Cardiology News

The timing of complete revascularization (CR) in patients with acute ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) may make little clinical difference.

The conclusion comes from a randomized outcomes trial of 840 patients that compared prompt same-session CR with a staged procedure carried out weeks later.

That CR is a worthy goal in such cases is largely settled, unlike the question of when to pursue revascularization of nonculprit lesions for best results. So the timing varies in practice, often depending on the patient’s clinical stability, risk status, or practical issues like cath lab resources or personnel.

The new trial, MULTISTARS-AMI, supports that kind of flexibility as safe in practice. Immediate, same-session CR led to a 48% drop in risk for a broad composite primary endpoint at 1 year, compared with staged CR an average of 37 days later. The finding was significant for noninferiority in the study’s primary analysis and secondarily, was significant for superiority (P < .001 in both cases).

The composite endpoint included death from any cause, MI, stroke, unplanned ischemia-driven revascularization, or heart failure (HF) hospitalization.

CR’s immediate effect on outcomes was numerically pronounced, but because it was prespecified as a noninferiority trial, MULTISTARS-AMI could show only that the strategy is comparable to staged CR, emphasized Barbara E. Stähli, MD, MPH, MBA, at a press conference.

Still, it appears to be the first trial of its kind to show that operators and patients can safely choose either percutaneous coronary intervention (PCI) approach and attain similar outcomes, said Dr. Stähli, University Hospital Zurich, MULTISTARS-AMI’s principal investigator.

Not only were the two approaches similar with respect to safety, she noted, but immediate CR seemed to require less use of contrast agent and fluoroscopy. “And you have only one procedure, so there’s only one arterial puncture.”

Dr. Stähli formally presented MULTISTARS-AMI at the annual congress of the European Society of Cardiology, held in Amsterdam. She is also lead author on its publication in the New England Journal of Medicine.

After her presentation, invited discussant Robert A. Byrne, PhD, MD, MB, BCh, said that the trial’s central message is that STEMI patients with MVD having primary PCI “should undergo complete revascularization within the first 45 days, with the timing of the non–infarct-related artery procedure individualized according to clinical risk and logistical considerations.”

Still, the trial “provides evidence, but not strong evidence, of benefits with routine immediate PCI during the index procedure as compared with staged outpatient PCI,” said Dr. Byrne, Mater Private Hospital and RCSI University of Medicine and Health Sciences, Dublin.

MULTISTARS-AMI randomly assigned patients at 37 European sites to undergo same-session CR (418 patients) or CR staged 19-45 days later (422 patients).

Rates for the primary endpoint at 1 year were 8.5% and 16.3%, respectively, for a risk ratio of 0.52 (95% confidence interval, 0.38-0.72). The difference was driven by fewer instances of nonfatal MI, 0.36 (95% CI, 0.16-0.80), and unplanned ischemia-driven revascularization, 0.42 (95% CI, 0.24-0.74), in the immediate-CR group.
 

The wee hours

Sunil V. Rao, MD, director of interventional cardiology at NYU Langone Health System, New York, said that, in general at his center, patients who are stable with a good primary PCI outcome and whose lesions aren’t very high risk are often discharged to return later for the staged CR procedure.

But after the new insights from MULTISTARS-AMI, Dr. Rao, who is not connected to the study, said in an interview that immediate same-session CR is indeed likely preferable to staged CR performed weeks later.

Same-session CR, however, may not always be practical or wise, he observed. For example, some patients with STEMI can be pretty sick with MVD that involves very complex lesions that might be better handled later.

“The wee hours of the night may not be the best time to tackle such complex lesions,” Dr. Rao observed. If confronted with, for example, a bifurcation that requires a complex procedure, “2 o’clock in the morning is probably not the best time to address something like that.”

So the trial’s more realistic translational message, he proposed, may be to perform CR after the primary PCI but during the same hospitalization, “unless there are some real mitigating circumstances.” 

The trial was supported by Boston Scientific. Dr. Stähli had no disclosures. Dr. Byrne discloses research funding to his institution from Abbott Vascular, Translumina, Biosensors, and Boston Scientific. Dr. Rao had no relevant disclosures.

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

The timing of complete revascularization (CR) in patients with acute ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) may make little clinical difference.

The conclusion comes from a randomized outcomes trial of 840 patients that compared prompt same-session CR with a staged procedure carried out weeks later.

That CR is a worthy goal in such cases is largely settled, unlike the question of when to pursue revascularization of nonculprit lesions for best results. So the timing varies in practice, often depending on the patient’s clinical stability, risk status, or practical issues like cath lab resources or personnel.

The new trial, MULTISTARS-AMI, supports that kind of flexibility as safe in practice. Immediate, same-session CR led to a 48% drop in risk for a broad composite primary endpoint at 1 year, compared with staged CR an average of 37 days later. The finding was significant for noninferiority in the study’s primary analysis and secondarily, was significant for superiority (P < .001 in both cases).

The composite endpoint included death from any cause, MI, stroke, unplanned ischemia-driven revascularization, or heart failure (HF) hospitalization.

CR’s immediate effect on outcomes was numerically pronounced, but because it was prespecified as a noninferiority trial, MULTISTARS-AMI could show only that the strategy is comparable to staged CR, emphasized Barbara E. Stähli, MD, MPH, MBA, at a press conference.

Still, it appears to be the first trial of its kind to show that operators and patients can safely choose either percutaneous coronary intervention (PCI) approach and attain similar outcomes, said Dr. Stähli, University Hospital Zurich, MULTISTARS-AMI’s principal investigator.

Not only were the two approaches similar with respect to safety, she noted, but immediate CR seemed to require less use of contrast agent and fluoroscopy. “And you have only one procedure, so there’s only one arterial puncture.”

Dr. Stähli formally presented MULTISTARS-AMI at the annual congress of the European Society of Cardiology, held in Amsterdam. She is also lead author on its publication in the New England Journal of Medicine.

After her presentation, invited discussant Robert A. Byrne, PhD, MD, MB, BCh, said that the trial’s central message is that STEMI patients with MVD having primary PCI “should undergo complete revascularization within the first 45 days, with the timing of the non–infarct-related artery procedure individualized according to clinical risk and logistical considerations.”

Still, the trial “provides evidence, but not strong evidence, of benefits with routine immediate PCI during the index procedure as compared with staged outpatient PCI,” said Dr. Byrne, Mater Private Hospital and RCSI University of Medicine and Health Sciences, Dublin.

MULTISTARS-AMI randomly assigned patients at 37 European sites to undergo same-session CR (418 patients) or CR staged 19-45 days later (422 patients).

Rates for the primary endpoint at 1 year were 8.5% and 16.3%, respectively, for a risk ratio of 0.52 (95% confidence interval, 0.38-0.72). The difference was driven by fewer instances of nonfatal MI, 0.36 (95% CI, 0.16-0.80), and unplanned ischemia-driven revascularization, 0.42 (95% CI, 0.24-0.74), in the immediate-CR group.
 

The wee hours

Sunil V. Rao, MD, director of interventional cardiology at NYU Langone Health System, New York, said that, in general at his center, patients who are stable with a good primary PCI outcome and whose lesions aren’t very high risk are often discharged to return later for the staged CR procedure.

But after the new insights from MULTISTARS-AMI, Dr. Rao, who is not connected to the study, said in an interview that immediate same-session CR is indeed likely preferable to staged CR performed weeks later.

Same-session CR, however, may not always be practical or wise, he observed. For example, some patients with STEMI can be pretty sick with MVD that involves very complex lesions that might be better handled later.

“The wee hours of the night may not be the best time to tackle such complex lesions,” Dr. Rao observed. If confronted with, for example, a bifurcation that requires a complex procedure, “2 o’clock in the morning is probably not the best time to address something like that.”

So the trial’s more realistic translational message, he proposed, may be to perform CR after the primary PCI but during the same hospitalization, “unless there are some real mitigating circumstances.” 

The trial was supported by Boston Scientific. Dr. Stähli had no disclosures. Dr. Byrne discloses research funding to his institution from Abbott Vascular, Translumina, Biosensors, and Boston Scientific. Dr. Rao had no relevant disclosures.

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

The timing of complete revascularization (CR) in patients with acute ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) may make little clinical difference.

The conclusion comes from a randomized outcomes trial of 840 patients that compared prompt same-session CR with a staged procedure carried out weeks later.

That CR is a worthy goal in such cases is largely settled, unlike the question of when to pursue revascularization of nonculprit lesions for best results. So the timing varies in practice, often depending on the patient’s clinical stability, risk status, or practical issues like cath lab resources or personnel.

The new trial, MULTISTARS-AMI, supports that kind of flexibility as safe in practice. Immediate, same-session CR led to a 48% drop in risk for a broad composite primary endpoint at 1 year, compared with staged CR an average of 37 days later. The finding was significant for noninferiority in the study’s primary analysis and secondarily, was significant for superiority (P < .001 in both cases).

The composite endpoint included death from any cause, MI, stroke, unplanned ischemia-driven revascularization, or heart failure (HF) hospitalization.

CR’s immediate effect on outcomes was numerically pronounced, but because it was prespecified as a noninferiority trial, MULTISTARS-AMI could show only that the strategy is comparable to staged CR, emphasized Barbara E. Stähli, MD, MPH, MBA, at a press conference.

Still, it appears to be the first trial of its kind to show that operators and patients can safely choose either percutaneous coronary intervention (PCI) approach and attain similar outcomes, said Dr. Stähli, University Hospital Zurich, MULTISTARS-AMI’s principal investigator.

Not only were the two approaches similar with respect to safety, she noted, but immediate CR seemed to require less use of contrast agent and fluoroscopy. “And you have only one procedure, so there’s only one arterial puncture.”

Dr. Stähli formally presented MULTISTARS-AMI at the annual congress of the European Society of Cardiology, held in Amsterdam. She is also lead author on its publication in the New England Journal of Medicine.

After her presentation, invited discussant Robert A. Byrne, PhD, MD, MB, BCh, said that the trial’s central message is that STEMI patients with MVD having primary PCI “should undergo complete revascularization within the first 45 days, with the timing of the non–infarct-related artery procedure individualized according to clinical risk and logistical considerations.”

Still, the trial “provides evidence, but not strong evidence, of benefits with routine immediate PCI during the index procedure as compared with staged outpatient PCI,” said Dr. Byrne, Mater Private Hospital and RCSI University of Medicine and Health Sciences, Dublin.

MULTISTARS-AMI randomly assigned patients at 37 European sites to undergo same-session CR (418 patients) or CR staged 19-45 days later (422 patients).

Rates for the primary endpoint at 1 year were 8.5% and 16.3%, respectively, for a risk ratio of 0.52 (95% confidence interval, 0.38-0.72). The difference was driven by fewer instances of nonfatal MI, 0.36 (95% CI, 0.16-0.80), and unplanned ischemia-driven revascularization, 0.42 (95% CI, 0.24-0.74), in the immediate-CR group.
 

The wee hours

Sunil V. Rao, MD, director of interventional cardiology at NYU Langone Health System, New York, said that, in general at his center, patients who are stable with a good primary PCI outcome and whose lesions aren’t very high risk are often discharged to return later for the staged CR procedure.

But after the new insights from MULTISTARS-AMI, Dr. Rao, who is not connected to the study, said in an interview that immediate same-session CR is indeed likely preferable to staged CR performed weeks later.

Same-session CR, however, may not always be practical or wise, he observed. For example, some patients with STEMI can be pretty sick with MVD that involves very complex lesions that might be better handled later.

“The wee hours of the night may not be the best time to tackle such complex lesions,” Dr. Rao observed. If confronted with, for example, a bifurcation that requires a complex procedure, “2 o’clock in the morning is probably not the best time to address something like that.”

So the trial’s more realistic translational message, he proposed, may be to perform CR after the primary PCI but during the same hospitalization, “unless there are some real mitigating circumstances.” 

The trial was supported by Boston Scientific. Dr. Stähli had no disclosures. Dr. Byrne discloses research funding to his institution from Abbott Vascular, Translumina, Biosensors, and Boston Scientific. Dr. Rao had no relevant disclosures.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – Systematic screening by primary care physicians for cardiovascular disease (CVD) in high-risk adults – those with type 2 diabetes, chronic obstructive pulmonary disease (COPD), or both – more than doubled the rate of incident CVD diagnosed, compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.

Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.

“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.

“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
 

A ‘very simple’ symptom questionnaire

The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.

The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.

The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.

About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.

The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.

The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
 

More than doubling the CVD diagnosis rate

The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.

The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.

An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.

RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.

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

AMSTERDAM – Systematic screening by primary care physicians for cardiovascular disease (CVD) in high-risk adults – those with type 2 diabetes, chronic obstructive pulmonary disease (COPD), or both – more than doubled the rate of incident CVD diagnosed, compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.

Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.

“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.

“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
 

A ‘very simple’ symptom questionnaire

The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.

The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.

The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.

About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.

The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.

The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
 

More than doubling the CVD diagnosis rate

The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.

The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.

An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.

RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.

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

AMSTERDAM – Systematic screening by primary care physicians for cardiovascular disease (CVD) in high-risk adults – those with type 2 diabetes, chronic obstructive pulmonary disease (COPD), or both – more than doubled the rate of incident CVD diagnosed, compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.

Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.

“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.

“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
 

A ‘very simple’ symptom questionnaire

The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.

The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.

The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.

About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.

The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.

The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
 

More than doubling the CVD diagnosis rate

The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.

The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.

An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.

RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.

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

People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.

The Biden administration on Aug. 29 revealed the first 10 drugs selected for direct Medicare price negotiations in accordance with a process mandated by the Inflation Reduction Act of 2022.

It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.

While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.

CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
 

• Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
• Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
• Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
• Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
• Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
• Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
• Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
• Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
• Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
• Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.

A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.

“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.

According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.

Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.

The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.

Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.

In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.

This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).

Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.

“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.

In addition, AARP issued a statement of its continued support for Medicare drug negotiations.

“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”

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

People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.

The Biden administration on Aug. 29 revealed the first 10 drugs selected for direct Medicare price negotiations in accordance with a process mandated by the Inflation Reduction Act of 2022.

It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.

While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.

CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
 

• Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
• Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
• Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
• Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
• Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
• Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
• Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
• Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
• Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
• Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.

A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.

“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.

According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.

Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.

The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.

Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.

In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.

This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).

Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.

“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.

In addition, AARP issued a statement of its continued support for Medicare drug negotiations.

“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”

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

People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.

The Biden administration on Aug. 29 revealed the first 10 drugs selected for direct Medicare price negotiations in accordance with a process mandated by the Inflation Reduction Act of 2022.

It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.

While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.

CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
 

• Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
• Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
• Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
• Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
• Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
• Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
• Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
• Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
• Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
• Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.

A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.

“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.

According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.

Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.

The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.

Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.

In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.

This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).

Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.

“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.

In addition, AARP issued a statement of its continued support for Medicare drug negotiations.

“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”

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

Catheter ablation had long taken atrial fibrillation (AF) rhythm control to the next level before clinical trials showed it could help keep AF patients with heart failure (HF) alive and out of the hospital.

But those trials didn’t include many patients with AF on top of advanced or even end-stage HF. Lacking much of an evidence base and often viewed as too sick to gain a lot from the procedure, patients with AF and advanced HF aren’t offered ablation very often.

Now a randomized trial suggests that, on the contrary, AF ablation may confer a similar benefit to patients with HF so advanced that they were referred for evaluation at a transplant center.

The study, modestly sized with fewer than 200 such patients and conducted at a single center, assigned half of them to receive ablation and the other half to continued medical management.

Risk for the composite primary endpoint plunged 76% over a median of 18 months for those who underwent ablation. The outcome comprised death from any cause, implantation of a left ventricular assist device (LVAD), or urgent heart transplantation.

The advantage for ablation emerged early enough that the trial, CASTLE-HTx, was halted for benefit only a year after reaching its planned enrollment, observed Christian Sohns, MD, when formally presenting the results in Amsterdam at the annual congress of the European Society of Cardiology.

The difference in the primary endpoint “in this severely sick cohort of advanced, end-stage heart failure patients,” he said, was driven mostly by fewer deaths, especially cardiovascular deaths, in the ablation group.

Ablation’s effect on outcomes was associated, perhaps causally, with significant gains in left ventricular (LV) function and more than triple the reduction in AF burden seen in the control group, noted Dr. Sohns, from the Heart and Diabetes Center North-Rhine Westphalia, Bad Oeynhausen, Germany.

“Our trial suggests that in patients with atrial fibrillation and end-stage heart failure, catheter ablation may ameliorate the clinical course,” states the CASTLE-HTx primary report, published in the New England Journal of Medicine, with Dr. Sohns as lead author, in tandem with his ESC presentation.

One of the study’s key messages “is that AF ablation is safe and effective in patients with end-stage heart failure” and “should be part of our armamentarium” for treating them, said Philipp Sommer, MD, also with Heart and Diabetes Center North-Rhine Westphalia, at a press conference preceding Dr. Sohns’ presentation of CASTLE-HTx.

The intervention could potentially help such patients survive longer on transplant wait lists and even delay need for the surgery, proposed Dr. Sommer, who is senior author on the trial’s publication.

CASTLE-HTx suggests that patients with advanced HF and even persistent AF, “if they have reasonably small atria, should be actually considered for ablation, as it may prevent the need for heart transplant or LVAD implant,” said invited discussant Finn Gustafsson, MD, PhD, DMSc, after Dr. Sohns’ presentation. “And that, of course, would be a huge achievement.”

The trial “should, if anything, help eradicate the current somewhat nihilistic approach to atrial fibrillation management in patients with advanced heart failure,” said Dr. Gustafsson, medical director of cardiac transplantation and mechanical circulatory support, Rigshopsitalet Copenhagen University Hospital.

Still, he disputed the characterization by the investigators and indeed the published report that the patients, or most of them, had “end-stage heart failure.”

For example, about a third of the trial’s patients started out in NYHA class 2, Dr. Gustafsson noted. Not that they weren’t “high-risk” or their HF wasn’t severe, he offered, but they don’t seem to have been “a truly advanced heart failure population.”

The trial population consisted of “patients referred to an advanced heart failure center, rather than patients with advanced heart failure,” agreed Mandeep R. Mehra, MD, director of the Center for Advanced Heart Disease at Brigham and Woman’s Hospital, Boston.

Also citing a large prevalence of patients in NYHA class-2, Dr. Mehra added that “we almost never see paroxysmal atrial fib in these patients. It’s usually an early-stage phenomenon.” In advanced HF, AF “is usually permanent,” he told this news organization. Yet it was paroxysmal in about 30% of cases.

To its credit, Dr. Mehra observed, the study does assert that advanced HF is no reason, necessarily, to avoid catheter ablation. Nor should an AF patient’s referral to an advanced-HF center “mean that you should rush to an LVAD or transplant” before considering ablation.

The study seems to be saying, “please exhaust all options before you biologically replace the heart or put in an LVAD,” Dr. Mehra said. “Certainly, this paper steers you in that direction.”

The trial entered 194 patients with symptomatic AF and HF of at least NYHA class 2, with impaired functional capacity by the 6-minute walk test, who had been referred to a major center in Germany for a heart-transplantation workup. With all on guideline-directed medical therapy, 97 were randomly assigned open-label to catheter ablation and 97 to continued standard care.

Catheter ablation was actually carried out in 81 patients (84%) who had been assigned to it and in 16 (16%) of those in the control group, the report states.

A total of 8 in the ablation group and 29 in the control arm died, received an LVAD, or went to urgent transplantation, for a hazard ratio of 0.24 (95% confidence interval, 0.11-0.52; P < .001) for the primary endpoint.

Death from any cause apparently played a big role in the risk reduction; its HR was 0.29 (95% CI, 0.12-0.72).

One peculiarity of the data, Dr. Mehra said, is that event curves for the primary endpoint and its individual components “diverge almost from day 1.” That would mean the ablation group right away started having fewer deaths, LVAD placements, or heart transplants than the control group.

“It is surprising to see such a large effect size on endpoints that are very much dependent on operators and diverge within the first day.” Probably, Dr. Mehra said, “it has to do with this being a single-center study that may not be generalizable to other practices.”

CASTLE HTx was supported by a grant from Else Kröner-Fresenius-Stiftung. Dr. Sommer discloses consulting for Abbott, Biosense Webster, Boston Scientific, and Medtronic. Dr. Sohns reported no relevant financial relationships. Dr. Gustafsson discloses receiving honoraria or fees for consulting from Abbott, Alnylam Amgen, Boehringer Ingelheim, Ionis, Novartis, and Pfizer; serving on a speakers bureau for Astra Zeneca and Orion; and receiving grants from Corvia Research. Dr. Mehra has reported receiving payments to his institution from Abbott for consulting; consulting fees from Janssen, Mesoblast, Broadview Ventures, Natera, Paragonix, Moderna, and the Baim Institute for Clinical Research; and serving on a scientific advisory board for NuPulseCV, Leviticus, and FineHeart.

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

Catheter ablation had long taken atrial fibrillation (AF) rhythm control to the next level before clinical trials showed it could help keep AF patients with heart failure (HF) alive and out of the hospital.

But those trials didn’t include many patients with AF on top of advanced or even end-stage HF. Lacking much of an evidence base and often viewed as too sick to gain a lot from the procedure, patients with AF and advanced HF aren’t offered ablation very often.

Now a randomized trial suggests that, on the contrary, AF ablation may confer a similar benefit to patients with HF so advanced that they were referred for evaluation at a transplant center.

The study, modestly sized with fewer than 200 such patients and conducted at a single center, assigned half of them to receive ablation and the other half to continued medical management.

Risk for the composite primary endpoint plunged 76% over a median of 18 months for those who underwent ablation. The outcome comprised death from any cause, implantation of a left ventricular assist device (LVAD), or urgent heart transplantation.

The advantage for ablation emerged early enough that the trial, CASTLE-HTx, was halted for benefit only a year after reaching its planned enrollment, observed Christian Sohns, MD, when formally presenting the results in Amsterdam at the annual congress of the European Society of Cardiology.

The difference in the primary endpoint “in this severely sick cohort of advanced, end-stage heart failure patients,” he said, was driven mostly by fewer deaths, especially cardiovascular deaths, in the ablation group.

Ablation’s effect on outcomes was associated, perhaps causally, with significant gains in left ventricular (LV) function and more than triple the reduction in AF burden seen in the control group, noted Dr. Sohns, from the Heart and Diabetes Center North-Rhine Westphalia, Bad Oeynhausen, Germany.

“Our trial suggests that in patients with atrial fibrillation and end-stage heart failure, catheter ablation may ameliorate the clinical course,” states the CASTLE-HTx primary report, published in the New England Journal of Medicine, with Dr. Sohns as lead author, in tandem with his ESC presentation.

One of the study’s key messages “is that AF ablation is safe and effective in patients with end-stage heart failure” and “should be part of our armamentarium” for treating them, said Philipp Sommer, MD, also with Heart and Diabetes Center North-Rhine Westphalia, at a press conference preceding Dr. Sohns’ presentation of CASTLE-HTx.

The intervention could potentially help such patients survive longer on transplant wait lists and even delay need for the surgery, proposed Dr. Sommer, who is senior author on the trial’s publication.

CASTLE-HTx suggests that patients with advanced HF and even persistent AF, “if they have reasonably small atria, should be actually considered for ablation, as it may prevent the need for heart transplant or LVAD implant,” said invited discussant Finn Gustafsson, MD, PhD, DMSc, after Dr. Sohns’ presentation. “And that, of course, would be a huge achievement.”

The trial “should, if anything, help eradicate the current somewhat nihilistic approach to atrial fibrillation management in patients with advanced heart failure,” said Dr. Gustafsson, medical director of cardiac transplantation and mechanical circulatory support, Rigshopsitalet Copenhagen University Hospital.

Still, he disputed the characterization by the investigators and indeed the published report that the patients, or most of them, had “end-stage heart failure.”

For example, about a third of the trial’s patients started out in NYHA class 2, Dr. Gustafsson noted. Not that they weren’t “high-risk” or their HF wasn’t severe, he offered, but they don’t seem to have been “a truly advanced heart failure population.”

The trial population consisted of “patients referred to an advanced heart failure center, rather than patients with advanced heart failure,” agreed Mandeep R. Mehra, MD, director of the Center for Advanced Heart Disease at Brigham and Woman’s Hospital, Boston.

Also citing a large prevalence of patients in NYHA class-2, Dr. Mehra added that “we almost never see paroxysmal atrial fib in these patients. It’s usually an early-stage phenomenon.” In advanced HF, AF “is usually permanent,” he told this news organization. Yet it was paroxysmal in about 30% of cases.

To its credit, Dr. Mehra observed, the study does assert that advanced HF is no reason, necessarily, to avoid catheter ablation. Nor should an AF patient’s referral to an advanced-HF center “mean that you should rush to an LVAD or transplant” before considering ablation.

The study seems to be saying, “please exhaust all options before you biologically replace the heart or put in an LVAD,” Dr. Mehra said. “Certainly, this paper steers you in that direction.”

The trial entered 194 patients with symptomatic AF and HF of at least NYHA class 2, with impaired functional capacity by the 6-minute walk test, who had been referred to a major center in Germany for a heart-transplantation workup. With all on guideline-directed medical therapy, 97 were randomly assigned open-label to catheter ablation and 97 to continued standard care.

Catheter ablation was actually carried out in 81 patients (84%) who had been assigned to it and in 16 (16%) of those in the control group, the report states.

A total of 8 in the ablation group and 29 in the control arm died, received an LVAD, or went to urgent transplantation, for a hazard ratio of 0.24 (95% confidence interval, 0.11-0.52; P < .001) for the primary endpoint.

Death from any cause apparently played a big role in the risk reduction; its HR was 0.29 (95% CI, 0.12-0.72).

One peculiarity of the data, Dr. Mehra said, is that event curves for the primary endpoint and its individual components “diverge almost from day 1.” That would mean the ablation group right away started having fewer deaths, LVAD placements, or heart transplants than the control group.

“It is surprising to see such a large effect size on endpoints that are very much dependent on operators and diverge within the first day.” Probably, Dr. Mehra said, “it has to do with this being a single-center study that may not be generalizable to other practices.”

CASTLE HTx was supported by a grant from Else Kröner-Fresenius-Stiftung. Dr. Sommer discloses consulting for Abbott, Biosense Webster, Boston Scientific, and Medtronic. Dr. Sohns reported no relevant financial relationships. Dr. Gustafsson discloses receiving honoraria or fees for consulting from Abbott, Alnylam Amgen, Boehringer Ingelheim, Ionis, Novartis, and Pfizer; serving on a speakers bureau for Astra Zeneca and Orion; and receiving grants from Corvia Research. Dr. Mehra has reported receiving payments to his institution from Abbott for consulting; consulting fees from Janssen, Mesoblast, Broadview Ventures, Natera, Paragonix, Moderna, and the Baim Institute for Clinical Research; and serving on a scientific advisory board for NuPulseCV, Leviticus, and FineHeart.

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

Catheter ablation had long taken atrial fibrillation (AF) rhythm control to the next level before clinical trials showed it could help keep AF patients with heart failure (HF) alive and out of the hospital.

But those trials didn’t include many patients with AF on top of advanced or even end-stage HF. Lacking much of an evidence base and often viewed as too sick to gain a lot from the procedure, patients with AF and advanced HF aren’t offered ablation very often.

Now a randomized trial suggests that, on the contrary, AF ablation may confer a similar benefit to patients with HF so advanced that they were referred for evaluation at a transplant center.

The study, modestly sized with fewer than 200 such patients and conducted at a single center, assigned half of them to receive ablation and the other half to continued medical management.

Risk for the composite primary endpoint plunged 76% over a median of 18 months for those who underwent ablation. The outcome comprised death from any cause, implantation of a left ventricular assist device (LVAD), or urgent heart transplantation.

The advantage for ablation emerged early enough that the trial, CASTLE-HTx, was halted for benefit only a year after reaching its planned enrollment, observed Christian Sohns, MD, when formally presenting the results in Amsterdam at the annual congress of the European Society of Cardiology.

The difference in the primary endpoint “in this severely sick cohort of advanced, end-stage heart failure patients,” he said, was driven mostly by fewer deaths, especially cardiovascular deaths, in the ablation group.

Ablation’s effect on outcomes was associated, perhaps causally, with significant gains in left ventricular (LV) function and more than triple the reduction in AF burden seen in the control group, noted Dr. Sohns, from the Heart and Diabetes Center North-Rhine Westphalia, Bad Oeynhausen, Germany.

“Our trial suggests that in patients with atrial fibrillation and end-stage heart failure, catheter ablation may ameliorate the clinical course,” states the CASTLE-HTx primary report, published in the New England Journal of Medicine, with Dr. Sohns as lead author, in tandem with his ESC presentation.

One of the study’s key messages “is that AF ablation is safe and effective in patients with end-stage heart failure” and “should be part of our armamentarium” for treating them, said Philipp Sommer, MD, also with Heart and Diabetes Center North-Rhine Westphalia, at a press conference preceding Dr. Sohns’ presentation of CASTLE-HTx.

The intervention could potentially help such patients survive longer on transplant wait lists and even delay need for the surgery, proposed Dr. Sommer, who is senior author on the trial’s publication.

CASTLE-HTx suggests that patients with advanced HF and even persistent AF, “if they have reasonably small atria, should be actually considered for ablation, as it may prevent the need for heart transplant or LVAD implant,” said invited discussant Finn Gustafsson, MD, PhD, DMSc, after Dr. Sohns’ presentation. “And that, of course, would be a huge achievement.”

The trial “should, if anything, help eradicate the current somewhat nihilistic approach to atrial fibrillation management in patients with advanced heart failure,” said Dr. Gustafsson, medical director of cardiac transplantation and mechanical circulatory support, Rigshopsitalet Copenhagen University Hospital.

Still, he disputed the characterization by the investigators and indeed the published report that the patients, or most of them, had “end-stage heart failure.”

For example, about a third of the trial’s patients started out in NYHA class 2, Dr. Gustafsson noted. Not that they weren’t “high-risk” or their HF wasn’t severe, he offered, but they don’t seem to have been “a truly advanced heart failure population.”

The trial population consisted of “patients referred to an advanced heart failure center, rather than patients with advanced heart failure,” agreed Mandeep R. Mehra, MD, director of the Center for Advanced Heart Disease at Brigham and Woman’s Hospital, Boston.

Also citing a large prevalence of patients in NYHA class-2, Dr. Mehra added that “we almost never see paroxysmal atrial fib in these patients. It’s usually an early-stage phenomenon.” In advanced HF, AF “is usually permanent,” he told this news organization. Yet it was paroxysmal in about 30% of cases.

To its credit, Dr. Mehra observed, the study does assert that advanced HF is no reason, necessarily, to avoid catheter ablation. Nor should an AF patient’s referral to an advanced-HF center “mean that you should rush to an LVAD or transplant” before considering ablation.

The study seems to be saying, “please exhaust all options before you biologically replace the heart or put in an LVAD,” Dr. Mehra said. “Certainly, this paper steers you in that direction.”

The trial entered 194 patients with symptomatic AF and HF of at least NYHA class 2, with impaired functional capacity by the 6-minute walk test, who had been referred to a major center in Germany for a heart-transplantation workup. With all on guideline-directed medical therapy, 97 were randomly assigned open-label to catheter ablation and 97 to continued standard care.

Catheter ablation was actually carried out in 81 patients (84%) who had been assigned to it and in 16 (16%) of those in the control group, the report states.

A total of 8 in the ablation group and 29 in the control arm died, received an LVAD, or went to urgent transplantation, for a hazard ratio of 0.24 (95% confidence interval, 0.11-0.52; P < .001) for the primary endpoint.

Death from any cause apparently played a big role in the risk reduction; its HR was 0.29 (95% CI, 0.12-0.72).

One peculiarity of the data, Dr. Mehra said, is that event curves for the primary endpoint and its individual components “diverge almost from day 1.” That would mean the ablation group right away started having fewer deaths, LVAD placements, or heart transplants than the control group.

“It is surprising to see such a large effect size on endpoints that are very much dependent on operators and diverge within the first day.” Probably, Dr. Mehra said, “it has to do with this being a single-center study that may not be generalizable to other practices.”

CASTLE HTx was supported by a grant from Else Kröner-Fresenius-Stiftung. Dr. Sommer discloses consulting for Abbott, Biosense Webster, Boston Scientific, and Medtronic. Dr. Sohns reported no relevant financial relationships. Dr. Gustafsson discloses receiving honoraria or fees for consulting from Abbott, Alnylam Amgen, Boehringer Ingelheim, Ionis, Novartis, and Pfizer; serving on a speakers bureau for Astra Zeneca and Orion; and receiving grants from Corvia Research. Dr. Mehra has reported receiving payments to his institution from Abbott for consulting; consulting fees from Janssen, Mesoblast, Broadview Ventures, Natera, Paragonix, Moderna, and the Baim Institute for Clinical Research; and serving on a scientific advisory board for NuPulseCV, Leviticus, and FineHeart.

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

AMSTERDAM – The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.

At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.

Mitchel L. Zoler/MDedge News

His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.

The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.

Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.

In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m²), class 2 (35-39 kg/m²), and class 3 (≥ 40 kg/m²) obesity.

Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
 

Not every benefit was fully mediated by weight loss

These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”

He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.

“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.

“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.

Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.

“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.

Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.

“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.

STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
 

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

AMSTERDAM – The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.

At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.

Mitchel L. Zoler/MDedge News

His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.

The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.

Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.

In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m²), class 2 (35-39 kg/m²), and class 3 (≥ 40 kg/m²) obesity.

Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
 

Not every benefit was fully mediated by weight loss

These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”

He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.

“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.

“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.

Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.

“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.

Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.

“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.

STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
 

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

AMSTERDAM – The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.

At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.

Mitchel L. Zoler/MDedge News

His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.

The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.

Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.

In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m²), class 2 (35-39 kg/m²), and class 3 (≥ 40 kg/m²) obesity.

Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
 

Not every benefit was fully mediated by weight loss

These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”

He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.

“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.

“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.

Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.

“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.

Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.

“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.

STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
 

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

Severe COVID infections may lead to lasting damage to the immune system, new research finds.

The small study, published in Cell and funded by the National Institutes of Health, details how immune cells were analyzed through blood samples collected from 38 patients recovering from severe COVID and other critical illnesses, and from 19 healthy people. Researchers from Weill Cornell Medicine, New York, and The Jackson Laboratory for Genomic Medicine, Farmington, Conn., found through isolating hematopoietic stem cells that people recovering from severe bouts of COVID had changes to their DNA that were passed down to offspring cells.

The research team, led by Steven Josefowicz, PhD, of Weill Cornell’s pathology department, and Duygu Ucar, PhD, associate professor at The Jackson Laboratory for Genomic Medicine, discovered that this chain reaction of stem cell changes caused a boost in the production of monocytes. The authors found that, due to the innate cellular changes from a severe case of COVID, patients in recovery ended up producing a larger amount of inflammatory cytokines, rather than monocytes – distinct from samples collected from healthy patients and those recovering from other critical illnesses.

These changes to patients’ epigenetic landscapes were observed even a year after the initial COVID-19 infection. While the small participant pool meant that the research team could not establish a direct line between these innate changes and any ensuing health outcomes, the research provides us with clues as to why patients continue to struggle with inflammation and long COVID symptoms well after they recover.

While the authors reiterate the study’s limitations and hesitate to make any clear-cut associations between the results and long-term health outcomes, Wolfgang Leitner, PhD, from the NIH’s National Institute of Allergy and Infectious Diseases, predicts that long COVID can, at least in part, be explained by the changes in innate immune responses.

“Ideally, the authors would have had cells from each patient before they got infected, as a comparator, to see what the epigenetic landscape was before COVID changed it,” said Dr. Leitner. “Clear links between the severity of COVID and genetics were discovered already early in the pandemic and this paper should prompt follow-up studies that link mutations in immune genes with the epigenetic changes described here.”

Dr. Leitner said he had some initial predictions about the long-term impact of COVID-19, but he had not anticipated some of what the study’s findings now show.

“Unlike in the case of, for example, influenza, where the lungs go into ‘repair mode’ after the infection has been resolved – which leaves people susceptible to secondary infections for up to several months – this study shows that after severe COVID, the immune system remains in ‘emergency mode’ and in a heightened state of inflammation,” said Dr. Leitner.

“That further aggravates the problem the initial strong inflammation causes: even higher risk of autoimmune disease, but also, cancer.”

Commenting on the findings, Eric Topol, MD, editor-in-chief of Medscape Medical News, said the study presents “evidence that a key line of immune cells are essentially irrevocably, epigenetically altered and activated.

“You do not want to have this [COVID],” he added.

The study also highlights the researchers’ novel approach to isolating hematopoietic stem cells, found largely in bone marrow. This type of research has been limited in the past because of how costly and invasive it can be to analyze cells in bone marrow. But, by isolating and enriching hematopoietic stem cells, the team can decipher the full cellular diversity of the cells’ bone marrow counterparts.

“This revelation opened the doors to study, at single-cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw,” representatives from the Jackson lab said in a press release.

A version of this article appeared on Medscape.com.

Severe COVID infections may lead to lasting damage to the immune system, new research finds.

The small study, published in Cell and funded by the National Institutes of Health, details how immune cells were analyzed through blood samples collected from 38 patients recovering from severe COVID and other critical illnesses, and from 19 healthy people. Researchers from Weill Cornell Medicine, New York, and The Jackson Laboratory for Genomic Medicine, Farmington, Conn., found through isolating hematopoietic stem cells that people recovering from severe bouts of COVID had changes to their DNA that were passed down to offspring cells.

The research team, led by Steven Josefowicz, PhD, of Weill Cornell’s pathology department, and Duygu Ucar, PhD, associate professor at The Jackson Laboratory for Genomic Medicine, discovered that this chain reaction of stem cell changes caused a boost in the production of monocytes. The authors found that, due to the innate cellular changes from a severe case of COVID, patients in recovery ended up producing a larger amount of inflammatory cytokines, rather than monocytes – distinct from samples collected from healthy patients and those recovering from other critical illnesses.

These changes to patients’ epigenetic landscapes were observed even a year after the initial COVID-19 infection. While the small participant pool meant that the research team could not establish a direct line between these innate changes and any ensuing health outcomes, the research provides us with clues as to why patients continue to struggle with inflammation and long COVID symptoms well after they recover.

While the authors reiterate the study’s limitations and hesitate to make any clear-cut associations between the results and long-term health outcomes, Wolfgang Leitner, PhD, from the NIH’s National Institute of Allergy and Infectious Diseases, predicts that long COVID can, at least in part, be explained by the changes in innate immune responses.

“Ideally, the authors would have had cells from each patient before they got infected, as a comparator, to see what the epigenetic landscape was before COVID changed it,” said Dr. Leitner. “Clear links between the severity of COVID and genetics were discovered already early in the pandemic and this paper should prompt follow-up studies that link mutations in immune genes with the epigenetic changes described here.”

Dr. Leitner said he had some initial predictions about the long-term impact of COVID-19, but he had not anticipated some of what the study’s findings now show.

“Unlike in the case of, for example, influenza, where the lungs go into ‘repair mode’ after the infection has been resolved – which leaves people susceptible to secondary infections for up to several months – this study shows that after severe COVID, the immune system remains in ‘emergency mode’ and in a heightened state of inflammation,” said Dr. Leitner.

“That further aggravates the problem the initial strong inflammation causes: even higher risk of autoimmune disease, but also, cancer.”

Commenting on the findings, Eric Topol, MD, editor-in-chief of Medscape Medical News, said the study presents “evidence that a key line of immune cells are essentially irrevocably, epigenetically altered and activated.

“You do not want to have this [COVID],” he added.

The study also highlights the researchers’ novel approach to isolating hematopoietic stem cells, found largely in bone marrow. This type of research has been limited in the past because of how costly and invasive it can be to analyze cells in bone marrow. But, by isolating and enriching hematopoietic stem cells, the team can decipher the full cellular diversity of the cells’ bone marrow counterparts.

“This revelation opened the doors to study, at single-cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw,” representatives from the Jackson lab said in a press release.

A version of this article appeared on Medscape.com.

Severe COVID infections may lead to lasting damage to the immune system, new research finds.

The small study, published in Cell and funded by the National Institutes of Health, details how immune cells were analyzed through blood samples collected from 38 patients recovering from severe COVID and other critical illnesses, and from 19 healthy people. Researchers from Weill Cornell Medicine, New York, and The Jackson Laboratory for Genomic Medicine, Farmington, Conn., found through isolating hematopoietic stem cells that people recovering from severe bouts of COVID had changes to their DNA that were passed down to offspring cells.

The research team, led by Steven Josefowicz, PhD, of Weill Cornell’s pathology department, and Duygu Ucar, PhD, associate professor at The Jackson Laboratory for Genomic Medicine, discovered that this chain reaction of stem cell changes caused a boost in the production of monocytes. The authors found that, due to the innate cellular changes from a severe case of COVID, patients in recovery ended up producing a larger amount of inflammatory cytokines, rather than monocytes – distinct from samples collected from healthy patients and those recovering from other critical illnesses.

These changes to patients’ epigenetic landscapes were observed even a year after the initial COVID-19 infection. While the small participant pool meant that the research team could not establish a direct line between these innate changes and any ensuing health outcomes, the research provides us with clues as to why patients continue to struggle with inflammation and long COVID symptoms well after they recover.

While the authors reiterate the study’s limitations and hesitate to make any clear-cut associations between the results and long-term health outcomes, Wolfgang Leitner, PhD, from the NIH’s National Institute of Allergy and Infectious Diseases, predicts that long COVID can, at least in part, be explained by the changes in innate immune responses.

“Ideally, the authors would have had cells from each patient before they got infected, as a comparator, to see what the epigenetic landscape was before COVID changed it,” said Dr. Leitner. “Clear links between the severity of COVID and genetics were discovered already early in the pandemic and this paper should prompt follow-up studies that link mutations in immune genes with the epigenetic changes described here.”

Dr. Leitner said he had some initial predictions about the long-term impact of COVID-19, but he had not anticipated some of what the study’s findings now show.

“Unlike in the case of, for example, influenza, where the lungs go into ‘repair mode’ after the infection has been resolved – which leaves people susceptible to secondary infections for up to several months – this study shows that after severe COVID, the immune system remains in ‘emergency mode’ and in a heightened state of inflammation,” said Dr. Leitner.

“That further aggravates the problem the initial strong inflammation causes: even higher risk of autoimmune disease, but also, cancer.”

Commenting on the findings, Eric Topol, MD, editor-in-chief of Medscape Medical News, said the study presents “evidence that a key line of immune cells are essentially irrevocably, epigenetically altered and activated.

“You do not want to have this [COVID],” he added.

The study also highlights the researchers’ novel approach to isolating hematopoietic stem cells, found largely in bone marrow. This type of research has been limited in the past because of how costly and invasive it can be to analyze cells in bone marrow. But, by isolating and enriching hematopoietic stem cells, the team can decipher the full cellular diversity of the cells’ bone marrow counterparts.

“This revelation opened the doors to study, at single-cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw,” representatives from the Jackson lab said in a press release.

A version of this article appeared on Medscape.com.

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.