Interventional Cardiology & Surgery

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Dr. Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.


 

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. P < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.
 

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Dr. Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Dr. Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Dr. Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Dr. Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Dr. Bhatt said.

Dr. Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Dr. Boden reports no potential conflicts of interest.

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Dr. Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.


 

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. P < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.
 

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Dr. Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Dr. Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Dr. Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Dr. Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Dr. Bhatt said.

Dr. Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Dr. Boden reports no potential conflicts of interest.

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Dr. Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.


 

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. P < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.
 

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Dr. Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Dr. Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Dr. Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Dr. Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Dr. Bhatt said.

Dr. Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Dr. Boden reports no potential conflicts of interest.

In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.

For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.

At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.

However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.

FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
 

FFR vs. IVUS differences revealed

However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.

Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.

“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”

Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.

In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.

In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm².

The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
 

Suboptimal IVUS differs from suboptimal FFR

In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.

FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.

“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.

A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.

Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.

Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.

In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.

For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.

At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.

However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.

FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
 

FFR vs. IVUS differences revealed

However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.

Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.

“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”

Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.

In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.

In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm².

The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
 

Suboptimal IVUS differs from suboptimal FFR

In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.

FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.

“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.

A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.

Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.

Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.

In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.

For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.

At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.

However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.

FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
 

FFR vs. IVUS differences revealed

However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.

Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.

“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”

Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.

In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.

In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm².

The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
 

Suboptimal IVUS differs from suboptimal FFR

In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.

FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.

“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.

A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.

Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.

Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.

WASHINGTON – Treatment of patients acutely hospitalized for heart failure with the SGLT2 inhibitor empagliflozin led to a rapid incremental increase in patient well-being, compared with control patients who received placebo, that appeared after 2 weeks on treatment in a secondary analysis from 530 randomized patients in the EMPULSE trial.

To Mikhail N. Kosiborod, MD, a coinvestigator for EMPULSE who presented new analysis at the annual scientific sessions of the American College of Cardiology, the message from the quick response of acutely hospitalized patients to empagliflozin was clear: “Use these medications, SGLT2 [sodium-glucose cotransporter 2] inhibitors, as early as possible. We’ve seen with other medications that if they are not prescribed during hospitalization it’s unlikely to happen post discharge,” said 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.

Mitchel L. Zoler/MDedge News

“To our knowledge, the very early improvement in the Kansas City Cardiomyopathy Questionnaire [KCCQ] score – a well-known predictor of cardiovascular death and heart failure readmissions – that we observed with empagliflozin at 15 days is the first such observation, and if corroborated by future studies would suggest that initiation of SGLT2 inhibitors during hospitalization for acute heart failure may be a tool for improving the quality of hospital-to-home transitions,” wrote Dr. Kosiborod and his associates in the published version of their report that appeared concurrently with his report at the meeting.

“These data really support initiation [of empagliflozin or another SGLT2 inhibitor] in hospital, presuming that the patient has no contraindications,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and designated discussant for the report.

“The fact that the benefit kicks in so early is really important, because there is a bit of a penalty to wait” to start treatment with an agent from the SGLT2-inhibitor class, added Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Health, in Boston.

In hospital creates a teachable moment

Starting treatment when a patient is hospitalized is also important as “a teachable moment,” added Dr. Bhatt in an interview. “A physician can say to a patient ‘take this drug, and it will prevent you from returning to the hospital,’ at a time when it’s more likely to be impactful, compared with when a patient is out of the hospital and feeling okay and adherence will likely be much lower.”

Mitchel L. Zoler/MDedge News

The results Dr. Kosiborod reported on quality-of-life parameters measured with the KCCQ expanded on what he and his coinvestigators first reported in 2021 with the primary results from EMPULSE, which enrolled 530 patients at 118 centers in 15 countries during June 2020–February 2021. The trial randomized patients hospitalized for acute heart failure after a brief period of stabilization regardless of their left ventricular ejection fraction or presence of diabetes to receive a single, daily dose of 10 mg of empagliflozin (Jardiance) or placebo starting a median of 3 days after admission. Enrolled patients averaged about 71 years of age, about two-thirds were men, 45% had diabetes, 32% had left ventricular ejection fraction greater than 40%, and about two-thirds had decompensated chronic heart failure, while a third had acute de novo heart failure.

The primary outcome for EMPULSE was a combined endpoint of “total clinical endpoints” that included all-cause mortality, heart failure events (heart failure hospitalizations, urgent heart failure visits, and unplanned outpatient heart failure visits) or at least a 5-point change from baseline in the KCCQ score. Using a “win ratio” method for analyzing the composite endpoint, the primary analysis showed that treatment with empagliflozin for 90 days boosted the win ratio by a significant 36% relative to placebo (Nature Med. 2022 Mar;28[3]: 568-74).
 

Benefit independent of baseline symptomatic impairment

Among the new secondary analyses that Dr. Kosiborod reported was a post-hoc calculation that divided the study cohort into tertiles of baseline KCCQ score. The results showed that the degree of improvement for the primary, 90-day outcome of “total clinical benefit” compared with placebo was consistent across all three KCCQ-score tertiles, showing that empagliflozin’s benefit was “independent of symptomatic impairment at baseline,” he said.

The degree of improvement was also similar across all the tested domains of the KCCQ, including the overall summary, clinical summary, the physical limitations, and quality-of-life scores. Average improvement in KCCQ total symptom score 15 days after treatment onset was 5.35 points, compared with control patients. On an individual-patient basis, a change in KCCQ score of 5 points or more was previously shown to represent a clinically meaningful change.

“Treatment of patients with heart failure is geared to making patients live longer and stay out of the hospital. Enabling patients to feel better is an equally important goal of management, but not all treatments for heart failure can do that. These data from EMPULSE show that, in addition to other clinical benefits, patients also feel better on an SGLT2 inhibitor after just 2 weeks,” Dr. Kosiborod said in an interview.

EMPULSE builds on SOLOIST-WHF

EMPULSE is the second trial to show that an SGLT2 inhibitor can safely and effectively treat patients hospitalized for acute heart failure. Previously, results from the SOLOIST-WHF pivotal trial, which enrolled 1,222 patients with type 2 diabetes recently hospitalized for worsening heart failure, showed that treatment with an investigational, combined SGLT2 and SGLT1 inhibitor, sotagliflozin, resulted in a significant, 33% relative reduction in the primary outcome compared with placebo after a median 9 months of treatment.

“It’s reassuring to see two different drugs and research groups get essentially the same result, showing that starting an SGLT2 inhibitor is safe and effective in selected patients with no contraindications,” said Dr. Bhatt, who was lead investigator for SOLOIST-WHF.

The accumulating evidence for the safety and value of starting an SGLT2 inhibitor when patients are hospitalized for acute heart failure is making this approach increasingly routine for patients who present with heart failure with reduced ejection fraction at Saint Luke’s-Mid America Heart Institute, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri, Kansas City.

“I think we’ll also gradually start using [an SGLT2 inhibitor] in patients hospitalized with heart failure with preserved ejection fraction [HFpEF],” he added, based on the findings from SOLOIST-WHF and EMPULSE, and also recent evidence showing safety and efficacy of empagliflozin in patients with chronic HFpEF in the EMPEROR-Preserved trial, and for dapagliflozin (Farxiga) in the PRESERVED-HF trial.

Empagliflozin recently received from the U.S. Food and Drug Administration an expanded label indication for treating patients with heart failure with no specification for a level of left ventricular ejection fraction. An outcome trial of dapagliflozin in more than 6,000 patients with HFpEF, DELIVER, is currently ongoing but is expected to report results soon.

“The evidence is already compelling that the benefits outweigh the risk. Results from both SOLOIST-WHF and EMPULSE show that there are no significant safety concerns” when these agents are used in patients with acute heart failure,” Dr. Kosiborod declared.

EMPULSE was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). SOLOIST-WHF was sponsored by Sanofi and Lexicon, the companies that have been developing sotagliflozin. Dr. Kosiborod has been a consultant to and received research funding from Boehringer Ingelheim and Eli Lilly, and he has been a consultant or adviser to or led trials on behalf of numerous other companies. Dr. Bhatt has been an adviser to Boehringer Ingelheim and numerous other companies, and he has received research funding from Sanofi, Lexicon, Boehringer Ingelheim, Eli Lilly, and numerous other companies.

WASHINGTON – Treatment of patients acutely hospitalized for heart failure with the SGLT2 inhibitor empagliflozin led to a rapid incremental increase in patient well-being, compared with control patients who received placebo, that appeared after 2 weeks on treatment in a secondary analysis from 530 randomized patients in the EMPULSE trial.

To Mikhail N. Kosiborod, MD, a coinvestigator for EMPULSE who presented new analysis at the annual scientific sessions of the American College of Cardiology, the message from the quick response of acutely hospitalized patients to empagliflozin was clear: “Use these medications, SGLT2 [sodium-glucose cotransporter 2] inhibitors, as early as possible. We’ve seen with other medications that if they are not prescribed during hospitalization it’s unlikely to happen post discharge,” said 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.

Mitchel L. Zoler/MDedge News

“To our knowledge, the very early improvement in the Kansas City Cardiomyopathy Questionnaire [KCCQ] score – a well-known predictor of cardiovascular death and heart failure readmissions – that we observed with empagliflozin at 15 days is the first such observation, and if corroborated by future studies would suggest that initiation of SGLT2 inhibitors during hospitalization for acute heart failure may be a tool for improving the quality of hospital-to-home transitions,” wrote Dr. Kosiborod and his associates in the published version of their report that appeared concurrently with his report at the meeting.

“These data really support initiation [of empagliflozin or another SGLT2 inhibitor] in hospital, presuming that the patient has no contraindications,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and designated discussant for the report.

“The fact that the benefit kicks in so early is really important, because there is a bit of a penalty to wait” to start treatment with an agent from the SGLT2-inhibitor class, added Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Health, in Boston.

In hospital creates a teachable moment

Starting treatment when a patient is hospitalized is also important as “a teachable moment,” added Dr. Bhatt in an interview. “A physician can say to a patient ‘take this drug, and it will prevent you from returning to the hospital,’ at a time when it’s more likely to be impactful, compared with when a patient is out of the hospital and feeling okay and adherence will likely be much lower.”

Mitchel L. Zoler/MDedge News

The results Dr. Kosiborod reported on quality-of-life parameters measured with the KCCQ expanded on what he and his coinvestigators first reported in 2021 with the primary results from EMPULSE, which enrolled 530 patients at 118 centers in 15 countries during June 2020–February 2021. The trial randomized patients hospitalized for acute heart failure after a brief period of stabilization regardless of their left ventricular ejection fraction or presence of diabetes to receive a single, daily dose of 10 mg of empagliflozin (Jardiance) or placebo starting a median of 3 days after admission. Enrolled patients averaged about 71 years of age, about two-thirds were men, 45% had diabetes, 32% had left ventricular ejection fraction greater than 40%, and about two-thirds had decompensated chronic heart failure, while a third had acute de novo heart failure.

The primary outcome for EMPULSE was a combined endpoint of “total clinical endpoints” that included all-cause mortality, heart failure events (heart failure hospitalizations, urgent heart failure visits, and unplanned outpatient heart failure visits) or at least a 5-point change from baseline in the KCCQ score. Using a “win ratio” method for analyzing the composite endpoint, the primary analysis showed that treatment with empagliflozin for 90 days boosted the win ratio by a significant 36% relative to placebo (Nature Med. 2022 Mar;28[3]: 568-74).
 

Benefit independent of baseline symptomatic impairment

Among the new secondary analyses that Dr. Kosiborod reported was a post-hoc calculation that divided the study cohort into tertiles of baseline KCCQ score. The results showed that the degree of improvement for the primary, 90-day outcome of “total clinical benefit” compared with placebo was consistent across all three KCCQ-score tertiles, showing that empagliflozin’s benefit was “independent of symptomatic impairment at baseline,” he said.

The degree of improvement was also similar across all the tested domains of the KCCQ, including the overall summary, clinical summary, the physical limitations, and quality-of-life scores. Average improvement in KCCQ total symptom score 15 days after treatment onset was 5.35 points, compared with control patients. On an individual-patient basis, a change in KCCQ score of 5 points or more was previously shown to represent a clinically meaningful change.

“Treatment of patients with heart failure is geared to making patients live longer and stay out of the hospital. Enabling patients to feel better is an equally important goal of management, but not all treatments for heart failure can do that. These data from EMPULSE show that, in addition to other clinical benefits, patients also feel better on an SGLT2 inhibitor after just 2 weeks,” Dr. Kosiborod said in an interview.

EMPULSE builds on SOLOIST-WHF

EMPULSE is the second trial to show that an SGLT2 inhibitor can safely and effectively treat patients hospitalized for acute heart failure. Previously, results from the SOLOIST-WHF pivotal trial, which enrolled 1,222 patients with type 2 diabetes recently hospitalized for worsening heart failure, showed that treatment with an investigational, combined SGLT2 and SGLT1 inhibitor, sotagliflozin, resulted in a significant, 33% relative reduction in the primary outcome compared with placebo after a median 9 months of treatment.

“It’s reassuring to see two different drugs and research groups get essentially the same result, showing that starting an SGLT2 inhibitor is safe and effective in selected patients with no contraindications,” said Dr. Bhatt, who was lead investigator for SOLOIST-WHF.

The accumulating evidence for the safety and value of starting an SGLT2 inhibitor when patients are hospitalized for acute heart failure is making this approach increasingly routine for patients who present with heart failure with reduced ejection fraction at Saint Luke’s-Mid America Heart Institute, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri, Kansas City.

“I think we’ll also gradually start using [an SGLT2 inhibitor] in patients hospitalized with heart failure with preserved ejection fraction [HFpEF],” he added, based on the findings from SOLOIST-WHF and EMPULSE, and also recent evidence showing safety and efficacy of empagliflozin in patients with chronic HFpEF in the EMPEROR-Preserved trial, and for dapagliflozin (Farxiga) in the PRESERVED-HF trial.

Empagliflozin recently received from the U.S. Food and Drug Administration an expanded label indication for treating patients with heart failure with no specification for a level of left ventricular ejection fraction. An outcome trial of dapagliflozin in more than 6,000 patients with HFpEF, DELIVER, is currently ongoing but is expected to report results soon.

“The evidence is already compelling that the benefits outweigh the risk. Results from both SOLOIST-WHF and EMPULSE show that there are no significant safety concerns” when these agents are used in patients with acute heart failure,” Dr. Kosiborod declared.

EMPULSE was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). SOLOIST-WHF was sponsored by Sanofi and Lexicon, the companies that have been developing sotagliflozin. Dr. Kosiborod has been a consultant to and received research funding from Boehringer Ingelheim and Eli Lilly, and he has been a consultant or adviser to or led trials on behalf of numerous other companies. Dr. Bhatt has been an adviser to Boehringer Ingelheim and numerous other companies, and he has received research funding from Sanofi, Lexicon, Boehringer Ingelheim, Eli Lilly, and numerous other companies.

WASHINGTON – Treatment of patients acutely hospitalized for heart failure with the SGLT2 inhibitor empagliflozin led to a rapid incremental increase in patient well-being, compared with control patients who received placebo, that appeared after 2 weeks on treatment in a secondary analysis from 530 randomized patients in the EMPULSE trial.

To Mikhail N. Kosiborod, MD, a coinvestigator for EMPULSE who presented new analysis at the annual scientific sessions of the American College of Cardiology, the message from the quick response of acutely hospitalized patients to empagliflozin was clear: “Use these medications, SGLT2 [sodium-glucose cotransporter 2] inhibitors, as early as possible. We’ve seen with other medications that if they are not prescribed during hospitalization it’s unlikely to happen post discharge,” said 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.

Mitchel L. Zoler/MDedge News

“To our knowledge, the very early improvement in the Kansas City Cardiomyopathy Questionnaire [KCCQ] score – a well-known predictor of cardiovascular death and heart failure readmissions – that we observed with empagliflozin at 15 days is the first such observation, and if corroborated by future studies would suggest that initiation of SGLT2 inhibitors during hospitalization for acute heart failure may be a tool for improving the quality of hospital-to-home transitions,” wrote Dr. Kosiborod and his associates in the published version of their report that appeared concurrently with his report at the meeting.

“These data really support initiation [of empagliflozin or another SGLT2 inhibitor] in hospital, presuming that the patient has no contraindications,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and designated discussant for the report.

“The fact that the benefit kicks in so early is really important, because there is a bit of a penalty to wait” to start treatment with an agent from the SGLT2-inhibitor class, added Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Health, in Boston.

In hospital creates a teachable moment

Starting treatment when a patient is hospitalized is also important as “a teachable moment,” added Dr. Bhatt in an interview. “A physician can say to a patient ‘take this drug, and it will prevent you from returning to the hospital,’ at a time when it’s more likely to be impactful, compared with when a patient is out of the hospital and feeling okay and adherence will likely be much lower.”

Mitchel L. Zoler/MDedge News

The results Dr. Kosiborod reported on quality-of-life parameters measured with the KCCQ expanded on what he and his coinvestigators first reported in 2021 with the primary results from EMPULSE, which enrolled 530 patients at 118 centers in 15 countries during June 2020–February 2021. The trial randomized patients hospitalized for acute heart failure after a brief period of stabilization regardless of their left ventricular ejection fraction or presence of diabetes to receive a single, daily dose of 10 mg of empagliflozin (Jardiance) or placebo starting a median of 3 days after admission. Enrolled patients averaged about 71 years of age, about two-thirds were men, 45% had diabetes, 32% had left ventricular ejection fraction greater than 40%, and about two-thirds had decompensated chronic heart failure, while a third had acute de novo heart failure.

The primary outcome for EMPULSE was a combined endpoint of “total clinical endpoints” that included all-cause mortality, heart failure events (heart failure hospitalizations, urgent heart failure visits, and unplanned outpatient heart failure visits) or at least a 5-point change from baseline in the KCCQ score. Using a “win ratio” method for analyzing the composite endpoint, the primary analysis showed that treatment with empagliflozin for 90 days boosted the win ratio by a significant 36% relative to placebo (Nature Med. 2022 Mar;28[3]: 568-74).
 

Benefit independent of baseline symptomatic impairment

Among the new secondary analyses that Dr. Kosiborod reported was a post-hoc calculation that divided the study cohort into tertiles of baseline KCCQ score. The results showed that the degree of improvement for the primary, 90-day outcome of “total clinical benefit” compared with placebo was consistent across all three KCCQ-score tertiles, showing that empagliflozin’s benefit was “independent of symptomatic impairment at baseline,” he said.

The degree of improvement was also similar across all the tested domains of the KCCQ, including the overall summary, clinical summary, the physical limitations, and quality-of-life scores. Average improvement in KCCQ total symptom score 15 days after treatment onset was 5.35 points, compared with control patients. On an individual-patient basis, a change in KCCQ score of 5 points or more was previously shown to represent a clinically meaningful change.

“Treatment of patients with heart failure is geared to making patients live longer and stay out of the hospital. Enabling patients to feel better is an equally important goal of management, but not all treatments for heart failure can do that. These data from EMPULSE show that, in addition to other clinical benefits, patients also feel better on an SGLT2 inhibitor after just 2 weeks,” Dr. Kosiborod said in an interview.

EMPULSE builds on SOLOIST-WHF

EMPULSE is the second trial to show that an SGLT2 inhibitor can safely and effectively treat patients hospitalized for acute heart failure. Previously, results from the SOLOIST-WHF pivotal trial, which enrolled 1,222 patients with type 2 diabetes recently hospitalized for worsening heart failure, showed that treatment with an investigational, combined SGLT2 and SGLT1 inhibitor, sotagliflozin, resulted in a significant, 33% relative reduction in the primary outcome compared with placebo after a median 9 months of treatment.

“It’s reassuring to see two different drugs and research groups get essentially the same result, showing that starting an SGLT2 inhibitor is safe and effective in selected patients with no contraindications,” said Dr. Bhatt, who was lead investigator for SOLOIST-WHF.

The accumulating evidence for the safety and value of starting an SGLT2 inhibitor when patients are hospitalized for acute heart failure is making this approach increasingly routine for patients who present with heart failure with reduced ejection fraction at Saint Luke’s-Mid America Heart Institute, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri, Kansas City.

“I think we’ll also gradually start using [an SGLT2 inhibitor] in patients hospitalized with heart failure with preserved ejection fraction [HFpEF],” he added, based on the findings from SOLOIST-WHF and EMPULSE, and also recent evidence showing safety and efficacy of empagliflozin in patients with chronic HFpEF in the EMPEROR-Preserved trial, and for dapagliflozin (Farxiga) in the PRESERVED-HF trial.

Empagliflozin recently received from the U.S. Food and Drug Administration an expanded label indication for treating patients with heart failure with no specification for a level of left ventricular ejection fraction. An outcome trial of dapagliflozin in more than 6,000 patients with HFpEF, DELIVER, is currently ongoing but is expected to report results soon.

“The evidence is already compelling that the benefits outweigh the risk. Results from both SOLOIST-WHF and EMPULSE show that there are no significant safety concerns” when these agents are used in patients with acute heart failure,” Dr. Kosiborod declared.

EMPULSE was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). SOLOIST-WHF was sponsored by Sanofi and Lexicon, the companies that have been developing sotagliflozin. Dr. Kosiborod has been a consultant to and received research funding from Boehringer Ingelheim and Eli Lilly, and he has been a consultant or adviser to or led trials on behalf of numerous other companies. Dr. Bhatt has been an adviser to Boehringer Ingelheim and numerous other companies, and he has received research funding from Sanofi, Lexicon, Boehringer Ingelheim, Eli Lilly, and numerous other companies.

Structural aortic valve deterioration (SVD) at 5 years is lower following repair with a contemporary transcatheter implantation (TAVI) device than with surgery, according to a pooled analysis of major trials.

For healthier patients with a relatively long life expectancy, this is important information for deciding whether to undergo TAVI or surgical aortic valve repair (SAVR), Michael J. Reardon, MD, said at the annual scientific sessions of the American College of Cardiology.

“Every week I get this question about which repair is more durable,” said Dr. Reardon, whose study was not only designed to compare device deterioration but to evaluate the effect of SVD on major outcomes.

In this analysis, the rates of SVD were compared for the self-expanding supra-annular CoreValve Evolut device and SAVR. The SVD curves separated within the first year. At 5 years, the differences were highly significant favoring TAVI (2.57% vs. 4.38%; P = .0095).

As part of this analysis, the impact of SVD was also assessed independent of type of repair. At 5 years, those with SVD relative to those without had an approximately twofold increase in all-cause mortality, cardiovascular mortality, and hospitalization of aortic valve worsening. These risks were elevated regardless of type of valve repair.

The data presented by Dr. Reardon can be considered device specific. The earlier PARTNER 2A study comparing older- and newer-generation TAVI devices with SAVR produced a different result. When a second-generation balloon-expandable SAPIEN XT device and a third-generation SAPIEN 3 device were compared with surgery, neither device achieved lower SVD rates relative to SAVR.

In PARTNER 2A, the SVD rate for the older device was nearly three times greater than SAVR (1.61 vs. 0.58 per 100 patient-years). The numerically higher SVD rates for the newer device (0.68 vs. 0.58 per 100 patient-years) was not statistically different, but the TAVI device was not superior.

More than 4,000 patients evaluated at 5 years

In the analysis presented by Dr. Reardon, data were pooled from the randomized CoreValve U.S. High-Risk Pivotal Trial and the SURTAVI Intermediate Risk Trial. Together, these studies randomized 971 patients to surgery and 1,128 patients to TAVI. Data on an additional 2,663 patients treated with the Evolut valve in two registries were added to the randomized trial data, providing data on 4,762 total patients with 5-year follow-up.

SVD was defined by two criteria. The first was a mean gradient increase of at least 10 mm Hg plus a mean overall gradient of at least 20 mm Hg as measured with echocardiography and assessed, when possible, by an independent core laboratory. The second was new-onset or increased intraprosthetic aortic regurgitation of at least moderate severity.

When graphed over time, the SVD curves separated in favor of TAVI after about 6 months of follow-up. The shape of the curves also differed. Unlike the steady rise in SVD observed in the surgery group, the SVD rate in the TAVI group remained below 1% for almost 4 years before beginning to climb.

There was greater relative benefit for the TAVI device in patients with annular diameters of 23 mm or less. Unlike the rise in SVD rates that began about 6 months after SAVR, the SVD rates in the TAVI patients remained at 0% for more than 2 years. At 5 years, the differences remained significant favoring TAVI (1.39% vs. 5.86%; P = .049).

In those with larger annular diameters, there was still a consistently lower SVD rate over time for TAVI relative to SAVR, but the trend for an advantage at 5 years fell just short of significance (2.48% vs. 3.96%; P = .067).
 

SVD linked to doubling of mortality

SVD worsened outcomes. When all data surgery and TAVI data were pooled, the hazard ratios corresponded with about a doubling of risk for major adverse outcomes, including all-cause mortality (HR, 1.98; P < .001), cardiovascular mortality (HR, 1.82; P = .008), and hospitalization for aortic valve disease or worsening heart failure (HR, 2.11; P = .01). The relative risks were similar in the two treatment groups, including the risk of all-cause mortality (HR, 2.24; P < .001 for TAVI vs. HR, 2.45; P = .002 for SAVR).

The predictors for SVD on multivariate analysis included female sex, increased body surface area, prior percutaneous coronary intervention, and a prior diagnosis of atrial fibrillation.

Design improvements in TAVI devices are likely to explain these results, said Dr. Reardon, chair of cardiovascular research at Houston Methodist Hospital.

“The CoreValve/Evolut supra-annular, self-expanding bioprosthesis is the first and only transcatheter bioprosthesis to demonstrate lower rates of SVD, compared with surgery,” Dr. Reardon said.

This analysis validated the risks posed by the definition of SVD applied in this study, which appears to be a practical tool for tracking valve function and patient risk. Dr. Reardon also said that the study confirms the value of serial Doppler transthoracic echocardiography as a tool for monitoring SVD.

Several experts agreed that this is important new information.

“This is a remarkable series of findings,” said James McClurken, MD, who is a cardiovascular surgeon affiliated with Temple University, Philadelphia, and practices in Doylestown, Penn. By both demonstrating the prognostic importance of SVD and showing differences between the study device and SAVR, this trial will yield practical data to inform patients about relative risks and benefits.

Athena Poppas, MD, the new president of the ACC and a professor of medicine at Brown University, Providence, R.I., called this study “practice changing” for the same reasons. She also thinks it has valuable data for guiding choice of intervention.

Overall, the data are likely to change thinking about the role of TAVI and surgery in younger, fit patients, according to Megan Coylewright, MD, chief of cardiology at Erlanger Cardiology, Chattanooga, Tenn.

“There are patients [in need of aortic valve repair] with a long life expectancy who have been told you have to have a surgical repair because we know they last longer,” she said. Although she said that relative outcomes after longer follow-up remain unknown, “I think this does throw that comment into question.”

Dr. Reardon has financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical. Dr. Poppas and McClurken reported no potential financial conflicts of interest. Dr. Coylewright reported financial relationships with Abbott, Alleviant, Boston Scientific, Cardiosmart, Edwards Lifesciences, Medtronic, and Occlutech. The study received financial support from Medtronic.

Structural aortic valve deterioration (SVD) at 5 years is lower following repair with a contemporary transcatheter implantation (TAVI) device than with surgery, according to a pooled analysis of major trials.

For healthier patients with a relatively long life expectancy, this is important information for deciding whether to undergo TAVI or surgical aortic valve repair (SAVR), Michael J. Reardon, MD, said at the annual scientific sessions of the American College of Cardiology.

“Every week I get this question about which repair is more durable,” said Dr. Reardon, whose study was not only designed to compare device deterioration but to evaluate the effect of SVD on major outcomes.

In this analysis, the rates of SVD were compared for the self-expanding supra-annular CoreValve Evolut device and SAVR. The SVD curves separated within the first year. At 5 years, the differences were highly significant favoring TAVI (2.57% vs. 4.38%; P = .0095).

As part of this analysis, the impact of SVD was also assessed independent of type of repair. At 5 years, those with SVD relative to those without had an approximately twofold increase in all-cause mortality, cardiovascular mortality, and hospitalization of aortic valve worsening. These risks were elevated regardless of type of valve repair.

The data presented by Dr. Reardon can be considered device specific. The earlier PARTNER 2A study comparing older- and newer-generation TAVI devices with SAVR produced a different result. When a second-generation balloon-expandable SAPIEN XT device and a third-generation SAPIEN 3 device were compared with surgery, neither device achieved lower SVD rates relative to SAVR.

In PARTNER 2A, the SVD rate for the older device was nearly three times greater than SAVR (1.61 vs. 0.58 per 100 patient-years). The numerically higher SVD rates for the newer device (0.68 vs. 0.58 per 100 patient-years) was not statistically different, but the TAVI device was not superior.

More than 4,000 patients evaluated at 5 years

In the analysis presented by Dr. Reardon, data were pooled from the randomized CoreValve U.S. High-Risk Pivotal Trial and the SURTAVI Intermediate Risk Trial. Together, these studies randomized 971 patients to surgery and 1,128 patients to TAVI. Data on an additional 2,663 patients treated with the Evolut valve in two registries were added to the randomized trial data, providing data on 4,762 total patients with 5-year follow-up.

SVD was defined by two criteria. The first was a mean gradient increase of at least 10 mm Hg plus a mean overall gradient of at least 20 mm Hg as measured with echocardiography and assessed, when possible, by an independent core laboratory. The second was new-onset or increased intraprosthetic aortic regurgitation of at least moderate severity.

When graphed over time, the SVD curves separated in favor of TAVI after about 6 months of follow-up. The shape of the curves also differed. Unlike the steady rise in SVD observed in the surgery group, the SVD rate in the TAVI group remained below 1% for almost 4 years before beginning to climb.

There was greater relative benefit for the TAVI device in patients with annular diameters of 23 mm or less. Unlike the rise in SVD rates that began about 6 months after SAVR, the SVD rates in the TAVI patients remained at 0% for more than 2 years. At 5 years, the differences remained significant favoring TAVI (1.39% vs. 5.86%; P = .049).

In those with larger annular diameters, there was still a consistently lower SVD rate over time for TAVI relative to SAVR, but the trend for an advantage at 5 years fell just short of significance (2.48% vs. 3.96%; P = .067).
 

SVD linked to doubling of mortality

SVD worsened outcomes. When all data surgery and TAVI data were pooled, the hazard ratios corresponded with about a doubling of risk for major adverse outcomes, including all-cause mortality (HR, 1.98; P < .001), cardiovascular mortality (HR, 1.82; P = .008), and hospitalization for aortic valve disease or worsening heart failure (HR, 2.11; P = .01). The relative risks were similar in the two treatment groups, including the risk of all-cause mortality (HR, 2.24; P < .001 for TAVI vs. HR, 2.45; P = .002 for SAVR).

The predictors for SVD on multivariate analysis included female sex, increased body surface area, prior percutaneous coronary intervention, and a prior diagnosis of atrial fibrillation.

Design improvements in TAVI devices are likely to explain these results, said Dr. Reardon, chair of cardiovascular research at Houston Methodist Hospital.

“The CoreValve/Evolut supra-annular, self-expanding bioprosthesis is the first and only transcatheter bioprosthesis to demonstrate lower rates of SVD, compared with surgery,” Dr. Reardon said.

This analysis validated the risks posed by the definition of SVD applied in this study, which appears to be a practical tool for tracking valve function and patient risk. Dr. Reardon also said that the study confirms the value of serial Doppler transthoracic echocardiography as a tool for monitoring SVD.

Several experts agreed that this is important new information.

“This is a remarkable series of findings,” said James McClurken, MD, who is a cardiovascular surgeon affiliated with Temple University, Philadelphia, and practices in Doylestown, Penn. By both demonstrating the prognostic importance of SVD and showing differences between the study device and SAVR, this trial will yield practical data to inform patients about relative risks and benefits.

Athena Poppas, MD, the new president of the ACC and a professor of medicine at Brown University, Providence, R.I., called this study “practice changing” for the same reasons. She also thinks it has valuable data for guiding choice of intervention.

Overall, the data are likely to change thinking about the role of TAVI and surgery in younger, fit patients, according to Megan Coylewright, MD, chief of cardiology at Erlanger Cardiology, Chattanooga, Tenn.

“There are patients [in need of aortic valve repair] with a long life expectancy who have been told you have to have a surgical repair because we know they last longer,” she said. Although she said that relative outcomes after longer follow-up remain unknown, “I think this does throw that comment into question.”

Dr. Reardon has financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical. Dr. Poppas and McClurken reported no potential financial conflicts of interest. Dr. Coylewright reported financial relationships with Abbott, Alleviant, Boston Scientific, Cardiosmart, Edwards Lifesciences, Medtronic, and Occlutech. The study received financial support from Medtronic.

Structural aortic valve deterioration (SVD) at 5 years is lower following repair with a contemporary transcatheter implantation (TAVI) device than with surgery, according to a pooled analysis of major trials.

For healthier patients with a relatively long life expectancy, this is important information for deciding whether to undergo TAVI or surgical aortic valve repair (SAVR), Michael J. Reardon, MD, said at the annual scientific sessions of the American College of Cardiology.

“Every week I get this question about which repair is more durable,” said Dr. Reardon, whose study was not only designed to compare device deterioration but to evaluate the effect of SVD on major outcomes.

In this analysis, the rates of SVD were compared for the self-expanding supra-annular CoreValve Evolut device and SAVR. The SVD curves separated within the first year. At 5 years, the differences were highly significant favoring TAVI (2.57% vs. 4.38%; P = .0095).

As part of this analysis, the impact of SVD was also assessed independent of type of repair. At 5 years, those with SVD relative to those without had an approximately twofold increase in all-cause mortality, cardiovascular mortality, and hospitalization of aortic valve worsening. These risks were elevated regardless of type of valve repair.

The data presented by Dr. Reardon can be considered device specific. The earlier PARTNER 2A study comparing older- and newer-generation TAVI devices with SAVR produced a different result. When a second-generation balloon-expandable SAPIEN XT device and a third-generation SAPIEN 3 device were compared with surgery, neither device achieved lower SVD rates relative to SAVR.

In PARTNER 2A, the SVD rate for the older device was nearly three times greater than SAVR (1.61 vs. 0.58 per 100 patient-years). The numerically higher SVD rates for the newer device (0.68 vs. 0.58 per 100 patient-years) was not statistically different, but the TAVI device was not superior.

More than 4,000 patients evaluated at 5 years

In the analysis presented by Dr. Reardon, data were pooled from the randomized CoreValve U.S. High-Risk Pivotal Trial and the SURTAVI Intermediate Risk Trial. Together, these studies randomized 971 patients to surgery and 1,128 patients to TAVI. Data on an additional 2,663 patients treated with the Evolut valve in two registries were added to the randomized trial data, providing data on 4,762 total patients with 5-year follow-up.

SVD was defined by two criteria. The first was a mean gradient increase of at least 10 mm Hg plus a mean overall gradient of at least 20 mm Hg as measured with echocardiography and assessed, when possible, by an independent core laboratory. The second was new-onset or increased intraprosthetic aortic regurgitation of at least moderate severity.

When graphed over time, the SVD curves separated in favor of TAVI after about 6 months of follow-up. The shape of the curves also differed. Unlike the steady rise in SVD observed in the surgery group, the SVD rate in the TAVI group remained below 1% for almost 4 years before beginning to climb.

There was greater relative benefit for the TAVI device in patients with annular diameters of 23 mm or less. Unlike the rise in SVD rates that began about 6 months after SAVR, the SVD rates in the TAVI patients remained at 0% for more than 2 years. At 5 years, the differences remained significant favoring TAVI (1.39% vs. 5.86%; P = .049).

In those with larger annular diameters, there was still a consistently lower SVD rate over time for TAVI relative to SAVR, but the trend for an advantage at 5 years fell just short of significance (2.48% vs. 3.96%; P = .067).
 

SVD linked to doubling of mortality

SVD worsened outcomes. When all data surgery and TAVI data were pooled, the hazard ratios corresponded with about a doubling of risk for major adverse outcomes, including all-cause mortality (HR, 1.98; P < .001), cardiovascular mortality (HR, 1.82; P = .008), and hospitalization for aortic valve disease or worsening heart failure (HR, 2.11; P = .01). The relative risks were similar in the two treatment groups, including the risk of all-cause mortality (HR, 2.24; P < .001 for TAVI vs. HR, 2.45; P = .002 for SAVR).

The predictors for SVD on multivariate analysis included female sex, increased body surface area, prior percutaneous coronary intervention, and a prior diagnosis of atrial fibrillation.

Design improvements in TAVI devices are likely to explain these results, said Dr. Reardon, chair of cardiovascular research at Houston Methodist Hospital.

“The CoreValve/Evolut supra-annular, self-expanding bioprosthesis is the first and only transcatheter bioprosthesis to demonstrate lower rates of SVD, compared with surgery,” Dr. Reardon said.

This analysis validated the risks posed by the definition of SVD applied in this study, which appears to be a practical tool for tracking valve function and patient risk. Dr. Reardon also said that the study confirms the value of serial Doppler transthoracic echocardiography as a tool for monitoring SVD.

Several experts agreed that this is important new information.

“This is a remarkable series of findings,” said James McClurken, MD, who is a cardiovascular surgeon affiliated with Temple University, Philadelphia, and practices in Doylestown, Penn. By both demonstrating the prognostic importance of SVD and showing differences between the study device and SAVR, this trial will yield practical data to inform patients about relative risks and benefits.

Athena Poppas, MD, the new president of the ACC and a professor of medicine at Brown University, Providence, R.I., called this study “practice changing” for the same reasons. She also thinks it has valuable data for guiding choice of intervention.

Overall, the data are likely to change thinking about the role of TAVI and surgery in younger, fit patients, according to Megan Coylewright, MD, chief of cardiology at Erlanger Cardiology, Chattanooga, Tenn.

“There are patients [in need of aortic valve repair] with a long life expectancy who have been told you have to have a surgical repair because we know they last longer,” she said. Although she said that relative outcomes after longer follow-up remain unknown, “I think this does throw that comment into question.”

Dr. Reardon has financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical. Dr. Poppas and McClurken reported no potential financial conflicts of interest. Dr. Coylewright reported financial relationships with Abbott, Alleviant, Boston Scientific, Cardiosmart, Edwards Lifesciences, Medtronic, and Occlutech. The study received financial support from Medtronic.

Radiofrequency renal denervation provided progressive reductions in blood pressure at 3 years in patients on antihypertensive medication, but this did not translate into fewer antihypertensive drugs, new results from the SPYRAL HTN-ON MED trial show.

At 36 months, 24-hour ambulatory systolic and diastolic blood pressures were 10.0 mm Hg (P = .003) and 5.9 mm Hg (P = .005) lower, respectively, in patients who underwent renal denervation with Medtronic’s Symplicity Spyral radiofrequency catheter, compared with patients treated with a sham procedure.

The number of antihypertensive drugs, however, increased in both groups from an average of two at baseline and 6 months to three at 3 years (P = .76).

Based on the number of drugs, class, and dose, medication burden increased significantly in the sham group at 12 months (6.5 vs. 4.9; P = .04) and trended higher at 3 years (10.3 vs. 7.6; P = .26).

The procedure appeared safe, with no renal safety events in the denervation group and only three safety events overall at 36 months. One cardiovascular death occurred 693 days after a sham procedure and one patient had a hypertensive crisis and stroke 427 days after renal denervation and was discharged in stable condition, according to results published in The Lancet.

“Given the long-term safety and efficacy of renal denervation, it may provide an alternative adjunctive treatment modality in the management of hypertension,” Felix Mahfoud, MD, Saarland University Hospital, Homburg, Germany, said during a presentation of the study at the recent American College of Cardiology (ACC) 2022 Scientific Session.

Ted Bosworth/MDedge News

Sham-controlled evidence

As previously reported, significant BP reductions at 6 months in SPYRAL HTN-ON provided proof of concept and helped revive enthusiasm for the procedure after failing to meet the primary endpoint in the SYMPLICITY HTN-3 trial. Results from the Global SYMPLICITY Registry have shown benefits out to 3 years, but sham-controlled data have been lacking.

The trial enrolled 80 patients with an office systolic BP of 150-180 mm Hg and diastolic of 90 mm Hg or greater and 24-hour ambulatory systolic BP of 140-170 mm Hg, who were on up to three antihypertensive medications.

Medication changes were allowed beginning at 6 months; patients and physicians were unblinded at 12 months. Between 24 and 36 months, 13 patients assigned to the sham procedure crossed over to denervation treatment. Medication adherence at 3 years was 77% in the denervation group versus 93% in the sham group.

At 3 years, the renal denervation group had significantly greater reductions from baseline in several ambulatory BP measures, compared with the sham group, including: 24-hour systolic (10.0 mm Hg), morning systolic (11.0 mm Hg), daytime systolic (8.9 mm Hg), and night-time systolic (11.8 mm Hg).

Renal denervation led to an 8.2 mm Hg greater fall in office systolic BP, but this failed to reach statistical significance (P = .07).

Almost twice as many patients in the denervation group achieved a 24-hour systolic BP less than 140 mm Hg than in the sham group (83.3%, vs. 43.8%; P = .002), Dr. Mahfoud reported.

“Although renal denervation appears to effectively lower blood pressure, participants in the renal denervation group did not quite reach guideline-recommended blood pressure thresholds,” Harini Sarathy, MD, University of California, San Francisco, and Liann Abu Salman, MD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, point out in an accompanying editorial. “This result could have been due to a degree of physician inertia or differential prescribing of blood pressure medications for the intervention group, compared with the sham control group, wherein physicians might have considered renal denervation to be the fourth antihypertensive medication.”

The editorialists also note that nearly a third of the sham group (13 of 42) underwent renal denervation. “The differentially missing BP readings at 24 months for the sham group are a cause for concern, although the absence of any meaningful differences in results after imputation is somewhat reassuring.”

A 10 mm Hg reduction in BP after 36 months would be expected to translate to a significant reduction in cardiovascular outcomes, they say. The sustained reductions in several systolic readings also speak to the “always-on distinctiveness” that renal denervation proponents claim.

“In the stark absence of novel antihypertensive drug development, renal denervation is seemingly poised to be an effective supplement, if not an alternative, to complex antihypertensive regimens with frequent dosing schedules,” they conclude. “We look forward to results of the Expansion trial in providing more definitive answers regarding whether this translates to meaningful protection from target organ damage.”

Dr. Mahfoud observed that BP control worsened during the COVID-19 pandemic, which may have impacted BP results, but that in-person follow-up visits were still performed. Other limitations are a lack of information on patients’ exercise, diet, and smoking habits and that blood and urine testing assessed medication adherence at discrete time points, but adherence over an extended period of time is uncertain.

Dr. Mahfoud reports research grants from Deutsche Forschungsgemeinschaft and Deutsche Gesellschaft für Kardiologie and scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. The study was funded by Medtronic. Dr. Sarathy and Dr. Salman report no relevant financial relationships.

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

Radiofrequency renal denervation provided progressive reductions in blood pressure at 3 years in patients on antihypertensive medication, but this did not translate into fewer antihypertensive drugs, new results from the SPYRAL HTN-ON MED trial show.

At 36 months, 24-hour ambulatory systolic and diastolic blood pressures were 10.0 mm Hg (P = .003) and 5.9 mm Hg (P = .005) lower, respectively, in patients who underwent renal denervation with Medtronic’s Symplicity Spyral radiofrequency catheter, compared with patients treated with a sham procedure.

The number of antihypertensive drugs, however, increased in both groups from an average of two at baseline and 6 months to three at 3 years (P = .76).

Based on the number of drugs, class, and dose, medication burden increased significantly in the sham group at 12 months (6.5 vs. 4.9; P = .04) and trended higher at 3 years (10.3 vs. 7.6; P = .26).

The procedure appeared safe, with no renal safety events in the denervation group and only three safety events overall at 36 months. One cardiovascular death occurred 693 days after a sham procedure and one patient had a hypertensive crisis and stroke 427 days after renal denervation and was discharged in stable condition, according to results published in The Lancet.

“Given the long-term safety and efficacy of renal denervation, it may provide an alternative adjunctive treatment modality in the management of hypertension,” Felix Mahfoud, MD, Saarland University Hospital, Homburg, Germany, said during a presentation of the study at the recent American College of Cardiology (ACC) 2022 Scientific Session.

Ted Bosworth/MDedge News

Sham-controlled evidence

As previously reported, significant BP reductions at 6 months in SPYRAL HTN-ON provided proof of concept and helped revive enthusiasm for the procedure after failing to meet the primary endpoint in the SYMPLICITY HTN-3 trial. Results from the Global SYMPLICITY Registry have shown benefits out to 3 years, but sham-controlled data have been lacking.

The trial enrolled 80 patients with an office systolic BP of 150-180 mm Hg and diastolic of 90 mm Hg or greater and 24-hour ambulatory systolic BP of 140-170 mm Hg, who were on up to three antihypertensive medications.

Medication changes were allowed beginning at 6 months; patients and physicians were unblinded at 12 months. Between 24 and 36 months, 13 patients assigned to the sham procedure crossed over to denervation treatment. Medication adherence at 3 years was 77% in the denervation group versus 93% in the sham group.

At 3 years, the renal denervation group had significantly greater reductions from baseline in several ambulatory BP measures, compared with the sham group, including: 24-hour systolic (10.0 mm Hg), morning systolic (11.0 mm Hg), daytime systolic (8.9 mm Hg), and night-time systolic (11.8 mm Hg).

Renal denervation led to an 8.2 mm Hg greater fall in office systolic BP, but this failed to reach statistical significance (P = .07).

Almost twice as many patients in the denervation group achieved a 24-hour systolic BP less than 140 mm Hg than in the sham group (83.3%, vs. 43.8%; P = .002), Dr. Mahfoud reported.

“Although renal denervation appears to effectively lower blood pressure, participants in the renal denervation group did not quite reach guideline-recommended blood pressure thresholds,” Harini Sarathy, MD, University of California, San Francisco, and Liann Abu Salman, MD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, point out in an accompanying editorial. “This result could have been due to a degree of physician inertia or differential prescribing of blood pressure medications for the intervention group, compared with the sham control group, wherein physicians might have considered renal denervation to be the fourth antihypertensive medication.”

The editorialists also note that nearly a third of the sham group (13 of 42) underwent renal denervation. “The differentially missing BP readings at 24 months for the sham group are a cause for concern, although the absence of any meaningful differences in results after imputation is somewhat reassuring.”

A 10 mm Hg reduction in BP after 36 months would be expected to translate to a significant reduction in cardiovascular outcomes, they say. The sustained reductions in several systolic readings also speak to the “always-on distinctiveness” that renal denervation proponents claim.

“In the stark absence of novel antihypertensive drug development, renal denervation is seemingly poised to be an effective supplement, if not an alternative, to complex antihypertensive regimens with frequent dosing schedules,” they conclude. “We look forward to results of the Expansion trial in providing more definitive answers regarding whether this translates to meaningful protection from target organ damage.”

Dr. Mahfoud observed that BP control worsened during the COVID-19 pandemic, which may have impacted BP results, but that in-person follow-up visits were still performed. Other limitations are a lack of information on patients’ exercise, diet, and smoking habits and that blood and urine testing assessed medication adherence at discrete time points, but adherence over an extended period of time is uncertain.

Dr. Mahfoud reports research grants from Deutsche Forschungsgemeinschaft and Deutsche Gesellschaft für Kardiologie and scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. The study was funded by Medtronic. Dr. Sarathy and Dr. Salman report no relevant financial relationships.

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

Radiofrequency renal denervation provided progressive reductions in blood pressure at 3 years in patients on antihypertensive medication, but this did not translate into fewer antihypertensive drugs, new results from the SPYRAL HTN-ON MED trial show.

At 36 months, 24-hour ambulatory systolic and diastolic blood pressures were 10.0 mm Hg (P = .003) and 5.9 mm Hg (P = .005) lower, respectively, in patients who underwent renal denervation with Medtronic’s Symplicity Spyral radiofrequency catheter, compared with patients treated with a sham procedure.

The number of antihypertensive drugs, however, increased in both groups from an average of two at baseline and 6 months to three at 3 years (P = .76).

Based on the number of drugs, class, and dose, medication burden increased significantly in the sham group at 12 months (6.5 vs. 4.9; P = .04) and trended higher at 3 years (10.3 vs. 7.6; P = .26).

The procedure appeared safe, with no renal safety events in the denervation group and only three safety events overall at 36 months. One cardiovascular death occurred 693 days after a sham procedure and one patient had a hypertensive crisis and stroke 427 days after renal denervation and was discharged in stable condition, according to results published in The Lancet.

“Given the long-term safety and efficacy of renal denervation, it may provide an alternative adjunctive treatment modality in the management of hypertension,” Felix Mahfoud, MD, Saarland University Hospital, Homburg, Germany, said during a presentation of the study at the recent American College of Cardiology (ACC) 2022 Scientific Session.

Ted Bosworth/MDedge News

Sham-controlled evidence

As previously reported, significant BP reductions at 6 months in SPYRAL HTN-ON provided proof of concept and helped revive enthusiasm for the procedure after failing to meet the primary endpoint in the SYMPLICITY HTN-3 trial. Results from the Global SYMPLICITY Registry have shown benefits out to 3 years, but sham-controlled data have been lacking.

The trial enrolled 80 patients with an office systolic BP of 150-180 mm Hg and diastolic of 90 mm Hg or greater and 24-hour ambulatory systolic BP of 140-170 mm Hg, who were on up to three antihypertensive medications.

Medication changes were allowed beginning at 6 months; patients and physicians were unblinded at 12 months. Between 24 and 36 months, 13 patients assigned to the sham procedure crossed over to denervation treatment. Medication adherence at 3 years was 77% in the denervation group versus 93% in the sham group.

At 3 years, the renal denervation group had significantly greater reductions from baseline in several ambulatory BP measures, compared with the sham group, including: 24-hour systolic (10.0 mm Hg), morning systolic (11.0 mm Hg), daytime systolic (8.9 mm Hg), and night-time systolic (11.8 mm Hg).

Renal denervation led to an 8.2 mm Hg greater fall in office systolic BP, but this failed to reach statistical significance (P = .07).

Almost twice as many patients in the denervation group achieved a 24-hour systolic BP less than 140 mm Hg than in the sham group (83.3%, vs. 43.8%; P = .002), Dr. Mahfoud reported.

“Although renal denervation appears to effectively lower blood pressure, participants in the renal denervation group did not quite reach guideline-recommended blood pressure thresholds,” Harini Sarathy, MD, University of California, San Francisco, and Liann Abu Salman, MD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, point out in an accompanying editorial. “This result could have been due to a degree of physician inertia or differential prescribing of blood pressure medications for the intervention group, compared with the sham control group, wherein physicians might have considered renal denervation to be the fourth antihypertensive medication.”

The editorialists also note that nearly a third of the sham group (13 of 42) underwent renal denervation. “The differentially missing BP readings at 24 months for the sham group are a cause for concern, although the absence of any meaningful differences in results after imputation is somewhat reassuring.”

A 10 mm Hg reduction in BP after 36 months would be expected to translate to a significant reduction in cardiovascular outcomes, they say. The sustained reductions in several systolic readings also speak to the “always-on distinctiveness” that renal denervation proponents claim.

“In the stark absence of novel antihypertensive drug development, renal denervation is seemingly poised to be an effective supplement, if not an alternative, to complex antihypertensive regimens with frequent dosing schedules,” they conclude. “We look forward to results of the Expansion trial in providing more definitive answers regarding whether this translates to meaningful protection from target organ damage.”

Dr. Mahfoud observed that BP control worsened during the COVID-19 pandemic, which may have impacted BP results, but that in-person follow-up visits were still performed. Other limitations are a lack of information on patients’ exercise, diet, and smoking habits and that blood and urine testing assessed medication adherence at discrete time points, but adherence over an extended period of time is uncertain.

Dr. Mahfoud reports research grants from Deutsche Forschungsgemeinschaft and Deutsche Gesellschaft für Kardiologie and scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. The study was funded by Medtronic. Dr. Sarathy and Dr. Salman report no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

The rates of infection involving cardiac implanted electronic devices (CIEDs), like pacemakers and cardioverter defibrillators (ICDs), are substantial, but only a minority of patients in the United States receive the guideline-directed recommendation of device removal, according to data from a Medicare population.

The study was conducted on the hypothesis that adherence to guidelines were low, “but we were surprised by how low the extraction rates turned out to be,” Sean D. Pokorney, MD, an electrophysiologist at the Duke Clinical Research Institute, Durham, N.C., reported at the annual scientific sessions of the American College of Cardiology.

The major U.S. and European guidelines are uniform in recommending complete extraction for a CIED infection. The American Heart Association and the Heart Rhythm Society and two out of the three other guidelines cited by Dr. Pokorney not only recommend extraction but specify prompt extraction.

Neither complete extraction nor prompt extraction are typical.

Of the 11,619 CIED infection cases identified in the Medicare database, 18.2% underwent extraction within 30 days of diagnosis. Only 13% were extracted within 6 days.
 

Lack of extraction may cause avoidable mortality

The result is likely to be avoidable mortality. Among those with extraction within 30 days, 80% were still alive 1 year later. Survival at 1 year fell to 67.6% in those without an extraction within this time frame.

This translated to a 22% lower rate of death at 1 year (hazard ratio, 0.78; P = .008) in those who underwent extraction within 30 days.

For those in whom the device was extracted within 7 days, the associated HR for death at 1 year was more than 40% lower (HR, 0.59; P < .001), reported Dr. Pokorney, who characterized these reductions as occurring in “a dose-response fashion.”

The very high risk of relapse despite antibiotics is the reason that “there is a class 1 indication for complete hardware removal,” Dr. Pokorney. He cited five studies that addressed this question. With partial device removal or medical therapy alone, relapse was consistently 50% or greater. In one study, it was 67%. In another it was 100%.

With complete removal, the rate of infection relapse was 1% or lower in four. In the fifth, the rate was 4.2%.

Infections can occur early or late after implantation, but cases accumulate over time. In the Medicare data sample, infection rates climbed from 0.3% at 1 year to 0.6% at 2 years and then to 1.1% at 3 years, Dr. Pokorney reported.

Other studies have also shown a steady increase in the proportion of implanted devices associated with infection over time. In a cohort study conducted in Olmstead County, Minnesota, the cumulative probability of a CIED infection reached 6.2% after 15 years and 11.7% after 25 years. While about half of these were infections localized to the device pocket, the others were potentially life-threatening systemic infections, according to Dr. Pokorney, who cited this study.

In his analysis of the Medicare data, all fee-for-service patients receiving a first CIED implant over a period of 14 years were included. The 14-year period ended just before the COVID-19 epidemic.

The more than 11,000 CIED infections were identified in 1,065,549 total CIED patients. Most (72%) had received a pacemaker. Of the others , more than half received an ICD and the others received a cardiac resynchronization device. The median age was 78 years.
 

Female and Black patients even less likely to undergo extraction

About half (49.1%) of the overall study population was female, but females represented only about 40% of those who developed an infection. Blacks represented just under 8% of the population but nearly 16% of the CIED infections. Both females and Blacks were significantly less likely than the overall study population to undergo extraction for their infection (P < .001 for both).

Perhaps predictably, patients with comorbidities were more likely to develop CIED infections. For example, 87% of those with infection, versus only 64.9% of the overall population, were in heart failure at the time of implantation. Diabetes (68.3% vs. 49.3%), ischemic heart disease (91.9% vs. 79.4%), renal disease (70.5% vs. 37.9%), and chronic obstructive pulmonary disease (70.6% vs. 55.0%) were also more common at baseline in those who went on to a CIED infection than in the overall population.

Based on the evidence that there is a large unmet need to improve adherence to the guidelines, Dr. Pokorney called for care pathways and other quality initiatives to address the problem.

The reasons that so many patients are not undergoing prompt device extraction at the time of infection is unclear, but Dr. Pokorney offered some hypotheses.

“There appears to be a false belief in the efficacy of antibiotics for treating CIED infections,” Dr. Pokorney said.
 

Comorbidities shouldn’t delay extraction

It is also possible that clinicians are concerned about performing extractions in patients with multiple comorbidities. If clinicians are delaying extractions for this reason, Dr. Pokorney suggested this behavior is misdirected given the fact that delays appear to increase mortality risk.

Several experts, including Rachel Lambert, MD, an electrophysiologist and professor of medicine at Yale University, New Haven, Conn., agreed that these data deserve a response.

“I was not surprised by the mortality data, but I was surprised at this low extraction rate,” said Dr. Lambert, who concurs with the guidelines. She indicated this study provides teeth to prompt action.

“It is great to have these data about the increased mortality risk to back up the guidelines,” she said.

More information is needed to understand exactly why CIED infection is not now leading to guideline-directed care. Dr. Pokorney said: “Where do we go from here is a key question.”

While several different types of initiatives might be needed, Dr. Pokorney called for regionalization of care to address the fact that not every center that places CIEDs has the capability to perform extractions.

“Extraction is not available at every center, and it probably should not be available at every center, so mechanisms are need to get patients with infection to the specialized centers that provide care,” he said.

Dr. Pokorney has financial relationships with Boston Scientific, Bristol-Myers Squibb, Gilead, Janssen, Medtronic, Pfizer, and Philips. Dr. Lambert reported financial relationships with Abbott, Amgen, and Medtronic.

The rates of infection involving cardiac implanted electronic devices (CIEDs), like pacemakers and cardioverter defibrillators (ICDs), are substantial, but only a minority of patients in the United States receive the guideline-directed recommendation of device removal, according to data from a Medicare population.

The study was conducted on the hypothesis that adherence to guidelines were low, “but we were surprised by how low the extraction rates turned out to be,” Sean D. Pokorney, MD, an electrophysiologist at the Duke Clinical Research Institute, Durham, N.C., reported at the annual scientific sessions of the American College of Cardiology.

The major U.S. and European guidelines are uniform in recommending complete extraction for a CIED infection. The American Heart Association and the Heart Rhythm Society and two out of the three other guidelines cited by Dr. Pokorney not only recommend extraction but specify prompt extraction.

Neither complete extraction nor prompt extraction are typical.

Of the 11,619 CIED infection cases identified in the Medicare database, 18.2% underwent extraction within 30 days of diagnosis. Only 13% were extracted within 6 days.
 

Lack of extraction may cause avoidable mortality

The result is likely to be avoidable mortality. Among those with extraction within 30 days, 80% were still alive 1 year later. Survival at 1 year fell to 67.6% in those without an extraction within this time frame.

This translated to a 22% lower rate of death at 1 year (hazard ratio, 0.78; P = .008) in those who underwent extraction within 30 days.

For those in whom the device was extracted within 7 days, the associated HR for death at 1 year was more than 40% lower (HR, 0.59; P < .001), reported Dr. Pokorney, who characterized these reductions as occurring in “a dose-response fashion.”

The very high risk of relapse despite antibiotics is the reason that “there is a class 1 indication for complete hardware removal,” Dr. Pokorney. He cited five studies that addressed this question. With partial device removal or medical therapy alone, relapse was consistently 50% or greater. In one study, it was 67%. In another it was 100%.

With complete removal, the rate of infection relapse was 1% or lower in four. In the fifth, the rate was 4.2%.

Infections can occur early or late after implantation, but cases accumulate over time. In the Medicare data sample, infection rates climbed from 0.3% at 1 year to 0.6% at 2 years and then to 1.1% at 3 years, Dr. Pokorney reported.

Other studies have also shown a steady increase in the proportion of implanted devices associated with infection over time. In a cohort study conducted in Olmstead County, Minnesota, the cumulative probability of a CIED infection reached 6.2% after 15 years and 11.7% after 25 years. While about half of these were infections localized to the device pocket, the others were potentially life-threatening systemic infections, according to Dr. Pokorney, who cited this study.

In his analysis of the Medicare data, all fee-for-service patients receiving a first CIED implant over a period of 14 years were included. The 14-year period ended just before the COVID-19 epidemic.

The more than 11,000 CIED infections were identified in 1,065,549 total CIED patients. Most (72%) had received a pacemaker. Of the others , more than half received an ICD and the others received a cardiac resynchronization device. The median age was 78 years.
 

Female and Black patients even less likely to undergo extraction

About half (49.1%) of the overall study population was female, but females represented only about 40% of those who developed an infection. Blacks represented just under 8% of the population but nearly 16% of the CIED infections. Both females and Blacks were significantly less likely than the overall study population to undergo extraction for their infection (P < .001 for both).

Perhaps predictably, patients with comorbidities were more likely to develop CIED infections. For example, 87% of those with infection, versus only 64.9% of the overall population, were in heart failure at the time of implantation. Diabetes (68.3% vs. 49.3%), ischemic heart disease (91.9% vs. 79.4%), renal disease (70.5% vs. 37.9%), and chronic obstructive pulmonary disease (70.6% vs. 55.0%) were also more common at baseline in those who went on to a CIED infection than in the overall population.

Based on the evidence that there is a large unmet need to improve adherence to the guidelines, Dr. Pokorney called for care pathways and other quality initiatives to address the problem.

The reasons that so many patients are not undergoing prompt device extraction at the time of infection is unclear, but Dr. Pokorney offered some hypotheses.

“There appears to be a false belief in the efficacy of antibiotics for treating CIED infections,” Dr. Pokorney said.
 

Comorbidities shouldn’t delay extraction

It is also possible that clinicians are concerned about performing extractions in patients with multiple comorbidities. If clinicians are delaying extractions for this reason, Dr. Pokorney suggested this behavior is misdirected given the fact that delays appear to increase mortality risk.

Several experts, including Rachel Lambert, MD, an electrophysiologist and professor of medicine at Yale University, New Haven, Conn., agreed that these data deserve a response.

“I was not surprised by the mortality data, but I was surprised at this low extraction rate,” said Dr. Lambert, who concurs with the guidelines. She indicated this study provides teeth to prompt action.

“It is great to have these data about the increased mortality risk to back up the guidelines,” she said.

More information is needed to understand exactly why CIED infection is not now leading to guideline-directed care. Dr. Pokorney said: “Where do we go from here is a key question.”

While several different types of initiatives might be needed, Dr. Pokorney called for regionalization of care to address the fact that not every center that places CIEDs has the capability to perform extractions.

“Extraction is not available at every center, and it probably should not be available at every center, so mechanisms are need to get patients with infection to the specialized centers that provide care,” he said.

Dr. Pokorney has financial relationships with Boston Scientific, Bristol-Myers Squibb, Gilead, Janssen, Medtronic, Pfizer, and Philips. Dr. Lambert reported financial relationships with Abbott, Amgen, and Medtronic.

The rates of infection involving cardiac implanted electronic devices (CIEDs), like pacemakers and cardioverter defibrillators (ICDs), are substantial, but only a minority of patients in the United States receive the guideline-directed recommendation of device removal, according to data from a Medicare population.

The study was conducted on the hypothesis that adherence to guidelines were low, “but we were surprised by how low the extraction rates turned out to be,” Sean D. Pokorney, MD, an electrophysiologist at the Duke Clinical Research Institute, Durham, N.C., reported at the annual scientific sessions of the American College of Cardiology.

The major U.S. and European guidelines are uniform in recommending complete extraction for a CIED infection. The American Heart Association and the Heart Rhythm Society and two out of the three other guidelines cited by Dr. Pokorney not only recommend extraction but specify prompt extraction.

Neither complete extraction nor prompt extraction are typical.

Of the 11,619 CIED infection cases identified in the Medicare database, 18.2% underwent extraction within 30 days of diagnosis. Only 13% were extracted within 6 days.
 

Lack of extraction may cause avoidable mortality

The result is likely to be avoidable mortality. Among those with extraction within 30 days, 80% were still alive 1 year later. Survival at 1 year fell to 67.6% in those without an extraction within this time frame.

This translated to a 22% lower rate of death at 1 year (hazard ratio, 0.78; P = .008) in those who underwent extraction within 30 days.

For those in whom the device was extracted within 7 days, the associated HR for death at 1 year was more than 40% lower (HR, 0.59; P < .001), reported Dr. Pokorney, who characterized these reductions as occurring in “a dose-response fashion.”

The very high risk of relapse despite antibiotics is the reason that “there is a class 1 indication for complete hardware removal,” Dr. Pokorney. He cited five studies that addressed this question. With partial device removal or medical therapy alone, relapse was consistently 50% or greater. In one study, it was 67%. In another it was 100%.

With complete removal, the rate of infection relapse was 1% or lower in four. In the fifth, the rate was 4.2%.

Infections can occur early or late after implantation, but cases accumulate over time. In the Medicare data sample, infection rates climbed from 0.3% at 1 year to 0.6% at 2 years and then to 1.1% at 3 years, Dr. Pokorney reported.

Other studies have also shown a steady increase in the proportion of implanted devices associated with infection over time. In a cohort study conducted in Olmstead County, Minnesota, the cumulative probability of a CIED infection reached 6.2% after 15 years and 11.7% after 25 years. While about half of these were infections localized to the device pocket, the others were potentially life-threatening systemic infections, according to Dr. Pokorney, who cited this study.

In his analysis of the Medicare data, all fee-for-service patients receiving a first CIED implant over a period of 14 years were included. The 14-year period ended just before the COVID-19 epidemic.

The more than 11,000 CIED infections were identified in 1,065,549 total CIED patients. Most (72%) had received a pacemaker. Of the others , more than half received an ICD and the others received a cardiac resynchronization device. The median age was 78 years.
 

Female and Black patients even less likely to undergo extraction

About half (49.1%) of the overall study population was female, but females represented only about 40% of those who developed an infection. Blacks represented just under 8% of the population but nearly 16% of the CIED infections. Both females and Blacks were significantly less likely than the overall study population to undergo extraction for their infection (P < .001 for both).

Perhaps predictably, patients with comorbidities were more likely to develop CIED infections. For example, 87% of those with infection, versus only 64.9% of the overall population, were in heart failure at the time of implantation. Diabetes (68.3% vs. 49.3%), ischemic heart disease (91.9% vs. 79.4%), renal disease (70.5% vs. 37.9%), and chronic obstructive pulmonary disease (70.6% vs. 55.0%) were also more common at baseline in those who went on to a CIED infection than in the overall population.

Based on the evidence that there is a large unmet need to improve adherence to the guidelines, Dr. Pokorney called for care pathways and other quality initiatives to address the problem.

The reasons that so many patients are not undergoing prompt device extraction at the time of infection is unclear, but Dr. Pokorney offered some hypotheses.

“There appears to be a false belief in the efficacy of antibiotics for treating CIED infections,” Dr. Pokorney said.
 

Comorbidities shouldn’t delay extraction

It is also possible that clinicians are concerned about performing extractions in patients with multiple comorbidities. If clinicians are delaying extractions for this reason, Dr. Pokorney suggested this behavior is misdirected given the fact that delays appear to increase mortality risk.

Several experts, including Rachel Lambert, MD, an electrophysiologist and professor of medicine at Yale University, New Haven, Conn., agreed that these data deserve a response.

“I was not surprised by the mortality data, but I was surprised at this low extraction rate,” said Dr. Lambert, who concurs with the guidelines. She indicated this study provides teeth to prompt action.

“It is great to have these data about the increased mortality risk to back up the guidelines,” she said.

More information is needed to understand exactly why CIED infection is not now leading to guideline-directed care. Dr. Pokorney said: “Where do we go from here is a key question.”

While several different types of initiatives might be needed, Dr. Pokorney called for regionalization of care to address the fact that not every center that places CIEDs has the capability to perform extractions.

“Extraction is not available at every center, and it probably should not be available at every center, so mechanisms are need to get patients with infection to the specialized centers that provide care,” he said.

Dr. Pokorney has financial relationships with Boston Scientific, Bristol-Myers Squibb, Gilead, Janssen, Medtronic, Pfizer, and Philips. Dr. Lambert reported financial relationships with Abbott, Amgen, and Medtronic.

Most surgeons report being affected by performance anxiety in relation to their work, with the anxiety frequently having a negative effect on well-being, a new study of surgeons in the United Kingdom shows.

“Performance anxiety or stage fright is a widely recognized problem in music and sports, and there are many similarities between these arenas and the operating theater,” first author Robert Miller, MRCS, of the Surgical Psychology and Performance Group and the department of plastic and reconstructive surgery at St. George’s Hospital NHS Trust, London, said in an interview. “We were aware of it anecdotally in a surgical context, but for one reason or another, perhaps professional pride and fear of negative perception, this is rarely openly discussed amongst surgeons.”

In the cross-sectional study, published in Annals of Surgery, Dr. Miller and colleagues surveyed surgeons in all specialties working in the United Kingdom who had at least 1 year of postgraduate surgical training.

Of a total of 631 responses received, 523 (83%) were included in the analysis. The median age of those who responded was 41.2 years, and the mean duration of surgical experience was 15.3 years (range, 1-52 years). Among them, 62% were men, and 52% were of consultant/attending grade.

All of the respondents – 100% – said they believed that performance anxiety affected surgeons, 87% reported having experienced it themselves, and 65% said they felt that performance anxiety had an effect on their surgical performance.

Both male and female surgeons who reported experiencing performance anxiety had significantly worse mental well-being, as assessed using the Short Warwick Edinburgh Mental Wellbeing Scale, compared with those who did not have performance anxiety (P < .0001 for men and P < .001 for women).

Overall, however, male surgeons had significantly better mental well-being, compared with female surgeons (P = .003), yet both genders had significantly lower mental well-being scores compared with U.K. population norms (P = .0019 for men and P = .0001 for women).

The gender differences are “clearly an important topic, which is likely multifactorial,” Dr. Miller told this news organization. “The gender well-being gap requires more in-depth research, and qualitative work involving female surgeons is critical.”

Surgical perfectionism was significantly more common among respondents who did have performance anxiety in comparison with those who did not (P < .0001).

“Although perfectionism may be a beneficial trait in surgery, our findings from hierarchical multiple regression analysis also indicate that perfectionism, [as well as] sex and experience, may drive surgical performance anxiety and help predict those experiencing [the anxiety],” the authors noted.
 

Performing in presence of colleagues a key trigger

By far, the leading trigger that was identified as prompting surgeon performance anxiety was the presence – and scrutiny – of colleagues within the parent specialty. This was reported by 151 respondents. Other triggers were having to perform on highly complex or high-risk cases (66 responses) and a lack of experience (30 responses).

Next to planning and preparation, opening up and talking about the anxiety and shedding light on the issue was seen as a leading strategy to help with the problem, but very few respondents reported openly sharing their struggles. Only 9% reported that they had shared it openly; 27% said they had confided in someone, and 47% did not respond to the question.

“I wish we talked about it more and shared our insecurities,” one respondent lamented. “Most of my colleagues pretend they are living gods.”

Only about 45% of respondents reported a specific technique for overcoming their anxiety. In addition to being open about the problem, other techniques included self-care, such as exercise; and distraction outside of work to get perspective; relaxation techniques such as deep or controlled breathing; music; mindfulness; and positive self-statements.

About 9% said they had received psychological counseling for performance anxiety, and only 3% reported using medication for the problem.
 

Anxiety a positive factor?

Surprisingly, 70% of respondents reported feeling that surgical performance anxiety could have a positive impact on surgical performance, which the authors noted is consistent with some theories.

“This may be explained by the traditional bell-curve relationship between arousal and performance, which describes a dose-dependent relationship between performance and arousal until a ‘tipping point,’ after which performance declines,” the authors explained. “A heightened awareness secondary to anxiety may be beneficial, but at high doses, anxiety can negatively affect attentional control and cause somatic symptoms.”

They noted that “the challenge would be to reap the benefits of low-level stimulation without incurring possible adverse effects.”

Dr. Miller said that, in determining whether selection bias had a role in the results, a detailed analysis showed that “our respondents were not skewed to those with only high levels of trait anxiety.

“We also had a good spread of consultants versus trainees [about half and half], and different specialties, so we feel this is likely to be a representative sample,” he told this news organization.

That being said, the results underscore the need for increased awareness – and open discussion – of the issue of surgical performance anxiety.

“Within other professions, particularly the performing arts and sports, performance psychology is becoming an integral part of training and development,” Dr. Miller said. “We feel surgeons should be supported in a similar manner.

“Surgical performance anxiety is normal for surgeons at all levels and not something to be ashamed about,” Dr. Miller added. “Talk about it, acknowledge it, and be supportive to your colleagues.”
 

Many keep it to themselves in ‘prevailing culture of stoicism’

Commenting on the study, Carter C. Lebares, MD, an associate professor of surgery and director of the Center for Mindfulness in Surgery, department of surgery, University of California, San Francisco, said she was not surprised to see the high rates of performance anxiety among surgeons.

“As surgeons, no matter how hard we train or how thoroughly we prepare our intellectual understanding or the patient, the disease process, and the operation, there may be surprises, unforeseen challenges, or off days,” Dr. Lebares said.

“And whatever we encounter, we are managing these things directly under the scrutiny of others – people who can affect our reputation, operating privileges, and mental health. So, I am not surprised this is a prevalent and widely recognized issue.”

Dr. Lebares noted that the reluctance to share the anxiety is part of a “challenging and recognized conundrum in both medicine and surgery and is a matter of the prevailing culture of stoicism.

“We often are called to shoulder tremendous weight intraoperatively (having perseverance, self-confidence, or sustained focus), and in owning the weight of complications (which eventually we all will have),” she said.

“So, we do need to be strong and not complain, [but] we also need to be able to set that aside [when appropriate] and ask for help or allow others to shoulder the weight for a while, and this is not [yet] a common part of surgical culture.”

Dr. Lebares added that randomized, controlled trials have shown benefits of mindfulness interventions on burnout and anxiety.

“We have observed positive effects on mental noise, self-perception, conflict resolution, and resilience in surgical residents trained in mindfulness-based cognitive skills,” she said. “[Residents] report applying these skills in the OR, in their home lives, and in how they approach their training/education.”

The authors disclosed no relevant financial relationships. Dr. Lebares has developed mindfulness-based cognitive skills training for surgeons but receives no financial compensation for the activities.

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

Most surgeons report being affected by performance anxiety in relation to their work, with the anxiety frequently having a negative effect on well-being, a new study of surgeons in the United Kingdom shows.

“Performance anxiety or stage fright is a widely recognized problem in music and sports, and there are many similarities between these arenas and the operating theater,” first author Robert Miller, MRCS, of the Surgical Psychology and Performance Group and the department of plastic and reconstructive surgery at St. George’s Hospital NHS Trust, London, said in an interview. “We were aware of it anecdotally in a surgical context, but for one reason or another, perhaps professional pride and fear of negative perception, this is rarely openly discussed amongst surgeons.”

In the cross-sectional study, published in Annals of Surgery, Dr. Miller and colleagues surveyed surgeons in all specialties working in the United Kingdom who had at least 1 year of postgraduate surgical training.

Of a total of 631 responses received, 523 (83%) were included in the analysis. The median age of those who responded was 41.2 years, and the mean duration of surgical experience was 15.3 years (range, 1-52 years). Among them, 62% were men, and 52% were of consultant/attending grade.

All of the respondents – 100% – said they believed that performance anxiety affected surgeons, 87% reported having experienced it themselves, and 65% said they felt that performance anxiety had an effect on their surgical performance.

Both male and female surgeons who reported experiencing performance anxiety had significantly worse mental well-being, as assessed using the Short Warwick Edinburgh Mental Wellbeing Scale, compared with those who did not have performance anxiety (P < .0001 for men and P < .001 for women).

Overall, however, male surgeons had significantly better mental well-being, compared with female surgeons (P = .003), yet both genders had significantly lower mental well-being scores compared with U.K. population norms (P = .0019 for men and P = .0001 for women).

The gender differences are “clearly an important topic, which is likely multifactorial,” Dr. Miller told this news organization. “The gender well-being gap requires more in-depth research, and qualitative work involving female surgeons is critical.”

Surgical perfectionism was significantly more common among respondents who did have performance anxiety in comparison with those who did not (P < .0001).

“Although perfectionism may be a beneficial trait in surgery, our findings from hierarchical multiple regression analysis also indicate that perfectionism, [as well as] sex and experience, may drive surgical performance anxiety and help predict those experiencing [the anxiety],” the authors noted.
 

Performing in presence of colleagues a key trigger

By far, the leading trigger that was identified as prompting surgeon performance anxiety was the presence – and scrutiny – of colleagues within the parent specialty. This was reported by 151 respondents. Other triggers were having to perform on highly complex or high-risk cases (66 responses) and a lack of experience (30 responses).

Next to planning and preparation, opening up and talking about the anxiety and shedding light on the issue was seen as a leading strategy to help with the problem, but very few respondents reported openly sharing their struggles. Only 9% reported that they had shared it openly; 27% said they had confided in someone, and 47% did not respond to the question.

“I wish we talked about it more and shared our insecurities,” one respondent lamented. “Most of my colleagues pretend they are living gods.”

Only about 45% of respondents reported a specific technique for overcoming their anxiety. In addition to being open about the problem, other techniques included self-care, such as exercise; and distraction outside of work to get perspective; relaxation techniques such as deep or controlled breathing; music; mindfulness; and positive self-statements.

About 9% said they had received psychological counseling for performance anxiety, and only 3% reported using medication for the problem.
 

Anxiety a positive factor?

Surprisingly, 70% of respondents reported feeling that surgical performance anxiety could have a positive impact on surgical performance, which the authors noted is consistent with some theories.

“This may be explained by the traditional bell-curve relationship between arousal and performance, which describes a dose-dependent relationship between performance and arousal until a ‘tipping point,’ after which performance declines,” the authors explained. “A heightened awareness secondary to anxiety may be beneficial, but at high doses, anxiety can negatively affect attentional control and cause somatic symptoms.”

They noted that “the challenge would be to reap the benefits of low-level stimulation without incurring possible adverse effects.”

Dr. Miller said that, in determining whether selection bias had a role in the results, a detailed analysis showed that “our respondents were not skewed to those with only high levels of trait anxiety.

“We also had a good spread of consultants versus trainees [about half and half], and different specialties, so we feel this is likely to be a representative sample,” he told this news organization.

That being said, the results underscore the need for increased awareness – and open discussion – of the issue of surgical performance anxiety.

“Within other professions, particularly the performing arts and sports, performance psychology is becoming an integral part of training and development,” Dr. Miller said. “We feel surgeons should be supported in a similar manner.

“Surgical performance anxiety is normal for surgeons at all levels and not something to be ashamed about,” Dr. Miller added. “Talk about it, acknowledge it, and be supportive to your colleagues.”
 

Many keep it to themselves in ‘prevailing culture of stoicism’

Commenting on the study, Carter C. Lebares, MD, an associate professor of surgery and director of the Center for Mindfulness in Surgery, department of surgery, University of California, San Francisco, said she was not surprised to see the high rates of performance anxiety among surgeons.

“As surgeons, no matter how hard we train or how thoroughly we prepare our intellectual understanding or the patient, the disease process, and the operation, there may be surprises, unforeseen challenges, or off days,” Dr. Lebares said.

“And whatever we encounter, we are managing these things directly under the scrutiny of others – people who can affect our reputation, operating privileges, and mental health. So, I am not surprised this is a prevalent and widely recognized issue.”

Dr. Lebares noted that the reluctance to share the anxiety is part of a “challenging and recognized conundrum in both medicine and surgery and is a matter of the prevailing culture of stoicism.

“We often are called to shoulder tremendous weight intraoperatively (having perseverance, self-confidence, or sustained focus), and in owning the weight of complications (which eventually we all will have),” she said.

“So, we do need to be strong and not complain, [but] we also need to be able to set that aside [when appropriate] and ask for help or allow others to shoulder the weight for a while, and this is not [yet] a common part of surgical culture.”

Dr. Lebares added that randomized, controlled trials have shown benefits of mindfulness interventions on burnout and anxiety.

“We have observed positive effects on mental noise, self-perception, conflict resolution, and resilience in surgical residents trained in mindfulness-based cognitive skills,” she said. “[Residents] report applying these skills in the OR, in their home lives, and in how they approach their training/education.”

The authors disclosed no relevant financial relationships. Dr. Lebares has developed mindfulness-based cognitive skills training for surgeons but receives no financial compensation for the activities.

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

Most surgeons report being affected by performance anxiety in relation to their work, with the anxiety frequently having a negative effect on well-being, a new study of surgeons in the United Kingdom shows.

“Performance anxiety or stage fright is a widely recognized problem in music and sports, and there are many similarities between these arenas and the operating theater,” first author Robert Miller, MRCS, of the Surgical Psychology and Performance Group and the department of plastic and reconstructive surgery at St. George’s Hospital NHS Trust, London, said in an interview. “We were aware of it anecdotally in a surgical context, but for one reason or another, perhaps professional pride and fear of negative perception, this is rarely openly discussed amongst surgeons.”

In the cross-sectional study, published in Annals of Surgery, Dr. Miller and colleagues surveyed surgeons in all specialties working in the United Kingdom who had at least 1 year of postgraduate surgical training.

Of a total of 631 responses received, 523 (83%) were included in the analysis. The median age of those who responded was 41.2 years, and the mean duration of surgical experience was 15.3 years (range, 1-52 years). Among them, 62% were men, and 52% were of consultant/attending grade.

All of the respondents – 100% – said they believed that performance anxiety affected surgeons, 87% reported having experienced it themselves, and 65% said they felt that performance anxiety had an effect on their surgical performance.

Both male and female surgeons who reported experiencing performance anxiety had significantly worse mental well-being, as assessed using the Short Warwick Edinburgh Mental Wellbeing Scale, compared with those who did not have performance anxiety (P < .0001 for men and P < .001 for women).

Overall, however, male surgeons had significantly better mental well-being, compared with female surgeons (P = .003), yet both genders had significantly lower mental well-being scores compared with U.K. population norms (P = .0019 for men and P = .0001 for women).

The gender differences are “clearly an important topic, which is likely multifactorial,” Dr. Miller told this news organization. “The gender well-being gap requires more in-depth research, and qualitative work involving female surgeons is critical.”

Surgical perfectionism was significantly more common among respondents who did have performance anxiety in comparison with those who did not (P < .0001).

“Although perfectionism may be a beneficial trait in surgery, our findings from hierarchical multiple regression analysis also indicate that perfectionism, [as well as] sex and experience, may drive surgical performance anxiety and help predict those experiencing [the anxiety],” the authors noted.
 

Performing in presence of colleagues a key trigger

By far, the leading trigger that was identified as prompting surgeon performance anxiety was the presence – and scrutiny – of colleagues within the parent specialty. This was reported by 151 respondents. Other triggers were having to perform on highly complex or high-risk cases (66 responses) and a lack of experience (30 responses).

Next to planning and preparation, opening up and talking about the anxiety and shedding light on the issue was seen as a leading strategy to help with the problem, but very few respondents reported openly sharing their struggles. Only 9% reported that they had shared it openly; 27% said they had confided in someone, and 47% did not respond to the question.

“I wish we talked about it more and shared our insecurities,” one respondent lamented. “Most of my colleagues pretend they are living gods.”

Only about 45% of respondents reported a specific technique for overcoming their anxiety. In addition to being open about the problem, other techniques included self-care, such as exercise; and distraction outside of work to get perspective; relaxation techniques such as deep or controlled breathing; music; mindfulness; and positive self-statements.

About 9% said they had received psychological counseling for performance anxiety, and only 3% reported using medication for the problem.
 

Anxiety a positive factor?

Surprisingly, 70% of respondents reported feeling that surgical performance anxiety could have a positive impact on surgical performance, which the authors noted is consistent with some theories.

“This may be explained by the traditional bell-curve relationship between arousal and performance, which describes a dose-dependent relationship between performance and arousal until a ‘tipping point,’ after which performance declines,” the authors explained. “A heightened awareness secondary to anxiety may be beneficial, but at high doses, anxiety can negatively affect attentional control and cause somatic symptoms.”

They noted that “the challenge would be to reap the benefits of low-level stimulation without incurring possible adverse effects.”

Dr. Miller said that, in determining whether selection bias had a role in the results, a detailed analysis showed that “our respondents were not skewed to those with only high levels of trait anxiety.

“We also had a good spread of consultants versus trainees [about half and half], and different specialties, so we feel this is likely to be a representative sample,” he told this news organization.

That being said, the results underscore the need for increased awareness – and open discussion – of the issue of surgical performance anxiety.

“Within other professions, particularly the performing arts and sports, performance psychology is becoming an integral part of training and development,” Dr. Miller said. “We feel surgeons should be supported in a similar manner.

“Surgical performance anxiety is normal for surgeons at all levels and not something to be ashamed about,” Dr. Miller added. “Talk about it, acknowledge it, and be supportive to your colleagues.”
 

Many keep it to themselves in ‘prevailing culture of stoicism’

Commenting on the study, Carter C. Lebares, MD, an associate professor of surgery and director of the Center for Mindfulness in Surgery, department of surgery, University of California, San Francisco, said she was not surprised to see the high rates of performance anxiety among surgeons.

“As surgeons, no matter how hard we train or how thoroughly we prepare our intellectual understanding or the patient, the disease process, and the operation, there may be surprises, unforeseen challenges, or off days,” Dr. Lebares said.

“And whatever we encounter, we are managing these things directly under the scrutiny of others – people who can affect our reputation, operating privileges, and mental health. So, I am not surprised this is a prevalent and widely recognized issue.”

Dr. Lebares noted that the reluctance to share the anxiety is part of a “challenging and recognized conundrum in both medicine and surgery and is a matter of the prevailing culture of stoicism.

“We often are called to shoulder tremendous weight intraoperatively (having perseverance, self-confidence, or sustained focus), and in owning the weight of complications (which eventually we all will have),” she said.

“So, we do need to be strong and not complain, [but] we also need to be able to set that aside [when appropriate] and ask for help or allow others to shoulder the weight for a while, and this is not [yet] a common part of surgical culture.”

Dr. Lebares added that randomized, controlled trials have shown benefits of mindfulness interventions on burnout and anxiety.

“We have observed positive effects on mental noise, self-perception, conflict resolution, and resilience in surgical residents trained in mindfulness-based cognitive skills,” she said. “[Residents] report applying these skills in the OR, in their home lives, and in how they approach their training/education.”

The authors disclosed no relevant financial relationships. Dr. Lebares has developed mindfulness-based cognitive skills training for surgeons but receives no financial compensation for the activities.

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

In patients undergoing transcatheter aortic valve replacement (TAVR), the incidence of leaflet thrombosis was numerically lower in those treated with the anticoagulant edoxaban for 6 months after the procedure than in those who received dual antiplatelet therapy, although the difference was not statistically significant, in the ADAPT-TAVR study.

There was no difference in new cerebral thromboembolism or neurologic/neurocognitive function between the two groups in the study.

Also, there was no significant relation between subclinical leaflet thrombosis and increased risk for cerebral thromboembolism and neurologic dysfunction.

The ADAPT-TAVR trial was presented April 4 at the American College of Cardiology (ACC) 2022 Scientific Session by Duk-Woo Park, MD, Asan Medical Center, Seoul, South Korea. It was simultaneously published online in Circulation.

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

In patients undergoing transcatheter aortic valve replacement (TAVR), the incidence of leaflet thrombosis was numerically lower in those treated with the anticoagulant edoxaban for 6 months after the procedure than in those who received dual antiplatelet therapy, although the difference was not statistically significant, in the ADAPT-TAVR study.

There was no difference in new cerebral thromboembolism or neurologic/neurocognitive function between the two groups in the study.

Also, there was no significant relation between subclinical leaflet thrombosis and increased risk for cerebral thromboembolism and neurologic dysfunction.

The ADAPT-TAVR trial was presented April 4 at the American College of Cardiology (ACC) 2022 Scientific Session by Duk-Woo Park, MD, Asan Medical Center, Seoul, South Korea. It was simultaneously published online in Circulation.

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

In patients undergoing transcatheter aortic valve replacement (TAVR), the incidence of leaflet thrombosis was numerically lower in those treated with the anticoagulant edoxaban for 6 months after the procedure than in those who received dual antiplatelet therapy, although the difference was not statistically significant, in the ADAPT-TAVR study.

There was no difference in new cerebral thromboembolism or neurologic/neurocognitive function between the two groups in the study.

Also, there was no significant relation between subclinical leaflet thrombosis and increased risk for cerebral thromboembolism and neurologic dysfunction.

The ADAPT-TAVR trial was presented April 4 at the American College of Cardiology (ACC) 2022 Scientific Session by Duk-Woo Park, MD, Asan Medical Center, Seoul, South Korea. It was simultaneously published online in Circulation.

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

When the PCSK9 inhibitor alirocumab is added to high-intensity statins soon after an acute myocardial infarction (AMI), the reduction in atheroma volume is doubled at 12 months, compared with placebo, while other key signs of plaque stabilization, such as fibrous cap thickness, are also significantly and substantially improved, according to the results of the PACMAN-AMI trial.

The study is consistent with other PCSK9 inhibitor trials, supporting the concept that “we should be seeking very low levels of LDL-C in high-risk patients,” reported Lorenz Räber, MD, PhD, of Bern (Switz.) University Hospital, at the annual scientific sessions of the American College of Cardiology.

Catherine Hackett/MDedge News

Primary outcome was atheroma volume

The primary endpoint was atheroma volume as determined by intravenous ultrasound (IVUS), but the secondary endpoints of maximum lipid core burden, as determined by near infrared spectroscopy (NIRS), and fibrous cap thickness, as determined by optical coherence tomography (OCT), were also adequately powered, according to Dr. Räber.

The imaging measures taken at baseline were repeated in exactly the same spot after 52 weeks on treatment.

For the primary outcome of atheroma volume, the mean 2.1% reduction among those randomized to alirocumab was more than double the 0.9% reduction in the placebo group (P = .001).

The mean reduction in lipid core volume based on a maximum lipid core burden index was also more than doubled (-79.42 vs. -37.60 maxLCBI­4mm; P = .006). The increase in fibrous cap thickness was not quite twofold greater but very close (62.67 vs. 33.19 mcm; P = .001).

From baseline, the relative reductions in LDL-C, which were reached about 4 weeks after starting treatment and maintained over the course of the study, were greater in the group randomized to alirocumab (-84.8% vs. -50.7%). This was expected, but the more important finding was a near linear relationship between reductions of LDL-C and each of these endpoints regardless of treatment, fully explaining the advantage of alirocumab, according to Dr. Räber.

For the addition of alirocumab, “these findings indicate incremental coronary plaque regression, lipid core reduction, and plaque stabilization, and provide a mechanistic rationale in favor of early initiation of very intensive LDL-C lower in the setting of an acute MI,” he said.

The results of the PACMAN-AMI trial were published simultaneously at the time of the ACC presentation.
 

Results consistent with earlier trials

Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.

The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.

However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.

Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
 

PACMAN-AMI confirms plaque stabilization

Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.

“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”

“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.

The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”

When the PCSK9 inhibitor alirocumab is added to high-intensity statins soon after an acute myocardial infarction (AMI), the reduction in atheroma volume is doubled at 12 months, compared with placebo, while other key signs of plaque stabilization, such as fibrous cap thickness, are also significantly and substantially improved, according to the results of the PACMAN-AMI trial.

The study is consistent with other PCSK9 inhibitor trials, supporting the concept that “we should be seeking very low levels of LDL-C in high-risk patients,” reported Lorenz Räber, MD, PhD, of Bern (Switz.) University Hospital, at the annual scientific sessions of the American College of Cardiology.

Catherine Hackett/MDedge News

Primary outcome was atheroma volume

The primary endpoint was atheroma volume as determined by intravenous ultrasound (IVUS), but the secondary endpoints of maximum lipid core burden, as determined by near infrared spectroscopy (NIRS), and fibrous cap thickness, as determined by optical coherence tomography (OCT), were also adequately powered, according to Dr. Räber.

The imaging measures taken at baseline were repeated in exactly the same spot after 52 weeks on treatment.

For the primary outcome of atheroma volume, the mean 2.1% reduction among those randomized to alirocumab was more than double the 0.9% reduction in the placebo group (P = .001).

The mean reduction in lipid core volume based on a maximum lipid core burden index was also more than doubled (-79.42 vs. -37.60 maxLCBI­4mm; P = .006). The increase in fibrous cap thickness was not quite twofold greater but very close (62.67 vs. 33.19 mcm; P = .001).

From baseline, the relative reductions in LDL-C, which were reached about 4 weeks after starting treatment and maintained over the course of the study, were greater in the group randomized to alirocumab (-84.8% vs. -50.7%). This was expected, but the more important finding was a near linear relationship between reductions of LDL-C and each of these endpoints regardless of treatment, fully explaining the advantage of alirocumab, according to Dr. Räber.

For the addition of alirocumab, “these findings indicate incremental coronary plaque regression, lipid core reduction, and plaque stabilization, and provide a mechanistic rationale in favor of early initiation of very intensive LDL-C lower in the setting of an acute MI,” he said.

The results of the PACMAN-AMI trial were published simultaneously at the time of the ACC presentation.
 

Results consistent with earlier trials

Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.

The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.

However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.

Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
 

PACMAN-AMI confirms plaque stabilization

Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.

“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”

“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.

The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”

When the PCSK9 inhibitor alirocumab is added to high-intensity statins soon after an acute myocardial infarction (AMI), the reduction in atheroma volume is doubled at 12 months, compared with placebo, while other key signs of plaque stabilization, such as fibrous cap thickness, are also significantly and substantially improved, according to the results of the PACMAN-AMI trial.

The study is consistent with other PCSK9 inhibitor trials, supporting the concept that “we should be seeking very low levels of LDL-C in high-risk patients,” reported Lorenz Räber, MD, PhD, of Bern (Switz.) University Hospital, at the annual scientific sessions of the American College of Cardiology.

Catherine Hackett/MDedge News

Primary outcome was atheroma volume

The primary endpoint was atheroma volume as determined by intravenous ultrasound (IVUS), but the secondary endpoints of maximum lipid core burden, as determined by near infrared spectroscopy (NIRS), and fibrous cap thickness, as determined by optical coherence tomography (OCT), were also adequately powered, according to Dr. Räber.

The imaging measures taken at baseline were repeated in exactly the same spot after 52 weeks on treatment.

For the primary outcome of atheroma volume, the mean 2.1% reduction among those randomized to alirocumab was more than double the 0.9% reduction in the placebo group (P = .001).

The mean reduction in lipid core volume based on a maximum lipid core burden index was also more than doubled (-79.42 vs. -37.60 maxLCBI­4mm; P = .006). The increase in fibrous cap thickness was not quite twofold greater but very close (62.67 vs. 33.19 mcm; P = .001).

From baseline, the relative reductions in LDL-C, which were reached about 4 weeks after starting treatment and maintained over the course of the study, were greater in the group randomized to alirocumab (-84.8% vs. -50.7%). This was expected, but the more important finding was a near linear relationship between reductions of LDL-C and each of these endpoints regardless of treatment, fully explaining the advantage of alirocumab, according to Dr. Räber.

For the addition of alirocumab, “these findings indicate incremental coronary plaque regression, lipid core reduction, and plaque stabilization, and provide a mechanistic rationale in favor of early initiation of very intensive LDL-C lower in the setting of an acute MI,” he said.

The results of the PACMAN-AMI trial were published simultaneously at the time of the ACC presentation.
 

Results consistent with earlier trials

Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.

The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.

However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.

Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
 

PACMAN-AMI confirms plaque stabilization

Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.

“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”

“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.

The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”