TBD Meeting (3134-19)

PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.

“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).

GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).

“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”

The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.

Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”

Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.

In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.

This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”

The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.

ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.

“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.

In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.

Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.

Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.

The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.

“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.

Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.

Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.

Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.

“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.

He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”

However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.

“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”

Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.

The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.

[email protected]

SOURCE: Mueller C. ESC 2019, Hot Line Session 3.

PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.

“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).

GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).

“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”

The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.

Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”

Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.

In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.

This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”

The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.

ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.

“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.

In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.

Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.

Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.

The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.

“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.

Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.

Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.

Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.

“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.

He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”

However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.

“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”

Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.

The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.

[email protected]

SOURCE: Mueller C. ESC 2019, Hot Line Session 3.

PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.

“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).

GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).

“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”

The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.

Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”

Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.

In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.

This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”

The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.

ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.

“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.

In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.

Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.

Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.

The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.

“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.

Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.

Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.

Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.

“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.

He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”

However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.

“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”

Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.

The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.

[email protected]

SOURCE: Mueller C. ESC 2019, Hot Line Session 3.

PARIS – The risk of infective endocarditis following transcatheter aortic valve replacement (TAVR) for the treatment of severe aortic stenosis proved to be the same as after surgical replacement in a French national propensity score–matched study.

This finding from what is believed to be the largest-ever study of infective endocarditis following TAVR will come as a surprise to many physicians. It’s easy to mistakenly assume the risk of this feared complication is lower – and perhaps even negligible – in TAVR patients since the procedure doesn’t involve a significant surgical wound, it’s briefer, the hospital length of stay is shorter, and recovery time is markedly less than with surgical aortic valve replacement (SAVR).

Not so, Laurent Fauchier, MD, PhD, said in presenting the study findings at the annual congress of the European Society of Cardiology.

“Do not think there is a lower risk of infective endocarditis. Be aware, be careful, and provide appropriate antibiotic prophylaxis, just as surgeons do in SAVR. Don’t think, as I did, that with TAVR with no pacemaker implantation there is no risk of infective endocarditis. The TAVR valve is a device, it’s a prosthesis, and the risk is very similar to that of surgery,” advised Dr. Fauchier, a cardiologist at Francois Rabelais University in Tours, France.

He presented a study of all of the nearly 108,000 patients who underwent isolated TAVR or SAVR in France during 2010-2018. The data source was the French national administrative hospital discharge record system. Since the TAVR patients were overall markedly older and sicker than the SAVR patients, especially during the first years of the study, he and his coinvestigators performed propensity score matching using 30 variables, which enabled them to narrow the field of inquiry down to a carefully selected study population of 16,291 TAVR patients and an equal number of closely similar SAVR patients.

A total of 1,070 cases of infective endocarditis occurred during a mean follow-up of just over 2 years. The rate of hospital admission for this complication was 1.89% per year in the TAVR group and similar at 1.71% per year in the SAVR cohort.

Of note, all-cause mortality in TAVR patients who developed infective endocarditis was 1.32-fold greater than it was in SAVR patients with infective endocarditis, a statistically significant difference. The explanation for the increased mortality risk in the TAVR group probably has to do at least in part with an inability on the part of the investigators to fully capture and control for the TAVR group’s greater frailty, according to the cardiologist.

Risk factors for infective endocarditis shared in common by TAVR and SAVR patients included male gender, a higher Charlson Comorbidity Index score, and a greater frailty index. The main predictors unique to the TAVR patients were atrial fibrillation, anemia, and tricuspid regurgitation. And although pacemaker and defibrillator implantation were risk factors for infective endocarditis in the SAVR patients, it wasn’t predictive of increased risk in the TAVR population. Dr. Fauchier called this finding “quite reassuring” given that roughly 20% of the TAVR group received a pacemaker.

The causative microorganisms for infective endocarditis were essentially the same in the TAVR and SAVR groups, simplifying antimicrobial prophylaxis decision making.

Dr. Fauchier reported having no financial conflicts regarding the study, conducted free of commercial support. He serves as a consultant to and/or on speakers’ bureaus for Bayer, BMS Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.

[email protected]

PARIS – The risk of infective endocarditis following transcatheter aortic valve replacement (TAVR) for the treatment of severe aortic stenosis proved to be the same as after surgical replacement in a French national propensity score–matched study.

This finding from what is believed to be the largest-ever study of infective endocarditis following TAVR will come as a surprise to many physicians. It’s easy to mistakenly assume the risk of this feared complication is lower – and perhaps even negligible – in TAVR patients since the procedure doesn’t involve a significant surgical wound, it’s briefer, the hospital length of stay is shorter, and recovery time is markedly less than with surgical aortic valve replacement (SAVR).

Not so, Laurent Fauchier, MD, PhD, said in presenting the study findings at the annual congress of the European Society of Cardiology.

“Do not think there is a lower risk of infective endocarditis. Be aware, be careful, and provide appropriate antibiotic prophylaxis, just as surgeons do in SAVR. Don’t think, as I did, that with TAVR with no pacemaker implantation there is no risk of infective endocarditis. The TAVR valve is a device, it’s a prosthesis, and the risk is very similar to that of surgery,” advised Dr. Fauchier, a cardiologist at Francois Rabelais University in Tours, France.

He presented a study of all of the nearly 108,000 patients who underwent isolated TAVR or SAVR in France during 2010-2018. The data source was the French national administrative hospital discharge record system. Since the TAVR patients were overall markedly older and sicker than the SAVR patients, especially during the first years of the study, he and his coinvestigators performed propensity score matching using 30 variables, which enabled them to narrow the field of inquiry down to a carefully selected study population of 16,291 TAVR patients and an equal number of closely similar SAVR patients.

A total of 1,070 cases of infective endocarditis occurred during a mean follow-up of just over 2 years. The rate of hospital admission for this complication was 1.89% per year in the TAVR group and similar at 1.71% per year in the SAVR cohort.

Of note, all-cause mortality in TAVR patients who developed infective endocarditis was 1.32-fold greater than it was in SAVR patients with infective endocarditis, a statistically significant difference. The explanation for the increased mortality risk in the TAVR group probably has to do at least in part with an inability on the part of the investigators to fully capture and control for the TAVR group’s greater frailty, according to the cardiologist.

Risk factors for infective endocarditis shared in common by TAVR and SAVR patients included male gender, a higher Charlson Comorbidity Index score, and a greater frailty index. The main predictors unique to the TAVR patients were atrial fibrillation, anemia, and tricuspid regurgitation. And although pacemaker and defibrillator implantation were risk factors for infective endocarditis in the SAVR patients, it wasn’t predictive of increased risk in the TAVR population. Dr. Fauchier called this finding “quite reassuring” given that roughly 20% of the TAVR group received a pacemaker.

The causative microorganisms for infective endocarditis were essentially the same in the TAVR and SAVR groups, simplifying antimicrobial prophylaxis decision making.

Dr. Fauchier reported having no financial conflicts regarding the study, conducted free of commercial support. He serves as a consultant to and/or on speakers’ bureaus for Bayer, BMS Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.

[email protected]

PARIS – The risk of infective endocarditis following transcatheter aortic valve replacement (TAVR) for the treatment of severe aortic stenosis proved to be the same as after surgical replacement in a French national propensity score–matched study.

This finding from what is believed to be the largest-ever study of infective endocarditis following TAVR will come as a surprise to many physicians. It’s easy to mistakenly assume the risk of this feared complication is lower – and perhaps even negligible – in TAVR patients since the procedure doesn’t involve a significant surgical wound, it’s briefer, the hospital length of stay is shorter, and recovery time is markedly less than with surgical aortic valve replacement (SAVR).

Not so, Laurent Fauchier, MD, PhD, said in presenting the study findings at the annual congress of the European Society of Cardiology.

“Do not think there is a lower risk of infective endocarditis. Be aware, be careful, and provide appropriate antibiotic prophylaxis, just as surgeons do in SAVR. Don’t think, as I did, that with TAVR with no pacemaker implantation there is no risk of infective endocarditis. The TAVR valve is a device, it’s a prosthesis, and the risk is very similar to that of surgery,” advised Dr. Fauchier, a cardiologist at Francois Rabelais University in Tours, France.

He presented a study of all of the nearly 108,000 patients who underwent isolated TAVR or SAVR in France during 2010-2018. The data source was the French national administrative hospital discharge record system. Since the TAVR patients were overall markedly older and sicker than the SAVR patients, especially during the first years of the study, he and his coinvestigators performed propensity score matching using 30 variables, which enabled them to narrow the field of inquiry down to a carefully selected study population of 16,291 TAVR patients and an equal number of closely similar SAVR patients.

A total of 1,070 cases of infective endocarditis occurred during a mean follow-up of just over 2 years. The rate of hospital admission for this complication was 1.89% per year in the TAVR group and similar at 1.71% per year in the SAVR cohort.

Of note, all-cause mortality in TAVR patients who developed infective endocarditis was 1.32-fold greater than it was in SAVR patients with infective endocarditis, a statistically significant difference. The explanation for the increased mortality risk in the TAVR group probably has to do at least in part with an inability on the part of the investigators to fully capture and control for the TAVR group’s greater frailty, according to the cardiologist.

Risk factors for infective endocarditis shared in common by TAVR and SAVR patients included male gender, a higher Charlson Comorbidity Index score, and a greater frailty index. The main predictors unique to the TAVR patients were atrial fibrillation, anemia, and tricuspid regurgitation. And although pacemaker and defibrillator implantation were risk factors for infective endocarditis in the SAVR patients, it wasn’t predictive of increased risk in the TAVR population. Dr. Fauchier called this finding “quite reassuring” given that roughly 20% of the TAVR group received a pacemaker.

The causative microorganisms for infective endocarditis were essentially the same in the TAVR and SAVR groups, simplifying antimicrobial prophylaxis decision making.

Dr. Fauchier reported having no financial conflicts regarding the study, conducted free of commercial support. He serves as a consultant to and/or on speakers’ bureaus for Bayer, BMS Pfizer, Boehringer Ingelheim, Medtronic, and Novartis.

[email protected]

PARIS – An accelerated rule-out pathway, reliant upon a single high-sensitivity cardiac troponin test upon presentation to the ED with suspected acute coronary syndrome, reduced length of stay and hospital admission rates without increasing cardiac events at 30 days or 1 year in a major Scottish study.

“We conclude that implementation of this early rule-out pathway is both effective and safe, and adoption of this pathway will have major benefits for patients and health care systems,” Nicholas L. Mills, MBChB, PhD, said in presenting the results of the HiSTORIC (High-Sensitivity Cardiac Troponin at Presentation to Rule Out Myocardial Infarction) trial at the annual congress of the European Society of Cardiology.

Indeed, in the Unites States, where more than 20 million people per year present to EDs with suspected ACS, the 3.3-hour reduction in length of stay achieved in the HiSTORIC trial by implementing the accelerated rule-out pathway would add up to a $3.6 billion annual savings in bed occupancy alone, according to Dr. Mills, who is chair of cardiology at the University of Edinburgh.

The HiSTORIC pathway incorporates separate thresholds for risk stratification and diagnosis. This strategy is based on an accumulation of persuasive evidence that the major advantage of high-sensitivity cardiac troponin testing is to rule out MI, rather than to rule it in, Dr. Mills explained.

HiSTORIC was a 2-year, prospective, stepped-wedge, cluster-randomized, controlled trial including 31,492 consecutive patients with suspected ACS who presented to seven participating hospitals in Scotland. Patients were randomized, at the hospital level, to one of two management pathways. The control group got a standard guideline-recommended strategy involving high-sensitivity cardiac troponin I testing upon presentation and again 6-12 hours later, with MI being ruled out if the troponin levels were not above the 99th percentile.

In contrast, the novel early rule-out strategy worked as follows: If the patient presented with at least 2 hours of symptoms and the initial troponin I level was below 5 ng/L, then MI was ruled out and the patient was triaged straightaway for outpatient management. If the level was above the 99th percentile, the patient was admitted for serial testing to be done 6-12 hours after symptom onset. And for an intermediate test result – that is, a troponin level between 5 ng/L and the 99th percentile – patients remained in the ED for retesting 3 hours from the time of presentation, and were subsequently admitted only if their troponin level was rising.

Using the accelerated rule-out strategy, two-thirds of patients were quickly discharged from the ED on the basis of a troponin level below 5 ng/mL, and another 7% were ruled out for MI and discharged from the ED after a 3-hour stay on the basis of their second test.

The primary efficacy outcome was length of stay from initial presentation to the ED to discharge. The duration was 10.1 hours with the guideline-recommended pathway and 6.8 hours with the accelerated rule-out pathway, for a statistically significant and clinically meaningful 3.3-hour difference. Moreover, the proportion of patients discharged directly from the ED without hospital admission increased from 53% to 74%, a 57% jump.

The primary safety outcome was the rate of MI or cardiac death post discharge. The rates at 30 days and 1 year were 0.4% and 2.6%, respectively, in the standard-pathway group, compared with 0.3% and 1.8% with the early rule-out pathway. Those between-group differences favoring the accelerated rule-out pathway weren’t statistically significant, but they provided reassurance that the novel pathway was safe.

Of note, this was the first-ever randomized trial to evaluate the safety and efficacy of an early rule-out pathway. Other rapid diagnostic pathways are largely based on observational experience and expert opinion, Dr. Mills said.

The assay utilized in the HiSTORIC trial was the Abbott Diagnostics Architect high sensitivity assay. The 5-ng/L threshold for early rule-out was chosen for the trial because an earlier study by Dr. Mills and coinvestigators showed that a level below that cutoff had a 99.6% negative predictive value for MI (Lancet. 2015 Dec 19;386[10012]:2481-8)

The early rule-out pathway was deliberately designed to be simple and pragmatic, according to the cardiologist. “One of the most remarkable observations in this trial was the adherence to the pathway. We prespecified three criteria to evaluate this and demonstrated adherence rates of 86%-92% for each of these criteria. This was despite the pathway being implemented in all consecutive patients at seven different hospitals and used by many hundreds of different clinicians.”

Discussant Hugo A. Katus, MD, called the HiSTORIC study “a really urgently needed and very well-conducted trial.”

Bruce Jancin/MDedge News

“There were very consistently low MI and cardiac death rates at 30 days and 1 year. So this really works,” commented Dr. Katus, who is chief of internal medicine and director of the department of cardiovascular medicine at Heidelberg (Germany) University.

“Accelerated rule-out high-sensitivity cardiac troponin protocols are here to stay,” he declared.

However, Dr. Katus voiced a concern: “By early discharge as rule out, are other life-threatening conditions ignored?”

He raised this issue because of what he views as the substantial 1-year all-cause mortality and return-to-hospital rates of 5.8% and 39.2% in the standard-pathway group and 5.2% and 38.9% in the accelerated rule-out patients in HiSTORIC. An accelerated rule-out strategy should not prohibit a careful clinical work-up, he emphasized.

Dr. Mills discussed the results in a video interview.

The HiSTORIC trial was funded by the British Heart Foundation. Dr. Mills reported receiving research grants from Abbott Diagnostics and Siemens.

Simultaneous with Dr. Mills’ presentation of the HiSTORIC trial results at the ESC congress, an earlier study that formed the scientific basis for the investigators’ decision to employ distinct risk stratification and diagnostic thresholds for cardiac troponin testing was published online (Circulation. 2019 Sep 1. doi: 10.1161/CIRCULATIONAHA.119.042866). The actual HiSTORIC trial results will be published later.

Dr. Katus reported holding a patent for a cardiac troponin T test and serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

[email protected]

PARIS – An accelerated rule-out pathway, reliant upon a single high-sensitivity cardiac troponin test upon presentation to the ED with suspected acute coronary syndrome, reduced length of stay and hospital admission rates without increasing cardiac events at 30 days or 1 year in a major Scottish study.

“We conclude that implementation of this early rule-out pathway is both effective and safe, and adoption of this pathway will have major benefits for patients and health care systems,” Nicholas L. Mills, MBChB, PhD, said in presenting the results of the HiSTORIC (High-Sensitivity Cardiac Troponin at Presentation to Rule Out Myocardial Infarction) trial at the annual congress of the European Society of Cardiology.

Indeed, in the Unites States, where more than 20 million people per year present to EDs with suspected ACS, the 3.3-hour reduction in length of stay achieved in the HiSTORIC trial by implementing the accelerated rule-out pathway would add up to a $3.6 billion annual savings in bed occupancy alone, according to Dr. Mills, who is chair of cardiology at the University of Edinburgh.

The HiSTORIC pathway incorporates separate thresholds for risk stratification and diagnosis. This strategy is based on an accumulation of persuasive evidence that the major advantage of high-sensitivity cardiac troponin testing is to rule out MI, rather than to rule it in, Dr. Mills explained.

HiSTORIC was a 2-year, prospective, stepped-wedge, cluster-randomized, controlled trial including 31,492 consecutive patients with suspected ACS who presented to seven participating hospitals in Scotland. Patients were randomized, at the hospital level, to one of two management pathways. The control group got a standard guideline-recommended strategy involving high-sensitivity cardiac troponin I testing upon presentation and again 6-12 hours later, with MI being ruled out if the troponin levels were not above the 99th percentile.

In contrast, the novel early rule-out strategy worked as follows: If the patient presented with at least 2 hours of symptoms and the initial troponin I level was below 5 ng/L, then MI was ruled out and the patient was triaged straightaway for outpatient management. If the level was above the 99th percentile, the patient was admitted for serial testing to be done 6-12 hours after symptom onset. And for an intermediate test result – that is, a troponin level between 5 ng/L and the 99th percentile – patients remained in the ED for retesting 3 hours from the time of presentation, and were subsequently admitted only if their troponin level was rising.

Using the accelerated rule-out strategy, two-thirds of patients were quickly discharged from the ED on the basis of a troponin level below 5 ng/mL, and another 7% were ruled out for MI and discharged from the ED after a 3-hour stay on the basis of their second test.

The primary efficacy outcome was length of stay from initial presentation to the ED to discharge. The duration was 10.1 hours with the guideline-recommended pathway and 6.8 hours with the accelerated rule-out pathway, for a statistically significant and clinically meaningful 3.3-hour difference. Moreover, the proportion of patients discharged directly from the ED without hospital admission increased from 53% to 74%, a 57% jump.

The primary safety outcome was the rate of MI or cardiac death post discharge. The rates at 30 days and 1 year were 0.4% and 2.6%, respectively, in the standard-pathway group, compared with 0.3% and 1.8% with the early rule-out pathway. Those between-group differences favoring the accelerated rule-out pathway weren’t statistically significant, but they provided reassurance that the novel pathway was safe.

Of note, this was the first-ever randomized trial to evaluate the safety and efficacy of an early rule-out pathway. Other rapid diagnostic pathways are largely based on observational experience and expert opinion, Dr. Mills said.

The assay utilized in the HiSTORIC trial was the Abbott Diagnostics Architect high sensitivity assay. The 5-ng/L threshold for early rule-out was chosen for the trial because an earlier study by Dr. Mills and coinvestigators showed that a level below that cutoff had a 99.6% negative predictive value for MI (Lancet. 2015 Dec 19;386[10012]:2481-8)

The early rule-out pathway was deliberately designed to be simple and pragmatic, according to the cardiologist. “One of the most remarkable observations in this trial was the adherence to the pathway. We prespecified three criteria to evaluate this and demonstrated adherence rates of 86%-92% for each of these criteria. This was despite the pathway being implemented in all consecutive patients at seven different hospitals and used by many hundreds of different clinicians.”

Discussant Hugo A. Katus, MD, called the HiSTORIC study “a really urgently needed and very well-conducted trial.”

Bruce Jancin/MDedge News

“There were very consistently low MI and cardiac death rates at 30 days and 1 year. So this really works,” commented Dr. Katus, who is chief of internal medicine and director of the department of cardiovascular medicine at Heidelberg (Germany) University.

“Accelerated rule-out high-sensitivity cardiac troponin protocols are here to stay,” he declared.

However, Dr. Katus voiced a concern: “By early discharge as rule out, are other life-threatening conditions ignored?”

He raised this issue because of what he views as the substantial 1-year all-cause mortality and return-to-hospital rates of 5.8% and 39.2% in the standard-pathway group and 5.2% and 38.9% in the accelerated rule-out patients in HiSTORIC. An accelerated rule-out strategy should not prohibit a careful clinical work-up, he emphasized.

Dr. Mills discussed the results in a video interview.

The HiSTORIC trial was funded by the British Heart Foundation. Dr. Mills reported receiving research grants from Abbott Diagnostics and Siemens.

Simultaneous with Dr. Mills’ presentation of the HiSTORIC trial results at the ESC congress, an earlier study that formed the scientific basis for the investigators’ decision to employ distinct risk stratification and diagnostic thresholds for cardiac troponin testing was published online (Circulation. 2019 Sep 1. doi: 10.1161/CIRCULATIONAHA.119.042866). The actual HiSTORIC trial results will be published later.

Dr. Katus reported holding a patent for a cardiac troponin T test and serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

[email protected]

PARIS – An accelerated rule-out pathway, reliant upon a single high-sensitivity cardiac troponin test upon presentation to the ED with suspected acute coronary syndrome, reduced length of stay and hospital admission rates without increasing cardiac events at 30 days or 1 year in a major Scottish study.

“We conclude that implementation of this early rule-out pathway is both effective and safe, and adoption of this pathway will have major benefits for patients and health care systems,” Nicholas L. Mills, MBChB, PhD, said in presenting the results of the HiSTORIC (High-Sensitivity Cardiac Troponin at Presentation to Rule Out Myocardial Infarction) trial at the annual congress of the European Society of Cardiology.

Indeed, in the Unites States, where more than 20 million people per year present to EDs with suspected ACS, the 3.3-hour reduction in length of stay achieved in the HiSTORIC trial by implementing the accelerated rule-out pathway would add up to a $3.6 billion annual savings in bed occupancy alone, according to Dr. Mills, who is chair of cardiology at the University of Edinburgh.

The HiSTORIC pathway incorporates separate thresholds for risk stratification and diagnosis. This strategy is based on an accumulation of persuasive evidence that the major advantage of high-sensitivity cardiac troponin testing is to rule out MI, rather than to rule it in, Dr. Mills explained.

HiSTORIC was a 2-year, prospective, stepped-wedge, cluster-randomized, controlled trial including 31,492 consecutive patients with suspected ACS who presented to seven participating hospitals in Scotland. Patients were randomized, at the hospital level, to one of two management pathways. The control group got a standard guideline-recommended strategy involving high-sensitivity cardiac troponin I testing upon presentation and again 6-12 hours later, with MI being ruled out if the troponin levels were not above the 99th percentile.

In contrast, the novel early rule-out strategy worked as follows: If the patient presented with at least 2 hours of symptoms and the initial troponin I level was below 5 ng/L, then MI was ruled out and the patient was triaged straightaway for outpatient management. If the level was above the 99th percentile, the patient was admitted for serial testing to be done 6-12 hours after symptom onset. And for an intermediate test result – that is, a troponin level between 5 ng/L and the 99th percentile – patients remained in the ED for retesting 3 hours from the time of presentation, and were subsequently admitted only if their troponin level was rising.

Using the accelerated rule-out strategy, two-thirds of patients were quickly discharged from the ED on the basis of a troponin level below 5 ng/mL, and another 7% were ruled out for MI and discharged from the ED after a 3-hour stay on the basis of their second test.

The primary efficacy outcome was length of stay from initial presentation to the ED to discharge. The duration was 10.1 hours with the guideline-recommended pathway and 6.8 hours with the accelerated rule-out pathway, for a statistically significant and clinically meaningful 3.3-hour difference. Moreover, the proportion of patients discharged directly from the ED without hospital admission increased from 53% to 74%, a 57% jump.

The primary safety outcome was the rate of MI or cardiac death post discharge. The rates at 30 days and 1 year were 0.4% and 2.6%, respectively, in the standard-pathway group, compared with 0.3% and 1.8% with the early rule-out pathway. Those between-group differences favoring the accelerated rule-out pathway weren’t statistically significant, but they provided reassurance that the novel pathway was safe.

Of note, this was the first-ever randomized trial to evaluate the safety and efficacy of an early rule-out pathway. Other rapid diagnostic pathways are largely based on observational experience and expert opinion, Dr. Mills said.

The assay utilized in the HiSTORIC trial was the Abbott Diagnostics Architect high sensitivity assay. The 5-ng/L threshold for early rule-out was chosen for the trial because an earlier study by Dr. Mills and coinvestigators showed that a level below that cutoff had a 99.6% negative predictive value for MI (Lancet. 2015 Dec 19;386[10012]:2481-8)

The early rule-out pathway was deliberately designed to be simple and pragmatic, according to the cardiologist. “One of the most remarkable observations in this trial was the adherence to the pathway. We prespecified three criteria to evaluate this and demonstrated adherence rates of 86%-92% for each of these criteria. This was despite the pathway being implemented in all consecutive patients at seven different hospitals and used by many hundreds of different clinicians.”

Discussant Hugo A. Katus, MD, called the HiSTORIC study “a really urgently needed and very well-conducted trial.”

Bruce Jancin/MDedge News

“There were very consistently low MI and cardiac death rates at 30 days and 1 year. So this really works,” commented Dr. Katus, who is chief of internal medicine and director of the department of cardiovascular medicine at Heidelberg (Germany) University.

“Accelerated rule-out high-sensitivity cardiac troponin protocols are here to stay,” he declared.

However, Dr. Katus voiced a concern: “By early discharge as rule out, are other life-threatening conditions ignored?”

He raised this issue because of what he views as the substantial 1-year all-cause mortality and return-to-hospital rates of 5.8% and 39.2% in the standard-pathway group and 5.2% and 38.9% in the accelerated rule-out patients in HiSTORIC. An accelerated rule-out strategy should not prohibit a careful clinical work-up, he emphasized.

Dr. Mills discussed the results in a video interview.

The HiSTORIC trial was funded by the British Heart Foundation. Dr. Mills reported receiving research grants from Abbott Diagnostics and Siemens.

Simultaneous with Dr. Mills’ presentation of the HiSTORIC trial results at the ESC congress, an earlier study that formed the scientific basis for the investigators’ decision to employ distinct risk stratification and diagnostic thresholds for cardiac troponin testing was published online (Circulation. 2019 Sep 1. doi: 10.1161/CIRCULATIONAHA.119.042866). The actual HiSTORIC trial results will be published later.

Dr. Katus reported holding a patent for a cardiac troponin T test and serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

[email protected]

PARIS – All lifestyle-related cardiovascular risk factors aren’t equal in power when it comes to secondary prevention after a first acute MI, according to a massive Swedish registry study.

Insufficient physical activity and current smoking were consistently the strongest risk factors for all-cause mortality, major adverse cardiovascular events, and other key adverse outcomes in an analysis from the SWEDEHEART registry. The study included 65,002 patients discharged after a first MI and 325,010 age- and sex-matched controls with no prior MI followed for a median of 5.5 years and maximum of 12, Emil Hagstrom, MD, PhD, reported at the annual congress of the European Society of Cardiology.

Strongest lifestyle risk factors

The study examined the long-term relative importance of control of six major lifestyle risk factors for secondary cardiovascular prevention: current smoking, insufficient physical activity, blood pressure of 140/90 mm Hg or more, obesity, a fasting blood glucose of at least 126 mg/dL, and an LDL cholesterol of 70 mg/dL or more. Notably, two risk factors that physicians often emphasize in working with their patients with known coronary heart disease – an elevated LDL cholesterol and obesity – barely moved the needle. Out of the six risk factors scrutinized, those two consistently showed the weakest association with long-term risk of adverse outcomes. Occupying the middle ground in terms of predictive strength were hypertension and elevated blood glucose, according to Dr. Hagstrom, a cardiologist at Uppsala (Sweden) University.

Risk factor status was assessed 6-10 weeks post MI. Insufficient physical activity was defined as not engaging in at least 30 minutes of moderate-intensity exercise on at least 5 days per week. And when Dr. Hagstrom recalculated the risk of adverse outcomes using an LDL cholesterol threshold of 55 mg/dL rather than using 70 mg/dL, as recommended in new ESC secondary prevention guidelines released during the congress, the study results remained unchanged.

Cumulative effects

A key SWEDEHEART finding underscoring the importance of lifestyle in secondary prevention was that a linear stepwise relationship existed between the number of risk factors at target levels and the risk of all of the various adverse outcomes assessed, including stroke and heart failure hospitalization as well as all-cause mortality, cardiovascular mortality, and major bleeding.

Moreover, patients with none of the six risk factors outside of target when assessed after their MI had the same risks of all-cause mortality, cardiovascular mortality, and stroke as the matched controls.

For example, in an analysis adjusted for comorbid cancer, chronic obstructive pulmonary disease, and dementia, post-MI patients with zero risk factors had the same long-term risk of cardiovascular mortality as controls without a history of MI at baseline. With one risk factor not at target, a patient had a 41% increased risk compared with controls, a statistically significant difference. With two out-of-whack risk factors, the risk climbed to 102%. With three, 185%. With four risk factors not at target, the all-cause mortality risk jumped to 291%. And patients with more than four of the six risk factors not at target had a 409% greater risk of all-cause mortality than controls who had never had a heart attack.

When Dr. Hagstrom stratified subjects by age at baseline – up to 55, 56-64, 65-70, and 70-75 years – he discovered that, regardless of age, patients with zero risk factors had the same risk of all-cause mortality and other adverse outcomes as controls. However, when risk factors were present, younger patients consistently had a higher risk of all adverse outcomes than older patients with the same number of risk factors. When asked for an explanation of this phenomenon, Dr. Hagstrom noted that younger patients with multiple risk factors have a longer time to be exposed to and accumulate risk.

Follow-up of the study cohort will continue for years to come, the cardiologist promised.

At an ESC congress highlights session that closed out the meeting, Eva Prescott, MD, put the SWEDEHEART study at the top of her list of important developments in preventive cardiology arising from the congress.

“This is an excellent national registry I think we’re all envious of,” commented Dr. Prescott, a cardiologist at Copenhagen University. “The conclusion of this registry-based data, I think, is that lifestyle really remains at the core of prevention of cardiovascular events still today.”

The SWEDEHEART study analysis was funded free of commercial support. Dr. Hagstrom reported serving as a consultant to or receiving speakers’ fees from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Sanofi.

[email protected]

PARIS – All lifestyle-related cardiovascular risk factors aren’t equal in power when it comes to secondary prevention after a first acute MI, according to a massive Swedish registry study.

Insufficient physical activity and current smoking were consistently the strongest risk factors for all-cause mortality, major adverse cardiovascular events, and other key adverse outcomes in an analysis from the SWEDEHEART registry. The study included 65,002 patients discharged after a first MI and 325,010 age- and sex-matched controls with no prior MI followed for a median of 5.5 years and maximum of 12, Emil Hagstrom, MD, PhD, reported at the annual congress of the European Society of Cardiology.

Strongest lifestyle risk factors

The study examined the long-term relative importance of control of six major lifestyle risk factors for secondary cardiovascular prevention: current smoking, insufficient physical activity, blood pressure of 140/90 mm Hg or more, obesity, a fasting blood glucose of at least 126 mg/dL, and an LDL cholesterol of 70 mg/dL or more. Notably, two risk factors that physicians often emphasize in working with their patients with known coronary heart disease – an elevated LDL cholesterol and obesity – barely moved the needle. Out of the six risk factors scrutinized, those two consistently showed the weakest association with long-term risk of adverse outcomes. Occupying the middle ground in terms of predictive strength were hypertension and elevated blood glucose, according to Dr. Hagstrom, a cardiologist at Uppsala (Sweden) University.

Risk factor status was assessed 6-10 weeks post MI. Insufficient physical activity was defined as not engaging in at least 30 minutes of moderate-intensity exercise on at least 5 days per week. And when Dr. Hagstrom recalculated the risk of adverse outcomes using an LDL cholesterol threshold of 55 mg/dL rather than using 70 mg/dL, as recommended in new ESC secondary prevention guidelines released during the congress, the study results remained unchanged.

Cumulative effects

A key SWEDEHEART finding underscoring the importance of lifestyle in secondary prevention was that a linear stepwise relationship existed between the number of risk factors at target levels and the risk of all of the various adverse outcomes assessed, including stroke and heart failure hospitalization as well as all-cause mortality, cardiovascular mortality, and major bleeding.

Moreover, patients with none of the six risk factors outside of target when assessed after their MI had the same risks of all-cause mortality, cardiovascular mortality, and stroke as the matched controls.

For example, in an analysis adjusted for comorbid cancer, chronic obstructive pulmonary disease, and dementia, post-MI patients with zero risk factors had the same long-term risk of cardiovascular mortality as controls without a history of MI at baseline. With one risk factor not at target, a patient had a 41% increased risk compared with controls, a statistically significant difference. With two out-of-whack risk factors, the risk climbed to 102%. With three, 185%. With four risk factors not at target, the all-cause mortality risk jumped to 291%. And patients with more than four of the six risk factors not at target had a 409% greater risk of all-cause mortality than controls who had never had a heart attack.

When Dr. Hagstrom stratified subjects by age at baseline – up to 55, 56-64, 65-70, and 70-75 years – he discovered that, regardless of age, patients with zero risk factors had the same risk of all-cause mortality and other adverse outcomes as controls. However, when risk factors were present, younger patients consistently had a higher risk of all adverse outcomes than older patients with the same number of risk factors. When asked for an explanation of this phenomenon, Dr. Hagstrom noted that younger patients with multiple risk factors have a longer time to be exposed to and accumulate risk.

Follow-up of the study cohort will continue for years to come, the cardiologist promised.

At an ESC congress highlights session that closed out the meeting, Eva Prescott, MD, put the SWEDEHEART study at the top of her list of important developments in preventive cardiology arising from the congress.

“This is an excellent national registry I think we’re all envious of,” commented Dr. Prescott, a cardiologist at Copenhagen University. “The conclusion of this registry-based data, I think, is that lifestyle really remains at the core of prevention of cardiovascular events still today.”

The SWEDEHEART study analysis was funded free of commercial support. Dr. Hagstrom reported serving as a consultant to or receiving speakers’ fees from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Sanofi.

[email protected]

PARIS – All lifestyle-related cardiovascular risk factors aren’t equal in power when it comes to secondary prevention after a first acute MI, according to a massive Swedish registry study.

Insufficient physical activity and current smoking were consistently the strongest risk factors for all-cause mortality, major adverse cardiovascular events, and other key adverse outcomes in an analysis from the SWEDEHEART registry. The study included 65,002 patients discharged after a first MI and 325,010 age- and sex-matched controls with no prior MI followed for a median of 5.5 years and maximum of 12, Emil Hagstrom, MD, PhD, reported at the annual congress of the European Society of Cardiology.

Strongest lifestyle risk factors

The study examined the long-term relative importance of control of six major lifestyle risk factors for secondary cardiovascular prevention: current smoking, insufficient physical activity, blood pressure of 140/90 mm Hg or more, obesity, a fasting blood glucose of at least 126 mg/dL, and an LDL cholesterol of 70 mg/dL or more. Notably, two risk factors that physicians often emphasize in working with their patients with known coronary heart disease – an elevated LDL cholesterol and obesity – barely moved the needle. Out of the six risk factors scrutinized, those two consistently showed the weakest association with long-term risk of adverse outcomes. Occupying the middle ground in terms of predictive strength were hypertension and elevated blood glucose, according to Dr. Hagstrom, a cardiologist at Uppsala (Sweden) University.

Risk factor status was assessed 6-10 weeks post MI. Insufficient physical activity was defined as not engaging in at least 30 minutes of moderate-intensity exercise on at least 5 days per week. And when Dr. Hagstrom recalculated the risk of adverse outcomes using an LDL cholesterol threshold of 55 mg/dL rather than using 70 mg/dL, as recommended in new ESC secondary prevention guidelines released during the congress, the study results remained unchanged.

Cumulative effects

A key SWEDEHEART finding underscoring the importance of lifestyle in secondary prevention was that a linear stepwise relationship existed between the number of risk factors at target levels and the risk of all of the various adverse outcomes assessed, including stroke and heart failure hospitalization as well as all-cause mortality, cardiovascular mortality, and major bleeding.

Moreover, patients with none of the six risk factors outside of target when assessed after their MI had the same risks of all-cause mortality, cardiovascular mortality, and stroke as the matched controls.

For example, in an analysis adjusted for comorbid cancer, chronic obstructive pulmonary disease, and dementia, post-MI patients with zero risk factors had the same long-term risk of cardiovascular mortality as controls without a history of MI at baseline. With one risk factor not at target, a patient had a 41% increased risk compared with controls, a statistically significant difference. With two out-of-whack risk factors, the risk climbed to 102%. With three, 185%. With four risk factors not at target, the all-cause mortality risk jumped to 291%. And patients with more than four of the six risk factors not at target had a 409% greater risk of all-cause mortality than controls who had never had a heart attack.

When Dr. Hagstrom stratified subjects by age at baseline – up to 55, 56-64, 65-70, and 70-75 years – he discovered that, regardless of age, patients with zero risk factors had the same risk of all-cause mortality and other adverse outcomes as controls. However, when risk factors were present, younger patients consistently had a higher risk of all adverse outcomes than older patients with the same number of risk factors. When asked for an explanation of this phenomenon, Dr. Hagstrom noted that younger patients with multiple risk factors have a longer time to be exposed to and accumulate risk.

Follow-up of the study cohort will continue for years to come, the cardiologist promised.

At an ESC congress highlights session that closed out the meeting, Eva Prescott, MD, put the SWEDEHEART study at the top of her list of important developments in preventive cardiology arising from the congress.

“This is an excellent national registry I think we’re all envious of,” commented Dr. Prescott, a cardiologist at Copenhagen University. “The conclusion of this registry-based data, I think, is that lifestyle really remains at the core of prevention of cardiovascular events still today.”

The SWEDEHEART study analysis was funded free of commercial support. Dr. Hagstrom reported serving as a consultant to or receiving speakers’ fees from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Sanofi.

[email protected]

PARIS – The 5-year mortality rate associated with untreated moderate aortic stenosis is just as grim as it is for severe aortic stenosis, according to new findings from the largest-ever study of the natural history of aortic stenosis.

“These data provide a clear signal of the expected adverse outcomes for individuals presenting across the globe with a mean aortic valve gradient greater than 20.0 mm Hg or a peak aortic valve velocity above 3.0 m/sec,” Geoff Strange, PhD, said in presenting an analysis from NEDA, the National Echocardiography Database of Australia, at the annual congress of the European Society of Cardiology.

These results, if confirmed in other large datasets, could potentially have enormous implications for the use of transcatheter and surgical aortic valve replacement, interventions which until now have been restricted to patients with severe aortic stenosis (AS) as defined by an aortic valve (AV) mean gradient in excess of 40 mm Hg or a peak AV velocity greater than 4.0 m/sec. This restriction was based on what Dr. Strange considers rather limited and flimsy evidence suggesting that the mortality associated with AS was negligible except in severe AS.

“Cut points used to stratify for interventional strategies are based on very small numbers,” observed Dr. Strange, professor of medicine at the University of Notre Dame in Fremantle, Australia.

The NEDA findings, he added, constitute a call to action: “These data provide the impetus for a contemporary evaluation of the risk-to-benefit ratio of intervention in the moderate AS population,” Dr. Strange declared.

He and his NEDA coinvestigators analyzed echocardiographic data on 241,303 individuals in the Australian database, zeroing in on the 25,827 with untreated mild, moderate, or severe native valve AS. To place the size and scope of this project into perspective, the next-largest study of the natural history of untreated AS included 1,375 individuals – and that study was in turn roughly 10-fold bigger than the handful of other published studies addressing this issue.

A key finding in the NEDA study was that the 5-year all-cause mortality rate of 61.4% in the group with moderate AS wasn’t significantly different from the 64.6% rate in those with severe AS (see graphic).

The investigators performed additional analyses, analyzing peak velocity and mean gradient as continuous variables and stratifying patients into quintiles on that basis. They found that the top quintile for AV velocity started very low, at 1.73 m/sec, while the top quintile for mean AV gradient also started at a surprisingly low level: greater than 9.6 mm Hg. They noted that both all-cause and cardiovascular-specific mortality rates were basically flat until taking what Dr. Strange described as “a sharp pivot point upward” right around 20 mm Hg or 3 m/sec.

“No matter how we looked at these data – whether we looked at patients with or without left heart disease, whether we used the dimensionless index, whether we adjusted for stroke volume index, whether we stratified between age above or below 65, whether we used the gradient, the velocity, or the AV area – this threshold of increasing mortality at around 20 mm Hg or 3 m/sec continued to emerge,” according to Dr. Strange.

He noted that this study used real-world data with hard endpoints – actuarial patient mortality outcomes obtained through linkage to the national database – rather than hypothetical projections based upon Kaplan-Meier curves. A study limitation was that comorbidity data couldn’t be obtained for the AS patients.

Session cochair Patrizio Lancellotti, MD, PhD, commented, “I think this study will change a bit our consideration about patients with moderate AS.”

However, Dr. Lancellotti, who was lead author of the second-largest study of the natural history of aortic stenosis (JAMA Cardiol. 2018 Nov 1;3[11]:1060-8), expressed misgivings about the NEDA system’s lack of a core echocardiographic laboratory for imaging adjudication. That’s a study weakness given that image quality and the accuracy of echocardiographic interpretation are so highly dependent upon an individual cardiologist’s skill, observed Dr. Lancellotti, who is head of cardiology at the University of Liege (Belgium).

Dr. Strange replied that he and his coinvestigators analyzed a random subset of the NEDA data and found very little interlaboratory variability in results.

“All I can say is that the labs that contributed to this study are the most eminent labs across Australia,” he added.

Simultaneously with Dr. Strange’s presentation at the congress, the NEDA study results were published online (J Am Coll Cardiol. Sep 2019. doi: 10.1016/j.jacc.2019.08.004).

Dr. Strange reported having no financial conflicts of interest regarding the NEDA project, which is funded by GlaxoSmithKline, Bayer, and Actelion.

[email protected]

PARIS – The 5-year mortality rate associated with untreated moderate aortic stenosis is just as grim as it is for severe aortic stenosis, according to new findings from the largest-ever study of the natural history of aortic stenosis.

“These data provide a clear signal of the expected adverse outcomes for individuals presenting across the globe with a mean aortic valve gradient greater than 20.0 mm Hg or a peak aortic valve velocity above 3.0 m/sec,” Geoff Strange, PhD, said in presenting an analysis from NEDA, the National Echocardiography Database of Australia, at the annual congress of the European Society of Cardiology.

These results, if confirmed in other large datasets, could potentially have enormous implications for the use of transcatheter and surgical aortic valve replacement, interventions which until now have been restricted to patients with severe aortic stenosis (AS) as defined by an aortic valve (AV) mean gradient in excess of 40 mm Hg or a peak AV velocity greater than 4.0 m/sec. This restriction was based on what Dr. Strange considers rather limited and flimsy evidence suggesting that the mortality associated with AS was negligible except in severe AS.

“Cut points used to stratify for interventional strategies are based on very small numbers,” observed Dr. Strange, professor of medicine at the University of Notre Dame in Fremantle, Australia.

The NEDA findings, he added, constitute a call to action: “These data provide the impetus for a contemporary evaluation of the risk-to-benefit ratio of intervention in the moderate AS population,” Dr. Strange declared.

He and his NEDA coinvestigators analyzed echocardiographic data on 241,303 individuals in the Australian database, zeroing in on the 25,827 with untreated mild, moderate, or severe native valve AS. To place the size and scope of this project into perspective, the next-largest study of the natural history of untreated AS included 1,375 individuals – and that study was in turn roughly 10-fold bigger than the handful of other published studies addressing this issue.

A key finding in the NEDA study was that the 5-year all-cause mortality rate of 61.4% in the group with moderate AS wasn’t significantly different from the 64.6% rate in those with severe AS (see graphic).

The investigators performed additional analyses, analyzing peak velocity and mean gradient as continuous variables and stratifying patients into quintiles on that basis. They found that the top quintile for AV velocity started very low, at 1.73 m/sec, while the top quintile for mean AV gradient also started at a surprisingly low level: greater than 9.6 mm Hg. They noted that both all-cause and cardiovascular-specific mortality rates were basically flat until taking what Dr. Strange described as “a sharp pivot point upward” right around 20 mm Hg or 3 m/sec.

“No matter how we looked at these data – whether we looked at patients with or without left heart disease, whether we used the dimensionless index, whether we adjusted for stroke volume index, whether we stratified between age above or below 65, whether we used the gradient, the velocity, or the AV area – this threshold of increasing mortality at around 20 mm Hg or 3 m/sec continued to emerge,” according to Dr. Strange.

He noted that this study used real-world data with hard endpoints – actuarial patient mortality outcomes obtained through linkage to the national database – rather than hypothetical projections based upon Kaplan-Meier curves. A study limitation was that comorbidity data couldn’t be obtained for the AS patients.

Session cochair Patrizio Lancellotti, MD, PhD, commented, “I think this study will change a bit our consideration about patients with moderate AS.”

However, Dr. Lancellotti, who was lead author of the second-largest study of the natural history of aortic stenosis (JAMA Cardiol. 2018 Nov 1;3[11]:1060-8), expressed misgivings about the NEDA system’s lack of a core echocardiographic laboratory for imaging adjudication. That’s a study weakness given that image quality and the accuracy of echocardiographic interpretation are so highly dependent upon an individual cardiologist’s skill, observed Dr. Lancellotti, who is head of cardiology at the University of Liege (Belgium).

Dr. Strange replied that he and his coinvestigators analyzed a random subset of the NEDA data and found very little interlaboratory variability in results.

“All I can say is that the labs that contributed to this study are the most eminent labs across Australia,” he added.

Simultaneously with Dr. Strange’s presentation at the congress, the NEDA study results were published online (J Am Coll Cardiol. Sep 2019. doi: 10.1016/j.jacc.2019.08.004).

Dr. Strange reported having no financial conflicts of interest regarding the NEDA project, which is funded by GlaxoSmithKline, Bayer, and Actelion.

[email protected]

PARIS – The 5-year mortality rate associated with untreated moderate aortic stenosis is just as grim as it is for severe aortic stenosis, according to new findings from the largest-ever study of the natural history of aortic stenosis.

“These data provide a clear signal of the expected adverse outcomes for individuals presenting across the globe with a mean aortic valve gradient greater than 20.0 mm Hg or a peak aortic valve velocity above 3.0 m/sec,” Geoff Strange, PhD, said in presenting an analysis from NEDA, the National Echocardiography Database of Australia, at the annual congress of the European Society of Cardiology.

These results, if confirmed in other large datasets, could potentially have enormous implications for the use of transcatheter and surgical aortic valve replacement, interventions which until now have been restricted to patients with severe aortic stenosis (AS) as defined by an aortic valve (AV) mean gradient in excess of 40 mm Hg or a peak AV velocity greater than 4.0 m/sec. This restriction was based on what Dr. Strange considers rather limited and flimsy evidence suggesting that the mortality associated with AS was negligible except in severe AS.

“Cut points used to stratify for interventional strategies are based on very small numbers,” observed Dr. Strange, professor of medicine at the University of Notre Dame in Fremantle, Australia.

The NEDA findings, he added, constitute a call to action: “These data provide the impetus for a contemporary evaluation of the risk-to-benefit ratio of intervention in the moderate AS population,” Dr. Strange declared.

He and his NEDA coinvestigators analyzed echocardiographic data on 241,303 individuals in the Australian database, zeroing in on the 25,827 with untreated mild, moderate, or severe native valve AS. To place the size and scope of this project into perspective, the next-largest study of the natural history of untreated AS included 1,375 individuals – and that study was in turn roughly 10-fold bigger than the handful of other published studies addressing this issue.

A key finding in the NEDA study was that the 5-year all-cause mortality rate of 61.4% in the group with moderate AS wasn’t significantly different from the 64.6% rate in those with severe AS (see graphic).

The investigators performed additional analyses, analyzing peak velocity and mean gradient as continuous variables and stratifying patients into quintiles on that basis. They found that the top quintile for AV velocity started very low, at 1.73 m/sec, while the top quintile for mean AV gradient also started at a surprisingly low level: greater than 9.6 mm Hg. They noted that both all-cause and cardiovascular-specific mortality rates were basically flat until taking what Dr. Strange described as “a sharp pivot point upward” right around 20 mm Hg or 3 m/sec.

“No matter how we looked at these data – whether we looked at patients with or without left heart disease, whether we used the dimensionless index, whether we adjusted for stroke volume index, whether we stratified between age above or below 65, whether we used the gradient, the velocity, or the AV area – this threshold of increasing mortality at around 20 mm Hg or 3 m/sec continued to emerge,” according to Dr. Strange.

He noted that this study used real-world data with hard endpoints – actuarial patient mortality outcomes obtained through linkage to the national database – rather than hypothetical projections based upon Kaplan-Meier curves. A study limitation was that comorbidity data couldn’t be obtained for the AS patients.

Session cochair Patrizio Lancellotti, MD, PhD, commented, “I think this study will change a bit our consideration about patients with moderate AS.”

However, Dr. Lancellotti, who was lead author of the second-largest study of the natural history of aortic stenosis (JAMA Cardiol. 2018 Nov 1;3[11]:1060-8), expressed misgivings about the NEDA system’s lack of a core echocardiographic laboratory for imaging adjudication. That’s a study weakness given that image quality and the accuracy of echocardiographic interpretation are so highly dependent upon an individual cardiologist’s skill, observed Dr. Lancellotti, who is head of cardiology at the University of Liege (Belgium).

Dr. Strange replied that he and his coinvestigators analyzed a random subset of the NEDA data and found very little interlaboratory variability in results.

“All I can say is that the labs that contributed to this study are the most eminent labs across Australia,” he added.

Simultaneously with Dr. Strange’s presentation at the congress, the NEDA study results were published online (J Am Coll Cardiol. Sep 2019. doi: 10.1016/j.jacc.2019.08.004).

Dr. Strange reported having no financial conflicts of interest regarding the NEDA project, which is funded by GlaxoSmithKline, Bayer, and Actelion.

[email protected]

PARIS – A massive randomized trial that included all New Zealanders with a suspected acute coronary syndrome during a 2-year period has provided definitive evidence that giving high-flow supplemental oxygen to those who are nonhypoxemic is of no clinical benefit, although it wasn’t harmful, either.

Vidyard Video

“Patients who have a normal blood oxygen saturation level are very unlikely to benefit from supplemental oxygen,” Ralph Stewart, MbChB, said in presenting the results of the NZOTACS (New Zealand Oxygen Therapy in Acute Coronary Syndromes) trial at the annual congress of the European Society of Cardiology.

“It’s amazing that oxygen has been used in patients with suspected heart attack for over 50 years, and during that time there’s never been definite evidence that it improves outcomes. And more recently some have even suggested giving high-level oxygen might actually cause harm,” observed Dr. Stewart, a cardiologist at Auckland City Hospital and the University of Auckland (New Zealand).

The primary outcome in NZOTACS was 30-day all-cause mortality. In the overall study population, the rate was 3.0% in the group assigned to the routine high-flow oxygen protocol and closely similar at 3.1% in those randomized to the conservative oxygen strategy. And there was reassuringly no signal that the liberal oxygen protocol caused any harm.

To conduct this cluster randomized crossover trial, Dr. Stewart and his coinvestigators divided New Zealand into quadrants and, taking advantage of the coordinated health care systems operative in the nation of 4.8 million, they arranged for all ambulances, emergency departments, and hospitals in each geographic region to utilize each supplemental oxygen strategy for a total of 12 months.

In the liberal oxygen strategy, patients with suspected ACS on the basis of ischemic chest pain or ECG changes received high-flow oxygen by face mask at 6-8 L/min regardless of their blood oxygen saturation (SaO₂) level. The oxygen was stopped only upon clinical resolution of myocardial ischemia. In contrast, in the low-oxygen protocol, supplemental oxygen was reserved for patients with an initial SaO₂ below 90%, with a target SaO₂ of 90%-94%.

Roughly 90% of the nearly 41,000 study participants had a normal SaO₂ of 90% or more. Their 30-day mortality was 2.1% with the high-oxygen protocol and similar at 1.9% with the conservative oxygen protocol.

In contrast, there was a suggestion of benefit for the routine liberal oxygen strategy in the subgroup of patients with ST-elevation MI. Their 30-day mortality was 8.8% with high-flow oxygen and 10.6% with the conservative oxygen protocol. The resultant 19% relative risk reduction barely missed statistical significance. There was also a trend for possible benefit of routine high-flow oxygen in the roughly 12% of NZOTACS participants with an SaO₂ below 95%, a lower bar than the 90% SaO₂ that defines hypoxemia. Their death rate at 30 days was 10.1% if they got supplemental oxygen and 11.1% if they only received oxygen in the event their SaO₂ was below 90%. But these exploratory findings must be viewed as hypothesis-generating, and a large confirmatory study would be required, Dr. Stewart noted.

Discussant Robin Hofmann, MD, PhD, commented that, based on the NZOTACS results, he believes a couple of changes to the current ESC guidelines on management of ACS are in order. The guidelines now state that oxygen is indicated in patients with suspected ACS and hypoxemia as defined by an SaO₂ below 90%, giving that recommendation a Class I Level of Evidence C. That should now be upgraded to the strongest-possible Class I A recommendation, according to Dr. Hofmann, a cardiologist at the Karolinska Institute in Stockholm.

The ESC guidelines also state that oxygen isn’t routinely recommended in patients with an SaO₂ of 90% or more, rating that guidance Class III B. On the basis of NZOTACS coupled with earlier far smaller studies, that should be changed to a Class III A recommendation, meaning simply don’t do it. The hint provided by NZOTACS of a possible small benefit for oxygen in patients with an SaO₂ below 95% isn’t strong enough evidence to carry the day, in Dr. Hofmann’s view.

Dr. Stewart and Dr. Hofmann reported having no financial conflicts of interest. The NZOTACS trial was funded by the National Heart Foundation of New Zealand.

[email protected]

SOURCE: Stewart R. ESC 2019, Hotline Session 2.

PARIS – A massive randomized trial that included all New Zealanders with a suspected acute coronary syndrome during a 2-year period has provided definitive evidence that giving high-flow supplemental oxygen to those who are nonhypoxemic is of no clinical benefit, although it wasn’t harmful, either.

Vidyard Video

“Patients who have a normal blood oxygen saturation level are very unlikely to benefit from supplemental oxygen,” Ralph Stewart, MbChB, said in presenting the results of the NZOTACS (New Zealand Oxygen Therapy in Acute Coronary Syndromes) trial at the annual congress of the European Society of Cardiology.

“It’s amazing that oxygen has been used in patients with suspected heart attack for over 50 years, and during that time there’s never been definite evidence that it improves outcomes. And more recently some have even suggested giving high-level oxygen might actually cause harm,” observed Dr. Stewart, a cardiologist at Auckland City Hospital and the University of Auckland (New Zealand).

The primary outcome in NZOTACS was 30-day all-cause mortality. In the overall study population, the rate was 3.0% in the group assigned to the routine high-flow oxygen protocol and closely similar at 3.1% in those randomized to the conservative oxygen strategy. And there was reassuringly no signal that the liberal oxygen protocol caused any harm.

To conduct this cluster randomized crossover trial, Dr. Stewart and his coinvestigators divided New Zealand into quadrants and, taking advantage of the coordinated health care systems operative in the nation of 4.8 million, they arranged for all ambulances, emergency departments, and hospitals in each geographic region to utilize each supplemental oxygen strategy for a total of 12 months.

In the liberal oxygen strategy, patients with suspected ACS on the basis of ischemic chest pain or ECG changes received high-flow oxygen by face mask at 6-8 L/min regardless of their blood oxygen saturation (SaO₂) level. The oxygen was stopped only upon clinical resolution of myocardial ischemia. In contrast, in the low-oxygen protocol, supplemental oxygen was reserved for patients with an initial SaO₂ below 90%, with a target SaO₂ of 90%-94%.

Roughly 90% of the nearly 41,000 study participants had a normal SaO₂ of 90% or more. Their 30-day mortality was 2.1% with the high-oxygen protocol and similar at 1.9% with the conservative oxygen protocol.

In contrast, there was a suggestion of benefit for the routine liberal oxygen strategy in the subgroup of patients with ST-elevation MI. Their 30-day mortality was 8.8% with high-flow oxygen and 10.6% with the conservative oxygen protocol. The resultant 19% relative risk reduction barely missed statistical significance. There was also a trend for possible benefit of routine high-flow oxygen in the roughly 12% of NZOTACS participants with an SaO₂ below 95%, a lower bar than the 90% SaO₂ that defines hypoxemia. Their death rate at 30 days was 10.1% if they got supplemental oxygen and 11.1% if they only received oxygen in the event their SaO₂ was below 90%. But these exploratory findings must be viewed as hypothesis-generating, and a large confirmatory study would be required, Dr. Stewart noted.

Discussant Robin Hofmann, MD, PhD, commented that, based on the NZOTACS results, he believes a couple of changes to the current ESC guidelines on management of ACS are in order. The guidelines now state that oxygen is indicated in patients with suspected ACS and hypoxemia as defined by an SaO₂ below 90%, giving that recommendation a Class I Level of Evidence C. That should now be upgraded to the strongest-possible Class I A recommendation, according to Dr. Hofmann, a cardiologist at the Karolinska Institute in Stockholm.

The ESC guidelines also state that oxygen isn’t routinely recommended in patients with an SaO₂ of 90% or more, rating that guidance Class III B. On the basis of NZOTACS coupled with earlier far smaller studies, that should be changed to a Class III A recommendation, meaning simply don’t do it. The hint provided by NZOTACS of a possible small benefit for oxygen in patients with an SaO₂ below 95% isn’t strong enough evidence to carry the day, in Dr. Hofmann’s view.

Dr. Stewart and Dr. Hofmann reported having no financial conflicts of interest. The NZOTACS trial was funded by the National Heart Foundation of New Zealand.

[email protected]

SOURCE: Stewart R. ESC 2019, Hotline Session 2.

PARIS – A massive randomized trial that included all New Zealanders with a suspected acute coronary syndrome during a 2-year period has provided definitive evidence that giving high-flow supplemental oxygen to those who are nonhypoxemic is of no clinical benefit, although it wasn’t harmful, either.

Vidyard Video

“Patients who have a normal blood oxygen saturation level are very unlikely to benefit from supplemental oxygen,” Ralph Stewart, MbChB, said in presenting the results of the NZOTACS (New Zealand Oxygen Therapy in Acute Coronary Syndromes) trial at the annual congress of the European Society of Cardiology.

“It’s amazing that oxygen has been used in patients with suspected heart attack for over 50 years, and during that time there’s never been definite evidence that it improves outcomes. And more recently some have even suggested giving high-level oxygen might actually cause harm,” observed Dr. Stewart, a cardiologist at Auckland City Hospital and the University of Auckland (New Zealand).

The primary outcome in NZOTACS was 30-day all-cause mortality. In the overall study population, the rate was 3.0% in the group assigned to the routine high-flow oxygen protocol and closely similar at 3.1% in those randomized to the conservative oxygen strategy. And there was reassuringly no signal that the liberal oxygen protocol caused any harm.

To conduct this cluster randomized crossover trial, Dr. Stewart and his coinvestigators divided New Zealand into quadrants and, taking advantage of the coordinated health care systems operative in the nation of 4.8 million, they arranged for all ambulances, emergency departments, and hospitals in each geographic region to utilize each supplemental oxygen strategy for a total of 12 months.

In the liberal oxygen strategy, patients with suspected ACS on the basis of ischemic chest pain or ECG changes received high-flow oxygen by face mask at 6-8 L/min regardless of their blood oxygen saturation (SaO₂) level. The oxygen was stopped only upon clinical resolution of myocardial ischemia. In contrast, in the low-oxygen protocol, supplemental oxygen was reserved for patients with an initial SaO₂ below 90%, with a target SaO₂ of 90%-94%.

Roughly 90% of the nearly 41,000 study participants had a normal SaO₂ of 90% or more. Their 30-day mortality was 2.1% with the high-oxygen protocol and similar at 1.9% with the conservative oxygen protocol.

In contrast, there was a suggestion of benefit for the routine liberal oxygen strategy in the subgroup of patients with ST-elevation MI. Their 30-day mortality was 8.8% with high-flow oxygen and 10.6% with the conservative oxygen protocol. The resultant 19% relative risk reduction barely missed statistical significance. There was also a trend for possible benefit of routine high-flow oxygen in the roughly 12% of NZOTACS participants with an SaO₂ below 95%, a lower bar than the 90% SaO₂ that defines hypoxemia. Their death rate at 30 days was 10.1% if they got supplemental oxygen and 11.1% if they only received oxygen in the event their SaO₂ was below 90%. But these exploratory findings must be viewed as hypothesis-generating, and a large confirmatory study would be required, Dr. Stewart noted.

Discussant Robin Hofmann, MD, PhD, commented that, based on the NZOTACS results, he believes a couple of changes to the current ESC guidelines on management of ACS are in order. The guidelines now state that oxygen is indicated in patients with suspected ACS and hypoxemia as defined by an SaO₂ below 90%, giving that recommendation a Class I Level of Evidence C. That should now be upgraded to the strongest-possible Class I A recommendation, according to Dr. Hofmann, a cardiologist at the Karolinska Institute in Stockholm.

The ESC guidelines also state that oxygen isn’t routinely recommended in patients with an SaO₂ of 90% or more, rating that guidance Class III B. On the basis of NZOTACS coupled with earlier far smaller studies, that should be changed to a Class III A recommendation, meaning simply don’t do it. The hint provided by NZOTACS of a possible small benefit for oxygen in patients with an SaO₂ below 95% isn’t strong enough evidence to carry the day, in Dr. Hofmann’s view.

Dr. Stewart and Dr. Hofmann reported having no financial conflicts of interest. The NZOTACS trial was funded by the National Heart Foundation of New Zealand.

[email protected]

SOURCE: Stewart R. ESC 2019, Hotline Session 2.

PARIS – Beta-blocking drugs were as effective for improving survival in patients with moderately severe renal dysfunction as they were in patients with normal renal function in a meta-analysis of more than 13,000 patients, a finding that seemed to solidify the role for this drug class for essentially all similar heart failure patients, regardless of their renal function.

Mitchel L. Zoler/MDedge News

This evidence could reshape usual care because “renal impairment is often considered a barrier in clinical practice” for starting a beta-blocker drug in patients with heart failure with reduced ejection fraction (HFrEF), Dipak Kotecha, MBChB, said at the annual congress of the European Society of Cardiology.

“We have shown with sufficient sample size that beta-blockers are effective in reducing mortality in patient with HFrEF and in sinus rhythm, even in those with an eGFR [estimated glomerular filtration rate] of 30-44 mL/min per 1.73 m²,” said Dr. Kotecha, a cardiologist at the University of Birmingham (England). “The results suggest that renal impairment should not obstruct the prescription and maintenance of beta-blockers in patients with HFrEF.”

“This important study was a novel attempt to look at [HFrEF] patients with renal insufficiency to see whether they received the same benefit from beta-blockers as other patients, and they did. So renal insufficiency is not a reason to withhold beta-blockers” from these patients, commented Mariell Jessup, MD, a heart failure physician and chief science and medical officer for the American Heart Association in Dallas. “The onus is on clinicians to find a reason not to give a beta-blocker to a patient with HFrEF because they are generally well tolerated and they can have enormous benefit, as we saw in this study,” she said in a video interview.

The analysis run by Dr. Kotecha and associates used data collected in 11 of the pivotal randomized, controlled trial run for beta-blockers during the 1990s and early 2000s, with each study comparing bucindolol, bisoprolol, carvedilol, metoprolol XL, or nebivolol against placebo. The studies collectively enrolled 18,637 patients, which the investigators whittled down in their analysis to 17,433 after excluding patients with a left ventricular ejection fraction below 50% or who were undocumented. The subgroup with HFrEF included 13,861 patient in sinus rhythm at entry, 2,879 with atrial fibrillation, and 693 with an unknown atrial status. The main analysis ran in the 13,861 patients with HFrEF and in sinus rhythm; 14% of this cohort had an eGFR of 30-44 mL/min per 1.73 m² and 27% had an eGFR of 45-59 mL/min per 1.73 m². The median age of all patients in the main analysis was 65 years, 23% were women, and their median left ventricular ejection fraction was 27%.

During follow-up of about 3 years, the impact of beta-blocker treatment on survival, compared with placebo, was “substantial” for all strata of patients by renal function, except for those with eGFRs below 30 mL/min per 1.73 m². (Survival was similar regardless of beta-blocker treatment in the small number of patients with severe renal dysfunction.) The number needed to treat to prevent 1 death in patients with an eGFR of 30-44 mL/min per 1.73 m² was 21, the same as among patients with an eGFR of 90 mL/min per 1.73 m² or more, Dr. Kotecha said.

Among the subgroup of patients with atrial fibrillation, beta-blockers appeared to exert no survival benefit, compared with placebo. The investigators did not assess the survival benefits exerted by any individual beta-blocker, compared with the others, and Dr. Kotecha stressed that “my belief is that this is a class effect” and is roughly similar across all the beta-blockers used in the studies.

The analysis also showed good safety and tolerability of the beta-blockers in patients with renal dysfunction. The incidence of adverse events leading to treatment termination was very similar in the beta-blocker and placebo arms, and more than three-quarters of patients in each of the two subgroups with renal dysfunction were maintained on more than 50% of their target beta-blocker dosage.

Dr. Kotecha has been an advisor to Bayer, a speaker on behalf of Atricure, and has received research funding from GlaxoSmithKline and Menarini. Dr. Jessup had no disclosures.

[email protected]

PARIS – Beta-blocking drugs were as effective for improving survival in patients with moderately severe renal dysfunction as they were in patients with normal renal function in a meta-analysis of more than 13,000 patients, a finding that seemed to solidify the role for this drug class for essentially all similar heart failure patients, regardless of their renal function.

Mitchel L. Zoler/MDedge News

This evidence could reshape usual care because “renal impairment is often considered a barrier in clinical practice” for starting a beta-blocker drug in patients with heart failure with reduced ejection fraction (HFrEF), Dipak Kotecha, MBChB, said at the annual congress of the European Society of Cardiology.

“We have shown with sufficient sample size that beta-blockers are effective in reducing mortality in patient with HFrEF and in sinus rhythm, even in those with an eGFR [estimated glomerular filtration rate] of 30-44 mL/min per 1.73 m²,” said Dr. Kotecha, a cardiologist at the University of Birmingham (England). “The results suggest that renal impairment should not obstruct the prescription and maintenance of beta-blockers in patients with HFrEF.”

“This important study was a novel attempt to look at [HFrEF] patients with renal insufficiency to see whether they received the same benefit from beta-blockers as other patients, and they did. So renal insufficiency is not a reason to withhold beta-blockers” from these patients, commented Mariell Jessup, MD, a heart failure physician and chief science and medical officer for the American Heart Association in Dallas. “The onus is on clinicians to find a reason not to give a beta-blocker to a patient with HFrEF because they are generally well tolerated and they can have enormous benefit, as we saw in this study,” she said in a video interview.

The analysis run by Dr. Kotecha and associates used data collected in 11 of the pivotal randomized, controlled trial run for beta-blockers during the 1990s and early 2000s, with each study comparing bucindolol, bisoprolol, carvedilol, metoprolol XL, or nebivolol against placebo. The studies collectively enrolled 18,637 patients, which the investigators whittled down in their analysis to 17,433 after excluding patients with a left ventricular ejection fraction below 50% or who were undocumented. The subgroup with HFrEF included 13,861 patient in sinus rhythm at entry, 2,879 with atrial fibrillation, and 693 with an unknown atrial status. The main analysis ran in the 13,861 patients with HFrEF and in sinus rhythm; 14% of this cohort had an eGFR of 30-44 mL/min per 1.73 m² and 27% had an eGFR of 45-59 mL/min per 1.73 m². The median age of all patients in the main analysis was 65 years, 23% were women, and their median left ventricular ejection fraction was 27%.

During follow-up of about 3 years, the impact of beta-blocker treatment on survival, compared with placebo, was “substantial” for all strata of patients by renal function, except for those with eGFRs below 30 mL/min per 1.73 m². (Survival was similar regardless of beta-blocker treatment in the small number of patients with severe renal dysfunction.) The number needed to treat to prevent 1 death in patients with an eGFR of 30-44 mL/min per 1.73 m² was 21, the same as among patients with an eGFR of 90 mL/min per 1.73 m² or more, Dr. Kotecha said.

Among the subgroup of patients with atrial fibrillation, beta-blockers appeared to exert no survival benefit, compared with placebo. The investigators did not assess the survival benefits exerted by any individual beta-blocker, compared with the others, and Dr. Kotecha stressed that “my belief is that this is a class effect” and is roughly similar across all the beta-blockers used in the studies.

The analysis also showed good safety and tolerability of the beta-blockers in patients with renal dysfunction. The incidence of adverse events leading to treatment termination was very similar in the beta-blocker and placebo arms, and more than three-quarters of patients in each of the two subgroups with renal dysfunction were maintained on more than 50% of their target beta-blocker dosage.

Dr. Kotecha has been an advisor to Bayer, a speaker on behalf of Atricure, and has received research funding from GlaxoSmithKline and Menarini. Dr. Jessup had no disclosures.

[email protected]

PARIS – Beta-blocking drugs were as effective for improving survival in patients with moderately severe renal dysfunction as they were in patients with normal renal function in a meta-analysis of more than 13,000 patients, a finding that seemed to solidify the role for this drug class for essentially all similar heart failure patients, regardless of their renal function.

Mitchel L. Zoler/MDedge News

This evidence could reshape usual care because “renal impairment is often considered a barrier in clinical practice” for starting a beta-blocker drug in patients with heart failure with reduced ejection fraction (HFrEF), Dipak Kotecha, MBChB, said at the annual congress of the European Society of Cardiology.

“We have shown with sufficient sample size that beta-blockers are effective in reducing mortality in patient with HFrEF and in sinus rhythm, even in those with an eGFR [estimated glomerular filtration rate] of 30-44 mL/min per 1.73 m²,” said Dr. Kotecha, a cardiologist at the University of Birmingham (England). “The results suggest that renal impairment should not obstruct the prescription and maintenance of beta-blockers in patients with HFrEF.”

“This important study was a novel attempt to look at [HFrEF] patients with renal insufficiency to see whether they received the same benefit from beta-blockers as other patients, and they did. So renal insufficiency is not a reason to withhold beta-blockers” from these patients, commented Mariell Jessup, MD, a heart failure physician and chief science and medical officer for the American Heart Association in Dallas. “The onus is on clinicians to find a reason not to give a beta-blocker to a patient with HFrEF because they are generally well tolerated and they can have enormous benefit, as we saw in this study,” she said in a video interview.

The analysis run by Dr. Kotecha and associates used data collected in 11 of the pivotal randomized, controlled trial run for beta-blockers during the 1990s and early 2000s, with each study comparing bucindolol, bisoprolol, carvedilol, metoprolol XL, or nebivolol against placebo. The studies collectively enrolled 18,637 patients, which the investigators whittled down in their analysis to 17,433 after excluding patients with a left ventricular ejection fraction below 50% or who were undocumented. The subgroup with HFrEF included 13,861 patient in sinus rhythm at entry, 2,879 with atrial fibrillation, and 693 with an unknown atrial status. The main analysis ran in the 13,861 patients with HFrEF and in sinus rhythm; 14% of this cohort had an eGFR of 30-44 mL/min per 1.73 m² and 27% had an eGFR of 45-59 mL/min per 1.73 m². The median age of all patients in the main analysis was 65 years, 23% were women, and their median left ventricular ejection fraction was 27%.

During follow-up of about 3 years, the impact of beta-blocker treatment on survival, compared with placebo, was “substantial” for all strata of patients by renal function, except for those with eGFRs below 30 mL/min per 1.73 m². (Survival was similar regardless of beta-blocker treatment in the small number of patients with severe renal dysfunction.) The number needed to treat to prevent 1 death in patients with an eGFR of 30-44 mL/min per 1.73 m² was 21, the same as among patients with an eGFR of 90 mL/min per 1.73 m² or more, Dr. Kotecha said.

Among the subgroup of patients with atrial fibrillation, beta-blockers appeared to exert no survival benefit, compared with placebo. The investigators did not assess the survival benefits exerted by any individual beta-blocker, compared with the others, and Dr. Kotecha stressed that “my belief is that this is a class effect” and is roughly similar across all the beta-blockers used in the studies.

The analysis also showed good safety and tolerability of the beta-blockers in patients with renal dysfunction. The incidence of adverse events leading to treatment termination was very similar in the beta-blocker and placebo arms, and more than three-quarters of patients in each of the two subgroups with renal dysfunction were maintained on more than 50% of their target beta-blocker dosage.

Dr. Kotecha has been an advisor to Bayer, a speaker on behalf of Atricure, and has received research funding from GlaxoSmithKline and Menarini. Dr. Jessup had no disclosures.

[email protected]

PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.

Catherine Hackett/MDedge News

The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.

Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”

The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.

Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.

The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.

Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).

The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.

On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.

Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.

These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).

Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.

Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.

Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.

The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.

Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”

Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.

Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.

However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.

Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.

In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.

The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.

Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.

“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”

Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.

Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).

The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.

[email protected]

SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.

PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.

Catherine Hackett/MDedge News

The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.

Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”

The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.

Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.

The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.

Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).

The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.

On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.

Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.

These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).

Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.

Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.

Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.

The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.

Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”

Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.

Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.

However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.

Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.

In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.

The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.

Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.

“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”

Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.

Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).

The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.

[email protected]

SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.

PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.

Catherine Hackett/MDedge News

The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.

Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”

The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.

Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.

The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.

Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).

The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.

On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.

Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.

These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).

Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.

Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.

Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.

The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.

Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”

Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.

Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.

However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.

Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.

In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.

The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.

Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.

“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”

Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.

Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).

The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.

[email protected]

SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.

PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.

Bruce Jancin/MDedge News

The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.

The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.

“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.

“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”

ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.

The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.

Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.

Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.

The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.

Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”

Bruce Jancin/MDedge News

In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.

The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.

The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.

“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.

Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.

Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).

[email protected]

PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.

Bruce Jancin/MDedge News

The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.

The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.

“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.

“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”

ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.

The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.

Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.

Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.

The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.

Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”

Bruce Jancin/MDedge News

In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.

The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.

The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.

“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.

Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.

Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).

[email protected]

PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.

Bruce Jancin/MDedge News

The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.

The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.

“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.

“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”

ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.

The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.

Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.

Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.

The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.

Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”

Bruce Jancin/MDedge News

In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.

The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.

The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.

“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.

Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.

Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).

[email protected]

PARIS – Patients with angina who were also more than 3 months out from a prior MI had a significantly increased rate of subsequent cardiovascular death or nonfatal MI in a study of nearly 33,000 patients, a finding that identified angina as a new red flag when following post-MI patients.

Mitchel L. Zoler/MDedge News

“Angina and prior MI was a higher-risk subgroup that may warrant more intensive management. This is new,” Emmanuel Sorbets, MD, said at the annual congress of the European Society of Cardiology.

The finding came from review of 32,703 patients from 45 countries with stable coronary artery disease enrolled in the CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) registry during 2009-2010, a population that appeared to uniformly meet the new definition of chronic chromic syndromes recently published by a task force of the society (Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz425).

Among the CLARIFY patients, 60% had an MI more than 3 months prior to enrollment (the registry excluded patients with more proximate MIs), and in this subgroup angina at baseline was linked with a 3.6% absolute increase in the rate of cardiovascular death or nonfatal MI compared with post-MI patients without angina at baseline during a median 5 year follow-up. This translated into a 44% relative increase that remained statistically significant after adjustment for several demographic and clinical factors, said Dr. Sorbets, a cardiologist at Avicenne Hospital in Bobigny, France. The cumulative incidence of the combined endpoint was 11.8% among post-MI patients with baseline angina and 8.2% in those without angina. Among patients without a prior MI, the presence or absence of angina at entry into the registry had no link with the incidence of later outcomes. Concurrently with Dr. Sorbets’ report at the congress, the results appeared in an article published online (Eur Heart J. 2019 Sep 3;doi: 10.1093/eurheartj/ehz660).

This finding should immediately influence practice, said Sanjay Sharma, MD, professor of inherited cardiac diseases and sports cardiology at St. George’s University, London. “One of the messages from this study is that we now have a very easy way to measure a high-risk factor,” and that patients who present with angina more than 3 months after an MI “require intensive investigation and aggressive management,” he said. The new evidence identified post-MI patients with angina as having a “semi-urgent” condition that needs added anti-anginal treatment and, if symptoms persist, possible revascularization, especially patients without prior revascularization, he said in a video interview. Although the study did not analyze the type of MI linked with these poor outcomes, Dr. Sharma speculated that certain patients with a prior non ST-elevation MI may face the greatest danger it they did not undergo percutaneous coronary revascularization at the time of their MI.

CLARIFY is sponsored by Servier. Dr. Sorbets has received personal fees from Servier, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Dr. Sharma had no relevant disclosures.

[email protected]

PARIS – Patients with angina who were also more than 3 months out from a prior MI had a significantly increased rate of subsequent cardiovascular death or nonfatal MI in a study of nearly 33,000 patients, a finding that identified angina as a new red flag when following post-MI patients.

Mitchel L. Zoler/MDedge News

“Angina and prior MI was a higher-risk subgroup that may warrant more intensive management. This is new,” Emmanuel Sorbets, MD, said at the annual congress of the European Society of Cardiology.

The finding came from review of 32,703 patients from 45 countries with stable coronary artery disease enrolled in the CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) registry during 2009-2010, a population that appeared to uniformly meet the new definition of chronic chromic syndromes recently published by a task force of the society (Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz425).

Among the CLARIFY patients, 60% had an MI more than 3 months prior to enrollment (the registry excluded patients with more proximate MIs), and in this subgroup angina at baseline was linked with a 3.6% absolute increase in the rate of cardiovascular death or nonfatal MI compared with post-MI patients without angina at baseline during a median 5 year follow-up. This translated into a 44% relative increase that remained statistically significant after adjustment for several demographic and clinical factors, said Dr. Sorbets, a cardiologist at Avicenne Hospital in Bobigny, France. The cumulative incidence of the combined endpoint was 11.8% among post-MI patients with baseline angina and 8.2% in those without angina. Among patients without a prior MI, the presence or absence of angina at entry into the registry had no link with the incidence of later outcomes. Concurrently with Dr. Sorbets’ report at the congress, the results appeared in an article published online (Eur Heart J. 2019 Sep 3;doi: 10.1093/eurheartj/ehz660).

This finding should immediately influence practice, said Sanjay Sharma, MD, professor of inherited cardiac diseases and sports cardiology at St. George’s University, London. “One of the messages from this study is that we now have a very easy way to measure a high-risk factor,” and that patients who present with angina more than 3 months after an MI “require intensive investigation and aggressive management,” he said. The new evidence identified post-MI patients with angina as having a “semi-urgent” condition that needs added anti-anginal treatment and, if symptoms persist, possible revascularization, especially patients without prior revascularization, he said in a video interview. Although the study did not analyze the type of MI linked with these poor outcomes, Dr. Sharma speculated that certain patients with a prior non ST-elevation MI may face the greatest danger it they did not undergo percutaneous coronary revascularization at the time of their MI.

CLARIFY is sponsored by Servier. Dr. Sorbets has received personal fees from Servier, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Dr. Sharma had no relevant disclosures.

[email protected]

PARIS – Patients with angina who were also more than 3 months out from a prior MI had a significantly increased rate of subsequent cardiovascular death or nonfatal MI in a study of nearly 33,000 patients, a finding that identified angina as a new red flag when following post-MI patients.

Mitchel L. Zoler/MDedge News

“Angina and prior MI was a higher-risk subgroup that may warrant more intensive management. This is new,” Emmanuel Sorbets, MD, said at the annual congress of the European Society of Cardiology.

The finding came from review of 32,703 patients from 45 countries with stable coronary artery disease enrolled in the CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) registry during 2009-2010, a population that appeared to uniformly meet the new definition of chronic chromic syndromes recently published by a task force of the society (Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz425).

Among the CLARIFY patients, 60% had an MI more than 3 months prior to enrollment (the registry excluded patients with more proximate MIs), and in this subgroup angina at baseline was linked with a 3.6% absolute increase in the rate of cardiovascular death or nonfatal MI compared with post-MI patients without angina at baseline during a median 5 year follow-up. This translated into a 44% relative increase that remained statistically significant after adjustment for several demographic and clinical factors, said Dr. Sorbets, a cardiologist at Avicenne Hospital in Bobigny, France. The cumulative incidence of the combined endpoint was 11.8% among post-MI patients with baseline angina and 8.2% in those without angina. Among patients without a prior MI, the presence or absence of angina at entry into the registry had no link with the incidence of later outcomes. Concurrently with Dr. Sorbets’ report at the congress, the results appeared in an article published online (Eur Heart J. 2019 Sep 3;doi: 10.1093/eurheartj/ehz660).

This finding should immediately influence practice, said Sanjay Sharma, MD, professor of inherited cardiac diseases and sports cardiology at St. George’s University, London. “One of the messages from this study is that we now have a very easy way to measure a high-risk factor,” and that patients who present with angina more than 3 months after an MI “require intensive investigation and aggressive management,” he said. The new evidence identified post-MI patients with angina as having a “semi-urgent” condition that needs added anti-anginal treatment and, if symptoms persist, possible revascularization, especially patients without prior revascularization, he said in a video interview. Although the study did not analyze the type of MI linked with these poor outcomes, Dr. Sharma speculated that certain patients with a prior non ST-elevation MI may face the greatest danger it they did not undergo percutaneous coronary revascularization at the time of their MI.

CLARIFY is sponsored by Servier. Dr. Sorbets has received personal fees from Servier, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Dr. Sharma had no relevant disclosures.

[email protected]