear,” they noted. “Perhaps our focus should shift from contrast and renal function to the heart, the role of which has probably been undervalued in this setting,” wrote Ms. Nijssen, a researcher at Maastricht (The Netherlands) University, and Dr. Wildberger, professor and chairman of the department of radiology at Maastricht University.

The editorial’s authors noted that the two new risk scores have the advantage of relying on variables that are “readily available in clinical practice.” But they also noted several limitations, such as the model’s development from largely low-risk patients who had a low, roughly 30% prevalence of chronic kidney disease. During 9 full years studied, 2012-2020, the annual incidence of AKI showed a downward trend, with an incidence of just over 3% in 2020.

Dr. Mehran attributed this decline in AKI to “great work identifying high-risk patients” and using the prophylactic measures she cited. But even when occurring at relatively low incidence, “AKI is still an important complication that is associated with mortality post PCI,” she stressed.

Establishing a safe contrast dose

“The study is great, and helps reinforce the risk factors that are most important to consider when risk stratifying patients prior to PCI,” said Neal Yuan, MD, a cardiologist at the University of California, San Francisco, who has studied contrast-associated AKI in patients who undergo PCI. The report from Dr. Mehran also “confirms in a large cohort the association between contrast-associated AKI and death,” and describes “an easy method for calculating risk,” he said in an interview.

Dr. Yuan agreed on the need for external validation, and once adequately validated he called for incorporation of the risk score into EHRs. Another important issue for future study is “how much [AKI] risk is too much risk,” he said.

The risk factors identified in Dr. Mehran’s report “are some of the same ones identified in previous studies. Even though this was a more contemporary dataset, there is not a ton of new [findings]; it mainly strengthens findings from prior studies.”

Results published by Dr. Yuan and his associates in 2020 used data from more than 20,000 U.S. patients who underwent PCI to try to identify a generally safe upper limit for the dose of iodinated contrast.

The main purpose for performing AKI risk stratification on PCI patients is to “identify high-risk patients and use preventive strategies when treating these patients.” Current AKI preventive strategies “mainly fall into intravascular volume expansion, and reduced contrast.” What’s less clear is “how to operationalize reduced contrast,” he said.

The report by Dr. Yuan showed that “about 10% of PCI patients were at very high risk” for contrast-associated AKI “no matter what is done.” In contrast, about two-thirds of PCI patients “could receive lots of contrast and still be very unlikely to develop AKI,” Dr. Yuan said.

He voiced some skepticism about the willingness of many clinicians to routinely use a formal risk score to assess their patients scheduled for PCI.

Most operators “approximate AKI risk based on variables such as age and creatinine level, but few take time to put the variables into a calculator to get an exact risk number.” In a “small survey” he ran, he found that these rough approximations often ignore important risk factors like hemoglobin level. This inertia by clinicians against routinely using a risk score could be addressed, at least in part, by integrating the risk score into an EHR for automatic calculation, Dr. Yuan suggested.

Dr. Mehran noted that the risk score that she introduced in 2004 is used “in many EHRs to identify high-risk patients.”

The current study received no commercial or external funding. Dr. Mehran has been a consultant to Boston Scientific, Cine-Med Research, CIRM, and Janssen, and she holds equity in Applied Therapeutics, Elixir Medical, and STEL. Dr. Wildberger had no relevant disclosures. Ms. Nijssen and Dr. Yuan had no disclosures.

mzoler@mdedge.com

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.
 

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL. 

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement. 

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”  

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.  

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”
 

Differences from other CETP inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Dr. Nicholls replied that obicetrapib is much more potent, as shown by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

“We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters,” he said.  

“The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class,” he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. “That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward,” he added.

“This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit,” Dr. Nicholls said.

“If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering,” he said. “And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

“I think you’ll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design,” he said, adding that a larger cardiovascular outcome trial is now being planned. 

“The regulatory perspective is that LDL is a pretty trusted surrogate ... but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be,” Dr. Nicholls noted.  

Dr. Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

“The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects,” he said.  

“The next agent, dalcetrapib (Roche), raised HDL but didn’t move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up – up to 5 years – to see a benefit,” he noted.  

Dr. Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

“Oxford academic researchers decided to continue follow-up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors,” Dr. Kastelein said.   

He pointed out that obicetrapib is much more potent than anacetrapib. “Obicetrapib reduces LDL by 50% at just a 10-mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction.”
 

Could HDL increase be beneficial after all?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Dr. Kastelein noted.

“We know that statins can increase risk of developing type 2 diabetes, and post hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect,” he said. “We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL.”

Commenting on the current data, Steven Nissen, MD, of Cleveland Clinic, said: “The results are truly impressive – a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

“Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high,” he added.

Dr. Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. “I have encouraged this company to develop this very promising drug,” he said.

The current study was funded by New Amsterdam Pharma. Dr. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Kastelein is chief scientific officer of New Amsterdam Pharma.  

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

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.
 

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL. 

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement. 

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”  

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.  

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”
 

Differences from other CETP inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Dr. Nicholls replied that obicetrapib is much more potent, as shown by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

“We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters,” he said.  

“The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class,” he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. “That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward,” he added.

“This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit,” Dr. Nicholls said.

“If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering,” he said. “And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

“I think you’ll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design,” he said, adding that a larger cardiovascular outcome trial is now being planned. 

“The regulatory perspective is that LDL is a pretty trusted surrogate ... but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be,” Dr. Nicholls noted.  

Dr. Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

“The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects,” he said.  

“The next agent, dalcetrapib (Roche), raised HDL but didn’t move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up – up to 5 years – to see a benefit,” he noted.  

Dr. Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

“Oxford academic researchers decided to continue follow-up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors,” Dr. Kastelein said.   

He pointed out that obicetrapib is much more potent than anacetrapib. “Obicetrapib reduces LDL by 50% at just a 10-mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction.”
 

Could HDL increase be beneficial after all?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Dr. Kastelein noted.

“We know that statins can increase risk of developing type 2 diabetes, and post hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect,” he said. “We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL.”

Commenting on the current data, Steven Nissen, MD, of Cleveland Clinic, said: “The results are truly impressive – a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

“Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high,” he added.

Dr. Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. “I have encouraged this company to develop this very promising drug,” he said.

The current study was funded by New Amsterdam Pharma. Dr. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Kastelein is chief scientific officer of New Amsterdam Pharma.  

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

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.
 

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL. 

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement. 

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”  

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.  

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”
 

Differences from other CETP inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Dr. Nicholls replied that obicetrapib is much more potent, as shown by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

“We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters,” he said.  

“The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class,” he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. “That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward,” he added.

“This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit,” Dr. Nicholls said.

“If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering,” he said. “And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

“I think you’ll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design,” he said, adding that a larger cardiovascular outcome trial is now being planned. 

“The regulatory perspective is that LDL is a pretty trusted surrogate ... but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be,” Dr. Nicholls noted.  

Dr. Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

“The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects,” he said.  

“The next agent, dalcetrapib (Roche), raised HDL but didn’t move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up – up to 5 years – to see a benefit,” he noted.  

Dr. Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

“Oxford academic researchers decided to continue follow-up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors,” Dr. Kastelein said.   

He pointed out that obicetrapib is much more potent than anacetrapib. “Obicetrapib reduces LDL by 50% at just a 10-mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction.”
 

Could HDL increase be beneficial after all?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Dr. Kastelein noted.

“We know that statins can increase risk of developing type 2 diabetes, and post hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect,” he said. “We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL.”

Commenting on the current data, Steven Nissen, MD, of Cleveland Clinic, said: “The results are truly impressive – a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

“Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high,” he added.

Dr. Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. “I have encouraged this company to develop this very promising drug,” he said.

The current study was funded by New Amsterdam Pharma. Dr. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Kastelein is chief scientific officer of New Amsterdam Pharma.  

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

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

mzoler@mdedge.com

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

mzoler@mdedge.com

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

mzoler@mdedge.com

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

In a randomized controlled trial of close to 1,000 Ugandan children and youth with latent rheumatic heart disease (RHD), those who received monthly injections of penicillin G benzathine for 2 years had less disease progression than those who did not.

RHD, a valvular heart disease caused by rheumatic fever that develops after untreated Streptococcus pyogenes infection, is the most common acquired cardiovascular disease among children and young adults.

“It is clear that secondary antibiotic prophylaxis can improve outcomes for children with echo-detected rheumatic RHD,” co–lead author of the study, Andrea Z. Beaton, MD, said in an interview.

“There is huge potential here, but we are not quite ready to advocate for this strategy as a broad public health approach,” said Dr. Beaton, a pediatric cardiologist at Cincinnati Children’s Hospital Medical Center.

“We need to understand more the practical translation of this strategy to a low-resourced public health system at scale, improve [penicillin G benzathine] supply, and improve community and health care worker knowledge of this disease.”

Dr. Beaton presented the findings at the American Heart Association scientific sessions, and the study was simultaneously published in the New England Journal of Medicine on Nov. 13, 2021.

The GOAL trial – or the Gwoko Adunu pa Lutino trial, meaning “protect the heart of a child” – screened 102,200 children and adolescents aged 5-17. Of these kids and teenagers, 926 (0.9%) were diagnosed with latent RHD based on a confirmatory electrocardiogram.

“For now, I would say, if you are screening, then kids found to have latent RHD should be put on prophylaxis,” Dr. Beaton said.

“I think this is also a powerful call for more research [severely lacking in RHD],” to improve risk stratification, determine how to implement screening and prophylaxis programs, and develop new and better approaches for RHD prevention and care.

“This essential trial partially addresses the clinical equipoise that has developed regarding penicillin administration in latent RHD,” said Gabriele Rossi, MD, MPH, who was not involved with this research.

It showed that, out of the final 818 participants included in the modified intention-to-treat analysis, a total of 3 (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, compared with 33 participants (8.2%) in the control group (risk difference, −7.5 percentage points; 95% confidence interval, −10.2 to −4.7; P < .001).

“This is a significant difference,” Dr. Rossi, from Médecins Sans Frontières (Doctors Without Borders), Brussels, said in an interview, noting that, however, it is not known what happens after 2 years.

The authors estimated that 13 children or adolescents with latent rheumatic heart disease would need to be treated to prevent disease progression in one person at 2 years, which is “acceptable,” he continued.

However, “screening, diagnosis, clinical follow-up, treatment, and program management [would] require substantial strengthening of health systems and the workforce, which is still far from being realizable in many African and low-income country settings,” Dr. Rossi noted.

Related study in Italy

Previously, Dr. Rossi and colleagues conducted a trial, published in 2019, that showed it was feasible to screen for asymptomatic RHD among refugee/migrant children and youths in Rome.

From February 2016 to January 2018, they screened more than 650 refugee/migrant children and adolescents who were younger than 18. They came largely from Egypt (65%) but also from 22 other countries and were often unaccompanied or with just one parent.

The number needed to screen was 5 to identify a child/youth with borderline RHD and around 40 to identify a child/youth with definite RHD.

Dr. Rossi noted that local resurgences of RHD have also been also documented in high-income countries such as Europe, Australia, New Zealand, Canada, and the United States, often among disadvantaged indigenous people, as described in a 2018 Letter to the Editor in the New England Journal of Medicine.

Dr. Beaton noted that a review of 10-year data (2008-2018) from 22 U.S. pediatric institutions showed that in the United States the prevalence of RHD “is higher in immigrant children from RHD endemic areas, but because of total numbers, more RHD cases than not are domestic.” Children living in more deprived communities are at risk for more severe disease, and the burden in U.S. territories is also quite high.
 

Screening and secondary prophylaxis

The aim of the current GOAL study was to evaluate if screening and treatment with penicillin G benzathine could detect and prevent progression of latent rheumatic heart disease in 5- to 17-year-olds living in Gulu, Uganda. The trial was conducted from July 2018 to October 2020.

“School education and community sensitization was done prior to the trial,” through radio shows or school-based education, Dr. Beaton explained. About 99% of the children/adolescents/families agreed to be screened.

The group has been conducting echo screening research in Uganda for 10 years, she noted. They have developed peer group and case manager strategies to aid participant retention, as they describe in an article about the study protocol.

The screening echocardiograms were interpreted by about 30 providers and four cardiologists reviewed confirmatory echocardiograms.

Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis).

Once children and adolescents have moderate/severe RHD, there is not much that can be done in lower- and middle-income countries, where surgery for this is uncommon, Dr. Beaton explained. Around 30% of children and adolescents with this condition who come to clinical attention in Uganda die within 9 months.
 

Further research

Dr. Beaton and colleagues have just started a trial to investigate the burden of RHD among Native American youth, which has not been studied since the 1970s.

They also have an ongoing study looking at the efficacy of a pragmatic, community-based sore throat program to prevent RHD.

“Unfortunately, this strategy has not worked well in low-to-middle income countries, for a variety of reasons so far,” Dr. Beaton noted, and the cost-effectiveness of this preventive strategy is questionable.

The trial was supported by the Thrasher Research Fund, Gift of Life International, Children’s National Hospital Foundation (Zachary Blumenfeld Fund and Race for Every Child [Team Jocelyn]), the Elias-Ginsburg Family, Wiley Rein, Philips Foundation, AT&T Foundation, Heart Healers International, the Karp Family Foundation, Huron Philanthropies, and the Cincinnati Children’s Hospital Heart Institute Research Core. Dr. Beaton and Dr. Rossi disclosed no relevant financial relationships.

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

In a randomized controlled trial of close to 1,000 Ugandan children and youth with latent rheumatic heart disease (RHD), those who received monthly injections of penicillin G benzathine for 2 years had less disease progression than those who did not.

RHD, a valvular heart disease caused by rheumatic fever that develops after untreated Streptococcus pyogenes infection, is the most common acquired cardiovascular disease among children and young adults.

“It is clear that secondary antibiotic prophylaxis can improve outcomes for children with echo-detected rheumatic RHD,” co–lead author of the study, Andrea Z. Beaton, MD, said in an interview.

“There is huge potential here, but we are not quite ready to advocate for this strategy as a broad public health approach,” said Dr. Beaton, a pediatric cardiologist at Cincinnati Children’s Hospital Medical Center.

“We need to understand more the practical translation of this strategy to a low-resourced public health system at scale, improve [penicillin G benzathine] supply, and improve community and health care worker knowledge of this disease.”

Dr. Beaton presented the findings at the American Heart Association scientific sessions, and the study was simultaneously published in the New England Journal of Medicine on Nov. 13, 2021.

The GOAL trial – or the Gwoko Adunu pa Lutino trial, meaning “protect the heart of a child” – screened 102,200 children and adolescents aged 5-17. Of these kids and teenagers, 926 (0.9%) were diagnosed with latent RHD based on a confirmatory electrocardiogram.

“For now, I would say, if you are screening, then kids found to have latent RHD should be put on prophylaxis,” Dr. Beaton said.

“I think this is also a powerful call for more research [severely lacking in RHD],” to improve risk stratification, determine how to implement screening and prophylaxis programs, and develop new and better approaches for RHD prevention and care.

“This essential trial partially addresses the clinical equipoise that has developed regarding penicillin administration in latent RHD,” said Gabriele Rossi, MD, MPH, who was not involved with this research.

It showed that, out of the final 818 participants included in the modified intention-to-treat analysis, a total of 3 (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, compared with 33 participants (8.2%) in the control group (risk difference, −7.5 percentage points; 95% confidence interval, −10.2 to −4.7; P < .001).

“This is a significant difference,” Dr. Rossi, from Médecins Sans Frontières (Doctors Without Borders), Brussels, said in an interview, noting that, however, it is not known what happens after 2 years.

The authors estimated that 13 children or adolescents with latent rheumatic heart disease would need to be treated to prevent disease progression in one person at 2 years, which is “acceptable,” he continued.

However, “screening, diagnosis, clinical follow-up, treatment, and program management [would] require substantial strengthening of health systems and the workforce, which is still far from being realizable in many African and low-income country settings,” Dr. Rossi noted.

Related study in Italy

Previously, Dr. Rossi and colleagues conducted a trial, published in 2019, that showed it was feasible to screen for asymptomatic RHD among refugee/migrant children and youths in Rome.

From February 2016 to January 2018, they screened more than 650 refugee/migrant children and adolescents who were younger than 18. They came largely from Egypt (65%) but also from 22 other countries and were often unaccompanied or with just one parent.

The number needed to screen was 5 to identify a child/youth with borderline RHD and around 40 to identify a child/youth with definite RHD.

Dr. Rossi noted that local resurgences of RHD have also been also documented in high-income countries such as Europe, Australia, New Zealand, Canada, and the United States, often among disadvantaged indigenous people, as described in a 2018 Letter to the Editor in the New England Journal of Medicine.

Dr. Beaton noted that a review of 10-year data (2008-2018) from 22 U.S. pediatric institutions showed that in the United States the prevalence of RHD “is higher in immigrant children from RHD endemic areas, but because of total numbers, more RHD cases than not are domestic.” Children living in more deprived communities are at risk for more severe disease, and the burden in U.S. territories is also quite high.
 

Screening and secondary prophylaxis

The aim of the current GOAL study was to evaluate if screening and treatment with penicillin G benzathine could detect and prevent progression of latent rheumatic heart disease in 5- to 17-year-olds living in Gulu, Uganda. The trial was conducted from July 2018 to October 2020.

“School education and community sensitization was done prior to the trial,” through radio shows or school-based education, Dr. Beaton explained. About 99% of the children/adolescents/families agreed to be screened.

The group has been conducting echo screening research in Uganda for 10 years, she noted. They have developed peer group and case manager strategies to aid participant retention, as they describe in an article about the study protocol.

The screening echocardiograms were interpreted by about 30 providers and four cardiologists reviewed confirmatory echocardiograms.

Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis).

Once children and adolescents have moderate/severe RHD, there is not much that can be done in lower- and middle-income countries, where surgery for this is uncommon, Dr. Beaton explained. Around 30% of children and adolescents with this condition who come to clinical attention in Uganda die within 9 months.
 

Further research

Dr. Beaton and colleagues have just started a trial to investigate the burden of RHD among Native American youth, which has not been studied since the 1970s.

They also have an ongoing study looking at the efficacy of a pragmatic, community-based sore throat program to prevent RHD.

“Unfortunately, this strategy has not worked well in low-to-middle income countries, for a variety of reasons so far,” Dr. Beaton noted, and the cost-effectiveness of this preventive strategy is questionable.

The trial was supported by the Thrasher Research Fund, Gift of Life International, Children’s National Hospital Foundation (Zachary Blumenfeld Fund and Race for Every Child [Team Jocelyn]), the Elias-Ginsburg Family, Wiley Rein, Philips Foundation, AT&T Foundation, Heart Healers International, the Karp Family Foundation, Huron Philanthropies, and the Cincinnati Children’s Hospital Heart Institute Research Core. Dr. Beaton and Dr. Rossi disclosed no relevant financial relationships.

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

In a randomized controlled trial of close to 1,000 Ugandan children and youth with latent rheumatic heart disease (RHD), those who received monthly injections of penicillin G benzathine for 2 years had less disease progression than those who did not.

RHD, a valvular heart disease caused by rheumatic fever that develops after untreated Streptococcus pyogenes infection, is the most common acquired cardiovascular disease among children and young adults.

“It is clear that secondary antibiotic prophylaxis can improve outcomes for children with echo-detected rheumatic RHD,” co–lead author of the study, Andrea Z. Beaton, MD, said in an interview.

“There is huge potential here, but we are not quite ready to advocate for this strategy as a broad public health approach,” said Dr. Beaton, a pediatric cardiologist at Cincinnati Children’s Hospital Medical Center.

“We need to understand more the practical translation of this strategy to a low-resourced public health system at scale, improve [penicillin G benzathine] supply, and improve community and health care worker knowledge of this disease.”

Dr. Beaton presented the findings at the American Heart Association scientific sessions, and the study was simultaneously published in the New England Journal of Medicine on Nov. 13, 2021.

The GOAL trial – or the Gwoko Adunu pa Lutino trial, meaning “protect the heart of a child” – screened 102,200 children and adolescents aged 5-17. Of these kids and teenagers, 926 (0.9%) were diagnosed with latent RHD based on a confirmatory electrocardiogram.

“For now, I would say, if you are screening, then kids found to have latent RHD should be put on prophylaxis,” Dr. Beaton said.

“I think this is also a powerful call for more research [severely lacking in RHD],” to improve risk stratification, determine how to implement screening and prophylaxis programs, and develop new and better approaches for RHD prevention and care.

“This essential trial partially addresses the clinical equipoise that has developed regarding penicillin administration in latent RHD,” said Gabriele Rossi, MD, MPH, who was not involved with this research.

It showed that, out of the final 818 participants included in the modified intention-to-treat analysis, a total of 3 (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, compared with 33 participants (8.2%) in the control group (risk difference, −7.5 percentage points; 95% confidence interval, −10.2 to −4.7; P < .001).

“This is a significant difference,” Dr. Rossi, from Médecins Sans Frontières (Doctors Without Borders), Brussels, said in an interview, noting that, however, it is not known what happens after 2 years.

The authors estimated that 13 children or adolescents with latent rheumatic heart disease would need to be treated to prevent disease progression in one person at 2 years, which is “acceptable,” he continued.

However, “screening, diagnosis, clinical follow-up, treatment, and program management [would] require substantial strengthening of health systems and the workforce, which is still far from being realizable in many African and low-income country settings,” Dr. Rossi noted.

Related study in Italy

Previously, Dr. Rossi and colleagues conducted a trial, published in 2019, that showed it was feasible to screen for asymptomatic RHD among refugee/migrant children and youths in Rome.

From February 2016 to January 2018, they screened more than 650 refugee/migrant children and adolescents who were younger than 18. They came largely from Egypt (65%) but also from 22 other countries and were often unaccompanied or with just one parent.

The number needed to screen was 5 to identify a child/youth with borderline RHD and around 40 to identify a child/youth with definite RHD.

Dr. Rossi noted that local resurgences of RHD have also been also documented in high-income countries such as Europe, Australia, New Zealand, Canada, and the United States, often among disadvantaged indigenous people, as described in a 2018 Letter to the Editor in the New England Journal of Medicine.

Dr. Beaton noted that a review of 10-year data (2008-2018) from 22 U.S. pediatric institutions showed that in the United States the prevalence of RHD “is higher in immigrant children from RHD endemic areas, but because of total numbers, more RHD cases than not are domestic.” Children living in more deprived communities are at risk for more severe disease, and the burden in U.S. territories is also quite high.
 

Screening and secondary prophylaxis

The aim of the current GOAL study was to evaluate if screening and treatment with penicillin G benzathine could detect and prevent progression of latent rheumatic heart disease in 5- to 17-year-olds living in Gulu, Uganda. The trial was conducted from July 2018 to October 2020.

“School education and community sensitization was done prior to the trial,” through radio shows or school-based education, Dr. Beaton explained. About 99% of the children/adolescents/families agreed to be screened.

The group has been conducting echo screening research in Uganda for 10 years, she noted. They have developed peer group and case manager strategies to aid participant retention, as they describe in an article about the study protocol.

The screening echocardiograms were interpreted by about 30 providers and four cardiologists reviewed confirmatory echocardiograms.

Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis).

Once children and adolescents have moderate/severe RHD, there is not much that can be done in lower- and middle-income countries, where surgery for this is uncommon, Dr. Beaton explained. Around 30% of children and adolescents with this condition who come to clinical attention in Uganda die within 9 months.
 

Further research

Dr. Beaton and colleagues have just started a trial to investigate the burden of RHD among Native American youth, which has not been studied since the 1970s.

They also have an ongoing study looking at the efficacy of a pragmatic, community-based sore throat program to prevent RHD.

“Unfortunately, this strategy has not worked well in low-to-middle income countries, for a variety of reasons so far,” Dr. Beaton noted, and the cost-effectiveness of this preventive strategy is questionable.

The trial was supported by the Thrasher Research Fund, Gift of Life International, Children’s National Hospital Foundation (Zachary Blumenfeld Fund and Race for Every Child [Team Jocelyn]), the Elias-Ginsburg Family, Wiley Rein, Philips Foundation, AT&T Foundation, Heart Healers International, the Karp Family Foundation, Huron Philanthropies, and the Cincinnati Children’s Hospital Heart Institute Research Core. Dr. Beaton and Dr. Rossi disclosed no relevant financial relationships.

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

In response to a 911 alert or page, firefighters’ systolic and diastolic blood pressure surges and their heart rate accelerates, with a similar response whether the call is for a fire or medical emergency, a small study suggests.

On average, the 41 firefighters monitored in the study, who were middle-aged and overweight, had a 9% increase in systolic blood pressure when called to a fire, a 9% increase in diastolic blood pressure when called to a medical emergency, and a 16% increase in heart rate for both types of calls.

Senior study author Deborah Feairheller, PhD, presented these results at the virtual American Heart Association scientific sessions.

Firefighters have a higher prevalence of cardiovascular disease (CVD) than that of the general population, explained Dr. Feairheller, director of the Hypertension and Endothelial Function with Aerobic and Resistance Training (HEART) Lab and clinical associate professor of kinesiology at the University of New Hampshire, Durham.

More than 50% of firefighter deaths in the line of duty are from CVD, she noted. Moreover, almost 75% of firefighters have hypertension and fewer than 25% have it under control.

The study findings show that all emergency and first responders “should know what their typical blood pressure level is and be aware of how it fluctuates,” Dr. Feairheller said in a press release from the AHA. “Most important, if they have high blood pressure, they should make sure it is well controlled,” she said.

“I really hope that fire departments everywhere see these data, rise to the occasion, and advocate for BP awareness in their crews,” Dr. Feairheller, a volunteer firefighter, said in an interview.

“I do think this has value to any occupation that wears a pager,” she added. “Clinicians, physicians, other emergency responders, all of those occupations are stressful and could place people at risk if they have undiagnosed or uncontrolled hypertension.”

Invited to comment, Comilla Sasson, MD, PhD, an emergency department physician who was not involved with this research, said in an interview that she saw parallels between stress experienced by firefighters and, for example, emergency department physicians.

The transient increases in BP, both systolic and diastolic, along with the heart rate are likely due to the body’s natural fight or flight response to an emergency call, including increases in epinephrine and cortisol, said Dr. Sasson, vice president of science and innovation for emergency cardiovascular care at the American Heart Association.

“The thing that is most interesting to me,” said Dr. Sasson, who can be subject to a series of high-stress situations on a shift, such as multiple trauma victims, a stroke victim, or a person in cardiac arrest, is “what is the cumulative impact of this over time?”

She said she wonders if “having to be ‘ready to go’ at any time, along with disruptions in sleep/wake schedules, and poorer eating and working-out habits when you are on shift, has long-term sequelae on the body.”

Stress-related surges in blood pressure “could be a reason for worse health outcomes in this group,” Dr. Sasson said, adding that this needs to be investigated further.
 

Firefighters with high normal BP, high BMI

Dr. Feairheller and colleagues recruited 41 volunteer and employee firefighters from suburban Philadelphia and Dover, N.H.

On average, the 37 men and 4 women had a mean age of 41 years, had been working as firefighters for 16.9 years, and had a mean body mass index of 30.3 kg/m².

They wore ambulatory blood pressure monitors during an on-call work shift for at least 12 consecutive hours.

In addition to the automatic readings, the participants were instructed to prompt the machine to take a reading whenever a pager or emergency call sounded or when they felt they were entering a stressful situation.

Over the 12-hour shift, on average, participants had a blood pressure of 131/79.3 mm Hg and a heart rate of 75.7 bpm.

When they were alerted go to a fire, their blood pressure surged by 19.2/10.5 mm Hg, and their heart rate rose to 85.5 bpm.

Similarly, when they were alerted to go to a medical emergency, their blood pressure jumped up by 18.7/16.5 mm Hg and their heart rate climbed to 90.5 bpm.

The surges in blood pressure and heart rate were similar when participants were riding in the fire truck to a call or when the call turned out to be a false alarm.
 

What can be done?

“If we can increase awareness and identify specific risk factors in firefighters,” Dr. Feairheller said, this could “save a life of someone who spends their day saving lives and property.”

To start, “regular, in-station or home BP monitoring should be encouraged,” she said. “Firefighters should start to track their BP levels in the morning, at night, at work. Being a volunteer firefighter myself, I know the stress and anxiety and sadness and heavy work that comes with the job,” she said. “I want to be able to do what I can to help make the crews healthier.”

Dr. Sasson suggested that ways to increase awareness and improve the health of firefighters might include “counseling, appropriate breaks, possibly food service/delivery to provide better nutritional options, built-in time for exercise (gym or cardio equipment on site), and discussions about how stress can impact the body over time.”

It is important to advocate for better mental health care, because people may have PTSD, depression, substance abuse, or other mental health conditions brought on by their stressful jobs, she said.

“Also, it would be interesting to know what is the current state of health monitoring (both physical, mental, and emotional) that occurs for firefighters,” she said.

The American Heart Association funded the study. The authors and Dr. Sasson report no disclosures.

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

In response to a 911 alert or page, firefighters’ systolic and diastolic blood pressure surges and their heart rate accelerates, with a similar response whether the call is for a fire or medical emergency, a small study suggests.

On average, the 41 firefighters monitored in the study, who were middle-aged and overweight, had a 9% increase in systolic blood pressure when called to a fire, a 9% increase in diastolic blood pressure when called to a medical emergency, and a 16% increase in heart rate for both types of calls.

Senior study author Deborah Feairheller, PhD, presented these results at the virtual American Heart Association scientific sessions.

Firefighters have a higher prevalence of cardiovascular disease (CVD) than that of the general population, explained Dr. Feairheller, director of the Hypertension and Endothelial Function with Aerobic and Resistance Training (HEART) Lab and clinical associate professor of kinesiology at the University of New Hampshire, Durham.

More than 50% of firefighter deaths in the line of duty are from CVD, she noted. Moreover, almost 75% of firefighters have hypertension and fewer than 25% have it under control.

The study findings show that all emergency and first responders “should know what their typical blood pressure level is and be aware of how it fluctuates,” Dr. Feairheller said in a press release from the AHA. “Most important, if they have high blood pressure, they should make sure it is well controlled,” she said.

“I really hope that fire departments everywhere see these data, rise to the occasion, and advocate for BP awareness in their crews,” Dr. Feairheller, a volunteer firefighter, said in an interview.

“I do think this has value to any occupation that wears a pager,” she added. “Clinicians, physicians, other emergency responders, all of those occupations are stressful and could place people at risk if they have undiagnosed or uncontrolled hypertension.”

Invited to comment, Comilla Sasson, MD, PhD, an emergency department physician who was not involved with this research, said in an interview that she saw parallels between stress experienced by firefighters and, for example, emergency department physicians.

The transient increases in BP, both systolic and diastolic, along with the heart rate are likely due to the body’s natural fight or flight response to an emergency call, including increases in epinephrine and cortisol, said Dr. Sasson, vice president of science and innovation for emergency cardiovascular care at the American Heart Association.

“The thing that is most interesting to me,” said Dr. Sasson, who can be subject to a series of high-stress situations on a shift, such as multiple trauma victims, a stroke victim, or a person in cardiac arrest, is “what is the cumulative impact of this over time?”

She said she wonders if “having to be ‘ready to go’ at any time, along with disruptions in sleep/wake schedules, and poorer eating and working-out habits when you are on shift, has long-term sequelae on the body.”

Stress-related surges in blood pressure “could be a reason for worse health outcomes in this group,” Dr. Sasson said, adding that this needs to be investigated further.
 

Firefighters with high normal BP, high BMI

Dr. Feairheller and colleagues recruited 41 volunteer and employee firefighters from suburban Philadelphia and Dover, N.H.

On average, the 37 men and 4 women had a mean age of 41 years, had been working as firefighters for 16.9 years, and had a mean body mass index of 30.3 kg/m².

They wore ambulatory blood pressure monitors during an on-call work shift for at least 12 consecutive hours.

In addition to the automatic readings, the participants were instructed to prompt the machine to take a reading whenever a pager or emergency call sounded or when they felt they were entering a stressful situation.

Over the 12-hour shift, on average, participants had a blood pressure of 131/79.3 mm Hg and a heart rate of 75.7 bpm.

When they were alerted go to a fire, their blood pressure surged by 19.2/10.5 mm Hg, and their heart rate rose to 85.5 bpm.

Similarly, when they were alerted to go to a medical emergency, their blood pressure jumped up by 18.7/16.5 mm Hg and their heart rate climbed to 90.5 bpm.

The surges in blood pressure and heart rate were similar when participants were riding in the fire truck to a call or when the call turned out to be a false alarm.
 

What can be done?

“If we can increase awareness and identify specific risk factors in firefighters,” Dr. Feairheller said, this could “save a life of someone who spends their day saving lives and property.”

To start, “regular, in-station or home BP monitoring should be encouraged,” she said. “Firefighters should start to track their BP levels in the morning, at night, at work. Being a volunteer firefighter myself, I know the stress and anxiety and sadness and heavy work that comes with the job,” she said. “I want to be able to do what I can to help make the crews healthier.”

Dr. Sasson suggested that ways to increase awareness and improve the health of firefighters might include “counseling, appropriate breaks, possibly food service/delivery to provide better nutritional options, built-in time for exercise (gym or cardio equipment on site), and discussions about how stress can impact the body over time.”

It is important to advocate for better mental health care, because people may have PTSD, depression, substance abuse, or other mental health conditions brought on by their stressful jobs, she said.

“Also, it would be interesting to know what is the current state of health monitoring (both physical, mental, and emotional) that occurs for firefighters,” she said.

The American Heart Association funded the study. The authors and Dr. Sasson report no disclosures.

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

In response to a 911 alert or page, firefighters’ systolic and diastolic blood pressure surges and their heart rate accelerates, with a similar response whether the call is for a fire or medical emergency, a small study suggests.

On average, the 41 firefighters monitored in the study, who were middle-aged and overweight, had a 9% increase in systolic blood pressure when called to a fire, a 9% increase in diastolic blood pressure when called to a medical emergency, and a 16% increase in heart rate for both types of calls.

Senior study author Deborah Feairheller, PhD, presented these results at the virtual American Heart Association scientific sessions.

Firefighters have a higher prevalence of cardiovascular disease (CVD) than that of the general population, explained Dr. Feairheller, director of the Hypertension and Endothelial Function with Aerobic and Resistance Training (HEART) Lab and clinical associate professor of kinesiology at the University of New Hampshire, Durham.

More than 50% of firefighter deaths in the line of duty are from CVD, she noted. Moreover, almost 75% of firefighters have hypertension and fewer than 25% have it under control.

The study findings show that all emergency and first responders “should know what their typical blood pressure level is and be aware of how it fluctuates,” Dr. Feairheller said in a press release from the AHA. “Most important, if they have high blood pressure, they should make sure it is well controlled,” she said.

“I really hope that fire departments everywhere see these data, rise to the occasion, and advocate for BP awareness in their crews,” Dr. Feairheller, a volunteer firefighter, said in an interview.

“I do think this has value to any occupation that wears a pager,” she added. “Clinicians, physicians, other emergency responders, all of those occupations are stressful and could place people at risk if they have undiagnosed or uncontrolled hypertension.”

Invited to comment, Comilla Sasson, MD, PhD, an emergency department physician who was not involved with this research, said in an interview that she saw parallels between stress experienced by firefighters and, for example, emergency department physicians.

The transient increases in BP, both systolic and diastolic, along with the heart rate are likely due to the body’s natural fight or flight response to an emergency call, including increases in epinephrine and cortisol, said Dr. Sasson, vice president of science and innovation for emergency cardiovascular care at the American Heart Association.

“The thing that is most interesting to me,” said Dr. Sasson, who can be subject to a series of high-stress situations on a shift, such as multiple trauma victims, a stroke victim, or a person in cardiac arrest, is “what is the cumulative impact of this over time?”

She said she wonders if “having to be ‘ready to go’ at any time, along with disruptions in sleep/wake schedules, and poorer eating and working-out habits when you are on shift, has long-term sequelae on the body.”

Stress-related surges in blood pressure “could be a reason for worse health outcomes in this group,” Dr. Sasson said, adding that this needs to be investigated further.
 

Firefighters with high normal BP, high BMI

Dr. Feairheller and colleagues recruited 41 volunteer and employee firefighters from suburban Philadelphia and Dover, N.H.

On average, the 37 men and 4 women had a mean age of 41 years, had been working as firefighters for 16.9 years, and had a mean body mass index of 30.3 kg/m².

They wore ambulatory blood pressure monitors during an on-call work shift for at least 12 consecutive hours.

In addition to the automatic readings, the participants were instructed to prompt the machine to take a reading whenever a pager or emergency call sounded or when they felt they were entering a stressful situation.

Over the 12-hour shift, on average, participants had a blood pressure of 131/79.3 mm Hg and a heart rate of 75.7 bpm.

When they were alerted go to a fire, their blood pressure surged by 19.2/10.5 mm Hg, and their heart rate rose to 85.5 bpm.

Similarly, when they were alerted to go to a medical emergency, their blood pressure jumped up by 18.7/16.5 mm Hg and their heart rate climbed to 90.5 bpm.

The surges in blood pressure and heart rate were similar when participants were riding in the fire truck to a call or when the call turned out to be a false alarm.
 

What can be done?

“If we can increase awareness and identify specific risk factors in firefighters,” Dr. Feairheller said, this could “save a life of someone who spends their day saving lives and property.”

To start, “regular, in-station or home BP monitoring should be encouraged,” she said. “Firefighters should start to track their BP levels in the morning, at night, at work. Being a volunteer firefighter myself, I know the stress and anxiety and sadness and heavy work that comes with the job,” she said. “I want to be able to do what I can to help make the crews healthier.”

Dr. Sasson suggested that ways to increase awareness and improve the health of firefighters might include “counseling, appropriate breaks, possibly food service/delivery to provide better nutritional options, built-in time for exercise (gym or cardio equipment on site), and discussions about how stress can impact the body over time.”

It is important to advocate for better mental health care, because people may have PTSD, depression, substance abuse, or other mental health conditions brought on by their stressful jobs, she said.

“Also, it would be interesting to know what is the current state of health monitoring (both physical, mental, and emotional) that occurs for firefighters,” she said.

The American Heart Association funded the study. The authors and Dr. Sasson report no disclosures.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

mzoler@mdedge.com

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

mzoler@mdedge.com

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

mzoler@mdedge.com

The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.

“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.

The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.

Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.

REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
 

Platelet function assays test reversal

On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.

On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.

The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
 

Hemostasis documented in all but one patient

Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.

Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.

There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.

While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.

The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
 

No good current options for reversal

Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.

“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.

Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.

“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.

For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”

Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.

Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
 

The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.

“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.

The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.

Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.

REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
 

Platelet function assays test reversal

On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.

On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.

The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
 

Hemostasis documented in all but one patient

Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.

Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.

There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.

While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.

The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
 

No good current options for reversal

Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.

“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.

Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.

“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.

For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”

Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.

Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
 

The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.

“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.

The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.

Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.

REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
 

Platelet function assays test reversal

On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.

On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.

The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
 

Hemostasis documented in all but one patient

Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.

Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.

There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.

While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.

The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
 

No good current options for reversal

Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.

“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.

Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.

“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.

For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”

Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.

Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
 

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

mzoler@mdedge.com

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

mzoler@mdedge.com

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

mzoler@mdedge.com