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Calcium burden drives CV risk whether coronary disease is obstructive or not
Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.
Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).
The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.
The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.
“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.
The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”
In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”
The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.
Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.
The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.
“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”
Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”
In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.
About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.
The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.
The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.
The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.
And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.
The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.
However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.
Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.
“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.
The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”
Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”
An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”
But they pointed out some limitations of the current study.
“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”
The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”
Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.
A version of this article originally appeared on Medscape.com.
Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.
Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).
The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.
The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.
“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.
The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”
In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”
The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.
Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.
The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.
“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”
Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”
In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.
About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.
The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.
The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.
The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.
And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.
The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.
However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.
Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.
“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.
The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”
Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”
An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”
But they pointed out some limitations of the current study.
“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”
The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”
Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.
A version of this article originally appeared on Medscape.com.
Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.
Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).
The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.
The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.
“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.
The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”
In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”
The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.
Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.
The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.
“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”
Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”
In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.
About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.
The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.
The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.
The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.
And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.
The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.
However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.
Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.
“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.
The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”
Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”
An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”
But they pointed out some limitations of the current study.
“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”
The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”
Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.
A version of this article originally appeared on Medscape.com.
COVID-19 and risk of clotting: ‘Be proactive about prevention’
The risk of arterial and venous thrombosis in patients with COVID-19 has been a major issue throughout the pandemic, and how best to manage this risk is the subject of a new review article.
The article, by Gregory Dr. Piazza, MD, and David A. Morrow, MD, Brigham and Women’s Hospital, Boston, was published online in JAMA on Nov. 23.
“Basically we’re saying: ‘Be proactive about prevention,’” Dr. Piazza told this news organization.
There is growing recognition among those on the frontline that there is an increased risk of thrombosis in COVID-19 patients, Dr. Piazza said. The risk is highest in patients in the intensive care unit, but the risk is also increased in patients hospitalized with COVID-19, even those not in ICU.
“We don’t really know what the risk is in nonhospitalized COVID-19 patients, but we think it’s much lower than in those who are hospitalized,” he said. “We are waiting for data on the optimal way of managing this increased risk of thrombosis in COVID patients, but for the time being, we believe a systematic way of addressing this risk is best, with every patient hospitalized with COVID-19 receiving some type of thromboprophylaxis. This would mainly be with anticoagulation, but in patients in whom anticoagulation is contraindicated, then mechanical methods could be used, such as pneumatic compression boots or compression stockings.”
The authors report thrombotic complication rates of 2.6% in noncritically ill hospitalized patients with COVID-19 and 35.3% in critically ill patients from a recent U.S. registry study.
Autopsy findings of microthrombi in multiple organ systems, including the lungs, heart, and kidneys, suggest that thrombosis may contribute to multisystem organ dysfunction in severe COVID-19, they note. Although the pathophysiology is not fully defined, prothrombotic abnormalities have been identified in patients with COVID-19, including elevated levels of D-dimer, fibrinogen, and factor VIII, they add.
“There are several major questions about which COVID-19 patients to treat with thromboprophylaxis, how to treat them in term of levels of anticoagulation, and there are many ongoing clinical trials to try and answer these questions,” Dr. Piazza commented. “We need results from these randomized trials to provide a better compass for COVID-19 patients at risk of clotting.”
At present, clinicians can follow two different sets of guidelines on the issue, one from the American College of Chest Physicians and the other from the International Society on Thrombosis and Hemostasis, the authors note.
“The ACCP guidelines are very conservative and basically follow the evidence base for medical patients, while the ISTH guidelines are more aggressive and recommend increased levels of anticoagulation in both ICU and hospitalized non-ICU patients and also extend prophylaxis after discharge,” Dr. Piazza said.
“There is quite a difference between the two sets of guidelines, which can be a point of confusion,” he added.
Dr. Piazza notes that at his center every hospitalized COVID patient who does not have a contraindication to anticoagulation receives a standard prophylactic dose of a once-daily low-molecular-weight heparin (for example, enoxaparin 40 mg). A once-daily product is used to minimize infection risk to staff.
While all COVID patients in the ICU should automatically receive some anticoagulation, the optimal dose is an area of active investigation, he explained. “There were several early reports of ICU patients developing blood clots despite receiving standard thromboprophylaxis so perhaps we need to use higher doses. There are trials underway looking at this, and we would advise enrolling patients into these trials.”
If patients can’t be enrolled into trials, and clinicians feel higher anticoagulation levels are needed, Dr. Piazza advises following the ISTH guidance, which allows an intermediate dose of low-molecular-weight heparin (up to 1 mg/kg enoxaparin).
“Some experts are suggesting even higher doses may be needed in some ICU patients, such as the full therapeutic dose, but I worry about the risk of bleeding with such a strategy,” he said.
Dr. Piazza says they do not routinely give anticoagulation after discharge, but if this is desired then patients could be switched to an oral agent, and some of the direct-acting oral anticoagulants are approved for prophylactic use in medically ill patients.
Dr. Piazza points out that whether thromboprophylaxis should be used for nonhospitalized COVID patients who have risk factors for clotting such as a prior history of thrombosis or obesity is a pressing question, and he encourages clinicians to enroll these patients in clinical trials evaluating this issue, such as the PREVENT-HD trial.
“If they can’t enroll patents in a trial, then they have to make a decision whether the patient is high-enough risk to justify off-label use of anticoagulant. There is a case to be made for this, but there is no evidence for or against such action at present,” he noted.
At this time, neither the ISTH nor ACCP recommend measuring D-dimer to screen for venous thromboembolism or to determine intensity of prophylaxis or treatment, the authors note.
“Ongoing investigation will determine optimal preventive regimens in COVID-19 in the intensive care unit, at hospital discharge, and in nonhospitalized patients at high risk for thrombosis,” they conclude.
Dr. Piazza reported grants from Bayer, Bristol Myers Squibb, Boston Scientific, Janssen, and Portola, and personal fees from Agile, Amgen, Pfizer, and the Prairie Education and Research Cooperative outside the submitted work. Dr. Morrow reported grants from Abbott Laboratories, Amgen, Anthos Therapeutics, Esai, GlaxoSmithKline, Takeda, and The Medicines Company; grants and personal fees from AstraZeneca, Merck, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma and InCarda outside the submitted work.
A version of this article originally appeared on Medscape.com.
The risk of arterial and venous thrombosis in patients with COVID-19 has been a major issue throughout the pandemic, and how best to manage this risk is the subject of a new review article.
The article, by Gregory Dr. Piazza, MD, and David A. Morrow, MD, Brigham and Women’s Hospital, Boston, was published online in JAMA on Nov. 23.
“Basically we’re saying: ‘Be proactive about prevention,’” Dr. Piazza told this news organization.
There is growing recognition among those on the frontline that there is an increased risk of thrombosis in COVID-19 patients, Dr. Piazza said. The risk is highest in patients in the intensive care unit, but the risk is also increased in patients hospitalized with COVID-19, even those not in ICU.
“We don’t really know what the risk is in nonhospitalized COVID-19 patients, but we think it’s much lower than in those who are hospitalized,” he said. “We are waiting for data on the optimal way of managing this increased risk of thrombosis in COVID patients, but for the time being, we believe a systematic way of addressing this risk is best, with every patient hospitalized with COVID-19 receiving some type of thromboprophylaxis. This would mainly be with anticoagulation, but in patients in whom anticoagulation is contraindicated, then mechanical methods could be used, such as pneumatic compression boots or compression stockings.”
The authors report thrombotic complication rates of 2.6% in noncritically ill hospitalized patients with COVID-19 and 35.3% in critically ill patients from a recent U.S. registry study.
Autopsy findings of microthrombi in multiple organ systems, including the lungs, heart, and kidneys, suggest that thrombosis may contribute to multisystem organ dysfunction in severe COVID-19, they note. Although the pathophysiology is not fully defined, prothrombotic abnormalities have been identified in patients with COVID-19, including elevated levels of D-dimer, fibrinogen, and factor VIII, they add.
“There are several major questions about which COVID-19 patients to treat with thromboprophylaxis, how to treat them in term of levels of anticoagulation, and there are many ongoing clinical trials to try and answer these questions,” Dr. Piazza commented. “We need results from these randomized trials to provide a better compass for COVID-19 patients at risk of clotting.”
At present, clinicians can follow two different sets of guidelines on the issue, one from the American College of Chest Physicians and the other from the International Society on Thrombosis and Hemostasis, the authors note.
“The ACCP guidelines are very conservative and basically follow the evidence base for medical patients, while the ISTH guidelines are more aggressive and recommend increased levels of anticoagulation in both ICU and hospitalized non-ICU patients and also extend prophylaxis after discharge,” Dr. Piazza said.
“There is quite a difference between the two sets of guidelines, which can be a point of confusion,” he added.
Dr. Piazza notes that at his center every hospitalized COVID patient who does not have a contraindication to anticoagulation receives a standard prophylactic dose of a once-daily low-molecular-weight heparin (for example, enoxaparin 40 mg). A once-daily product is used to minimize infection risk to staff.
While all COVID patients in the ICU should automatically receive some anticoagulation, the optimal dose is an area of active investigation, he explained. “There were several early reports of ICU patients developing blood clots despite receiving standard thromboprophylaxis so perhaps we need to use higher doses. There are trials underway looking at this, and we would advise enrolling patients into these trials.”
If patients can’t be enrolled into trials, and clinicians feel higher anticoagulation levels are needed, Dr. Piazza advises following the ISTH guidance, which allows an intermediate dose of low-molecular-weight heparin (up to 1 mg/kg enoxaparin).
“Some experts are suggesting even higher doses may be needed in some ICU patients, such as the full therapeutic dose, but I worry about the risk of bleeding with such a strategy,” he said.
Dr. Piazza says they do not routinely give anticoagulation after discharge, but if this is desired then patients could be switched to an oral agent, and some of the direct-acting oral anticoagulants are approved for prophylactic use in medically ill patients.
Dr. Piazza points out that whether thromboprophylaxis should be used for nonhospitalized COVID patients who have risk factors for clotting such as a prior history of thrombosis or obesity is a pressing question, and he encourages clinicians to enroll these patients in clinical trials evaluating this issue, such as the PREVENT-HD trial.
“If they can’t enroll patents in a trial, then they have to make a decision whether the patient is high-enough risk to justify off-label use of anticoagulant. There is a case to be made for this, but there is no evidence for or against such action at present,” he noted.
At this time, neither the ISTH nor ACCP recommend measuring D-dimer to screen for venous thromboembolism or to determine intensity of prophylaxis or treatment, the authors note.
“Ongoing investigation will determine optimal preventive regimens in COVID-19 in the intensive care unit, at hospital discharge, and in nonhospitalized patients at high risk for thrombosis,” they conclude.
Dr. Piazza reported grants from Bayer, Bristol Myers Squibb, Boston Scientific, Janssen, and Portola, and personal fees from Agile, Amgen, Pfizer, and the Prairie Education and Research Cooperative outside the submitted work. Dr. Morrow reported grants from Abbott Laboratories, Amgen, Anthos Therapeutics, Esai, GlaxoSmithKline, Takeda, and The Medicines Company; grants and personal fees from AstraZeneca, Merck, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma and InCarda outside the submitted work.
A version of this article originally appeared on Medscape.com.
The risk of arterial and venous thrombosis in patients with COVID-19 has been a major issue throughout the pandemic, and how best to manage this risk is the subject of a new review article.
The article, by Gregory Dr. Piazza, MD, and David A. Morrow, MD, Brigham and Women’s Hospital, Boston, was published online in JAMA on Nov. 23.
“Basically we’re saying: ‘Be proactive about prevention,’” Dr. Piazza told this news organization.
There is growing recognition among those on the frontline that there is an increased risk of thrombosis in COVID-19 patients, Dr. Piazza said. The risk is highest in patients in the intensive care unit, but the risk is also increased in patients hospitalized with COVID-19, even those not in ICU.
“We don’t really know what the risk is in nonhospitalized COVID-19 patients, but we think it’s much lower than in those who are hospitalized,” he said. “We are waiting for data on the optimal way of managing this increased risk of thrombosis in COVID patients, but for the time being, we believe a systematic way of addressing this risk is best, with every patient hospitalized with COVID-19 receiving some type of thromboprophylaxis. This would mainly be with anticoagulation, but in patients in whom anticoagulation is contraindicated, then mechanical methods could be used, such as pneumatic compression boots or compression stockings.”
The authors report thrombotic complication rates of 2.6% in noncritically ill hospitalized patients with COVID-19 and 35.3% in critically ill patients from a recent U.S. registry study.
Autopsy findings of microthrombi in multiple organ systems, including the lungs, heart, and kidneys, suggest that thrombosis may contribute to multisystem organ dysfunction in severe COVID-19, they note. Although the pathophysiology is not fully defined, prothrombotic abnormalities have been identified in patients with COVID-19, including elevated levels of D-dimer, fibrinogen, and factor VIII, they add.
“There are several major questions about which COVID-19 patients to treat with thromboprophylaxis, how to treat them in term of levels of anticoagulation, and there are many ongoing clinical trials to try and answer these questions,” Dr. Piazza commented. “We need results from these randomized trials to provide a better compass for COVID-19 patients at risk of clotting.”
At present, clinicians can follow two different sets of guidelines on the issue, one from the American College of Chest Physicians and the other from the International Society on Thrombosis and Hemostasis, the authors note.
“The ACCP guidelines are very conservative and basically follow the evidence base for medical patients, while the ISTH guidelines are more aggressive and recommend increased levels of anticoagulation in both ICU and hospitalized non-ICU patients and also extend prophylaxis after discharge,” Dr. Piazza said.
“There is quite a difference between the two sets of guidelines, which can be a point of confusion,” he added.
Dr. Piazza notes that at his center every hospitalized COVID patient who does not have a contraindication to anticoagulation receives a standard prophylactic dose of a once-daily low-molecular-weight heparin (for example, enoxaparin 40 mg). A once-daily product is used to minimize infection risk to staff.
While all COVID patients in the ICU should automatically receive some anticoagulation, the optimal dose is an area of active investigation, he explained. “There were several early reports of ICU patients developing blood clots despite receiving standard thromboprophylaxis so perhaps we need to use higher doses. There are trials underway looking at this, and we would advise enrolling patients into these trials.”
If patients can’t be enrolled into trials, and clinicians feel higher anticoagulation levels are needed, Dr. Piazza advises following the ISTH guidance, which allows an intermediate dose of low-molecular-weight heparin (up to 1 mg/kg enoxaparin).
“Some experts are suggesting even higher doses may be needed in some ICU patients, such as the full therapeutic dose, but I worry about the risk of bleeding with such a strategy,” he said.
Dr. Piazza says they do not routinely give anticoagulation after discharge, but if this is desired then patients could be switched to an oral agent, and some of the direct-acting oral anticoagulants are approved for prophylactic use in medically ill patients.
Dr. Piazza points out that whether thromboprophylaxis should be used for nonhospitalized COVID patients who have risk factors for clotting such as a prior history of thrombosis or obesity is a pressing question, and he encourages clinicians to enroll these patients in clinical trials evaluating this issue, such as the PREVENT-HD trial.
“If they can’t enroll patents in a trial, then they have to make a decision whether the patient is high-enough risk to justify off-label use of anticoagulant. There is a case to be made for this, but there is no evidence for or against such action at present,” he noted.
At this time, neither the ISTH nor ACCP recommend measuring D-dimer to screen for venous thromboembolism or to determine intensity of prophylaxis or treatment, the authors note.
“Ongoing investigation will determine optimal preventive regimens in COVID-19 in the intensive care unit, at hospital discharge, and in nonhospitalized patients at high risk for thrombosis,” they conclude.
Dr. Piazza reported grants from Bayer, Bristol Myers Squibb, Boston Scientific, Janssen, and Portola, and personal fees from Agile, Amgen, Pfizer, and the Prairie Education and Research Cooperative outside the submitted work. Dr. Morrow reported grants from Abbott Laboratories, Amgen, Anthos Therapeutics, Esai, GlaxoSmithKline, Takeda, and The Medicines Company; grants and personal fees from AstraZeneca, Merck, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma and InCarda outside the submitted work.
A version of this article originally appeared on Medscape.com.
Infant’s COVID-19–related myocardial injury reversed
Reports of signs of heart failure in adults with COVID-19 have been rare – just four such cases have been published since the outbreak started in China – and now a team of pediatric cardiologists in New York have reported a case of acute but reversible myocardial injury in an infant with COVID-19.
and right upper lobe atelectasis.
The 2-month-old infant went home after more than 2 weeks in the hospital with no apparent lingering cardiac effects of the illness and not needing any oral heart failure medications, Madhu Sharma, MD, of the Children’s Hospital and Montefiore in New York and colleagues reported in JACC Case Reports. With close follow-up, the child’s left ventricle size and systolic function have remained normal and mitral regurgitation resolved. The case report didn’t mention the infant’s gender.
But before the straightforward postdischarge course emerged, the infant was in a precarious state, and Dr. Sharma and her team were challenged to diagnose the underlying causes.
The child, who was born about 7 weeks premature, first came to the hospital having turned blue after choking on food. Nonrebreather mask ventilation was initiated in the ED, and an examination detected a holosystolic murmur. A test for COVID-19 was negative, but a later test was positive, and a chest x-ray exhibited cardiomegaly and signs of fluid and inflammation in the lungs.
An electrocardiogram detected sinus tachycardia, ST-segment depression and other anomalies in cardiac function. Further investigation with a transthoracic ECG showed severely depressed left ventricle systolic function with an ejection fraction of 30%, severe mitral regurgitation, and normal right ventricular systolic function.
Treatment included remdesivir and intravenous antibiotics. Through the hospital course, the patient was extubated to noninvasive ventilation, reintubated, put on intravenous steroid (methylprednisolone) and low-molecular-weight heparin, extubated, and tested throughout for cardiac function.
By day 14, left ventricle size and function normalized, and while the mitral regurgitation remained severe, it improved later without HF therapies. Left ventricle ejection fraction had recovered to 60%, and key cardiac biomarkers had normalized. On day 16, milrinone was discontinued, and the care team determined the patient no longer needed oral heart failure therapies.
“Most children with COVID-19 are either asymptomatic or have mild symptoms, but our case shows the potential for reversible myocardial injury in infants with COVID-19,” said Dr. Sharma. “Testing for COVID-19 in children presenting with signs and symptoms of heart failure is very important as we learn more about the impact of this virus.”
Dr. Sharma and coauthors have no relevant financial relationships to disclose.
SOURCE: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.
Reports of signs of heart failure in adults with COVID-19 have been rare – just four such cases have been published since the outbreak started in China – and now a team of pediatric cardiologists in New York have reported a case of acute but reversible myocardial injury in an infant with COVID-19.
and right upper lobe atelectasis.
The 2-month-old infant went home after more than 2 weeks in the hospital with no apparent lingering cardiac effects of the illness and not needing any oral heart failure medications, Madhu Sharma, MD, of the Children’s Hospital and Montefiore in New York and colleagues reported in JACC Case Reports. With close follow-up, the child’s left ventricle size and systolic function have remained normal and mitral regurgitation resolved. The case report didn’t mention the infant’s gender.
But before the straightforward postdischarge course emerged, the infant was in a precarious state, and Dr. Sharma and her team were challenged to diagnose the underlying causes.
The child, who was born about 7 weeks premature, first came to the hospital having turned blue after choking on food. Nonrebreather mask ventilation was initiated in the ED, and an examination detected a holosystolic murmur. A test for COVID-19 was negative, but a later test was positive, and a chest x-ray exhibited cardiomegaly and signs of fluid and inflammation in the lungs.
An electrocardiogram detected sinus tachycardia, ST-segment depression and other anomalies in cardiac function. Further investigation with a transthoracic ECG showed severely depressed left ventricle systolic function with an ejection fraction of 30%, severe mitral regurgitation, and normal right ventricular systolic function.
Treatment included remdesivir and intravenous antibiotics. Through the hospital course, the patient was extubated to noninvasive ventilation, reintubated, put on intravenous steroid (methylprednisolone) and low-molecular-weight heparin, extubated, and tested throughout for cardiac function.
By day 14, left ventricle size and function normalized, and while the mitral regurgitation remained severe, it improved later without HF therapies. Left ventricle ejection fraction had recovered to 60%, and key cardiac biomarkers had normalized. On day 16, milrinone was discontinued, and the care team determined the patient no longer needed oral heart failure therapies.
“Most children with COVID-19 are either asymptomatic or have mild symptoms, but our case shows the potential for reversible myocardial injury in infants with COVID-19,” said Dr. Sharma. “Testing for COVID-19 in children presenting with signs and symptoms of heart failure is very important as we learn more about the impact of this virus.”
Dr. Sharma and coauthors have no relevant financial relationships to disclose.
SOURCE: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.
Reports of signs of heart failure in adults with COVID-19 have been rare – just four such cases have been published since the outbreak started in China – and now a team of pediatric cardiologists in New York have reported a case of acute but reversible myocardial injury in an infant with COVID-19.
and right upper lobe atelectasis.
The 2-month-old infant went home after more than 2 weeks in the hospital with no apparent lingering cardiac effects of the illness and not needing any oral heart failure medications, Madhu Sharma, MD, of the Children’s Hospital and Montefiore in New York and colleagues reported in JACC Case Reports. With close follow-up, the child’s left ventricle size and systolic function have remained normal and mitral regurgitation resolved. The case report didn’t mention the infant’s gender.
But before the straightforward postdischarge course emerged, the infant was in a precarious state, and Dr. Sharma and her team were challenged to diagnose the underlying causes.
The child, who was born about 7 weeks premature, first came to the hospital having turned blue after choking on food. Nonrebreather mask ventilation was initiated in the ED, and an examination detected a holosystolic murmur. A test for COVID-19 was negative, but a later test was positive, and a chest x-ray exhibited cardiomegaly and signs of fluid and inflammation in the lungs.
An electrocardiogram detected sinus tachycardia, ST-segment depression and other anomalies in cardiac function. Further investigation with a transthoracic ECG showed severely depressed left ventricle systolic function with an ejection fraction of 30%, severe mitral regurgitation, and normal right ventricular systolic function.
Treatment included remdesivir and intravenous antibiotics. Through the hospital course, the patient was extubated to noninvasive ventilation, reintubated, put on intravenous steroid (methylprednisolone) and low-molecular-weight heparin, extubated, and tested throughout for cardiac function.
By day 14, left ventricle size and function normalized, and while the mitral regurgitation remained severe, it improved later without HF therapies. Left ventricle ejection fraction had recovered to 60%, and key cardiac biomarkers had normalized. On day 16, milrinone was discontinued, and the care team determined the patient no longer needed oral heart failure therapies.
“Most children with COVID-19 are either asymptomatic or have mild symptoms, but our case shows the potential for reversible myocardial injury in infants with COVID-19,” said Dr. Sharma. “Testing for COVID-19 in children presenting with signs and symptoms of heart failure is very important as we learn more about the impact of this virus.”
Dr. Sharma and coauthors have no relevant financial relationships to disclose.
SOURCE: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.
FROM JACC CASE REPORTS
Key clinical point: Children presenting with COVID-19 should be tested for heart failure.
Major finding: A 2-month-old infant with COVID-19 had acute but reversible myocardial injury.
Study details: Single case report.
Disclosures: Dr. Sharma, MD, has no relevant financial relationships to disclose.
Source: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.
Noninvasive, low-cost CGM for type 2 diabetes coming in U.S. and EU
A novel lower-cost noninvasive continuous glucose monitor (CGM) combined with a digital education/guidance program is set to launch in the United States and Europe this month for use in type 2 diabetes.
With the goal of improving management, or even reversing the condition, Neumara’s SugarBEAT device is thought to be the world’s first noninvasive CGM.
Its cost is anticipated to be far lower than traditional CGM, and it’s aimed at a different patient population: those with type 2 diabetes or prediabetes who may or may not be performing fingerstick glucose monitoring, but if they are, they still aren’t using the information to guide management.
“This isn’t about handing out devices and letting patients get on about it on their own accord. This is really about supporting those individuals,” Faz Chowdhury, MD, Nemaura’s chief executive officer, said in an interview.
He pointed to studies showing improvements in glycemic control in patients with type 2 diabetes who were instructed to perform fingerstick blood glucose testing seven times a day for 3-4 days a month and given advice about how to respond to the data.
“This is well established. We’re saying we can make that process a lot more scalable and affordable and convenient for the patient. ... The behavior change side is digitized,” Dr. Chowdhury said. “We want to provide a program to help people reverse their diabetes or at least stabilize it as much as possible.”
Nicholas Argento, MD, diabetes technology director at Maryland Endocrine and Diabetes, Columbia, said in an interview: “It’s interesting. They’re taking a very different approach. I think there’s a lot of validity to what they’re looking at because we have great CGMs right now, but because of the price point it’s not accessible to a lot of people.
“I think they’re onto something that could prove to be useful to a larger group of patients,” he added.
Worn a few days per month and accurate despite being noninvasive
Instead of inserting a catheter under the skin with a needle, as do current CGMs, the device comprises a small rechargeable transmitter and adhesive patch with a sensor that sits on the top of the skin, typically the upper arm. Glucose molecules are drawn out of the interstitial fluid just below the skin and into a chamber where the transmitter measures the glucose level and transmits the data every 5 minutes via Bluetooth to a smartphone app.
Despite this noninvasive approach, the device appears to be about as accurate as traditional CGMs, with comparable mean absolute relative difference (MARD) from a gold standard glucose measure of about 11%-12% with once-daily calibration versus 10%-11% for the Abbott FreeStyle Libre.
Unlike traditional CGMs, SugarBEAT is meant to be worn for only 14 hours at a time during the day and for 2-4 days per month rather than every day.
It’s not aimed at patients with type 1 diabetes or those with type 2 diabetes who are at high risk for hypoglycemia. It requires once-daily fingerstick calibration and is not indicated to replace fingersticks for treatment decisions.
SugarBEAT received a CE Mark in Europe as a Class IIb medical device in May 2019. That version provides real-time glucose values visible to the wearer. In the United States the company submitted a premarketing approval application for the device to the Food and Drug Administration in July 2020, which awaits a decision.
However, FDA is allowing it to enter the U.S. market as a “wellness” device that won’t deliver real-time values for now but instead will generate retroactive reports available to the physician and the patient.
And last month, U.K.-based Neumara launched the BEATdiabetes site, which allows users to sign in and link to the device once it becomes available.
The site provides “scientifically validated, personalized coaching” based on a program developed at the Joslin Diabetes Clinic in Syracuse, N.Y., and will ultimately include monitoring of other cardiovascular risk factors with digital connectivity to a variety of wearables.
Fingerstick monitoring in type 2 diabetes is only so useful
“Fingerstick monitoring for type 2 diabetes is only so useful,” Dr. Argento said in an interview.
“It’s difficult to get people to monitor in a meaningful way.” If patients perform them only in the morning or at other sporadic times of the day, he said, “Then you get a one-dimensional picture ... and they don’t know what to do with the information anyway, so they stop doing it.”
In contrast, with SugarBEAT and BEATDiabetes, “I think it does address a need that fingerstick monitoring doesn’t.”
Dr. Argento did express a few caveats about the device, however. For one, it still requires one fingerstick a day for calibration. “If people don’t like needles, that might be a disincentive.”
Also, despite the apparently comparable mean absolute relative difference with that of conventional CGMs, that measure can still “hide” values that may be consistently either above or below target range.
“MARD is like A1c in that it’s useful but limited. ... It doesn’t tell you about variability or systemic bias,” he said.
Dr. Argento also said that he’d like to see data on the lag time between the interstitial fluid and blood glucose measures with this noninvasive method as compared with that of a subcutaneous catheter.
However, he acknowledged that these potentials for error would be less important for patients with type 2 diabetes who aren’t generally taking medications that increase their risk for hypoglycemia.
In all, he said, “stay tuned. I think this is part of a movement going away from point-in-time to looking at trends and wearables and data to enrich decision-making…There are still some unanswered questions I have but I think they’re onto a concept that’s useful for a broader population.”
Dr. Chowdhury is an employee of Neumara. Dr. Argento consults for Senseonics and Dexcom, and is also a speaker for Dexcom.
This article first appeared on Medscape.com.
A novel lower-cost noninvasive continuous glucose monitor (CGM) combined with a digital education/guidance program is set to launch in the United States and Europe this month for use in type 2 diabetes.
With the goal of improving management, or even reversing the condition, Neumara’s SugarBEAT device is thought to be the world’s first noninvasive CGM.
Its cost is anticipated to be far lower than traditional CGM, and it’s aimed at a different patient population: those with type 2 diabetes or prediabetes who may or may not be performing fingerstick glucose monitoring, but if they are, they still aren’t using the information to guide management.
“This isn’t about handing out devices and letting patients get on about it on their own accord. This is really about supporting those individuals,” Faz Chowdhury, MD, Nemaura’s chief executive officer, said in an interview.
He pointed to studies showing improvements in glycemic control in patients with type 2 diabetes who were instructed to perform fingerstick blood glucose testing seven times a day for 3-4 days a month and given advice about how to respond to the data.
“This is well established. We’re saying we can make that process a lot more scalable and affordable and convenient for the patient. ... The behavior change side is digitized,” Dr. Chowdhury said. “We want to provide a program to help people reverse their diabetes or at least stabilize it as much as possible.”
Nicholas Argento, MD, diabetes technology director at Maryland Endocrine and Diabetes, Columbia, said in an interview: “It’s interesting. They’re taking a very different approach. I think there’s a lot of validity to what they’re looking at because we have great CGMs right now, but because of the price point it’s not accessible to a lot of people.
“I think they’re onto something that could prove to be useful to a larger group of patients,” he added.
Worn a few days per month and accurate despite being noninvasive
Instead of inserting a catheter under the skin with a needle, as do current CGMs, the device comprises a small rechargeable transmitter and adhesive patch with a sensor that sits on the top of the skin, typically the upper arm. Glucose molecules are drawn out of the interstitial fluid just below the skin and into a chamber where the transmitter measures the glucose level and transmits the data every 5 minutes via Bluetooth to a smartphone app.
Despite this noninvasive approach, the device appears to be about as accurate as traditional CGMs, with comparable mean absolute relative difference (MARD) from a gold standard glucose measure of about 11%-12% with once-daily calibration versus 10%-11% for the Abbott FreeStyle Libre.
Unlike traditional CGMs, SugarBEAT is meant to be worn for only 14 hours at a time during the day and for 2-4 days per month rather than every day.
It’s not aimed at patients with type 1 diabetes or those with type 2 diabetes who are at high risk for hypoglycemia. It requires once-daily fingerstick calibration and is not indicated to replace fingersticks for treatment decisions.
SugarBEAT received a CE Mark in Europe as a Class IIb medical device in May 2019. That version provides real-time glucose values visible to the wearer. In the United States the company submitted a premarketing approval application for the device to the Food and Drug Administration in July 2020, which awaits a decision.
However, FDA is allowing it to enter the U.S. market as a “wellness” device that won’t deliver real-time values for now but instead will generate retroactive reports available to the physician and the patient.
And last month, U.K.-based Neumara launched the BEATdiabetes site, which allows users to sign in and link to the device once it becomes available.
The site provides “scientifically validated, personalized coaching” based on a program developed at the Joslin Diabetes Clinic in Syracuse, N.Y., and will ultimately include monitoring of other cardiovascular risk factors with digital connectivity to a variety of wearables.
Fingerstick monitoring in type 2 diabetes is only so useful
“Fingerstick monitoring for type 2 diabetes is only so useful,” Dr. Argento said in an interview.
“It’s difficult to get people to monitor in a meaningful way.” If patients perform them only in the morning or at other sporadic times of the day, he said, “Then you get a one-dimensional picture ... and they don’t know what to do with the information anyway, so they stop doing it.”
In contrast, with SugarBEAT and BEATDiabetes, “I think it does address a need that fingerstick monitoring doesn’t.”
Dr. Argento did express a few caveats about the device, however. For one, it still requires one fingerstick a day for calibration. “If people don’t like needles, that might be a disincentive.”
Also, despite the apparently comparable mean absolute relative difference with that of conventional CGMs, that measure can still “hide” values that may be consistently either above or below target range.
“MARD is like A1c in that it’s useful but limited. ... It doesn’t tell you about variability or systemic bias,” he said.
Dr. Argento also said that he’d like to see data on the lag time between the interstitial fluid and blood glucose measures with this noninvasive method as compared with that of a subcutaneous catheter.
However, he acknowledged that these potentials for error would be less important for patients with type 2 diabetes who aren’t generally taking medications that increase their risk for hypoglycemia.
In all, he said, “stay tuned. I think this is part of a movement going away from point-in-time to looking at trends and wearables and data to enrich decision-making…There are still some unanswered questions I have but I think they’re onto a concept that’s useful for a broader population.”
Dr. Chowdhury is an employee of Neumara. Dr. Argento consults for Senseonics and Dexcom, and is also a speaker for Dexcom.
This article first appeared on Medscape.com.
A novel lower-cost noninvasive continuous glucose monitor (CGM) combined with a digital education/guidance program is set to launch in the United States and Europe this month for use in type 2 diabetes.
With the goal of improving management, or even reversing the condition, Neumara’s SugarBEAT device is thought to be the world’s first noninvasive CGM.
Its cost is anticipated to be far lower than traditional CGM, and it’s aimed at a different patient population: those with type 2 diabetes or prediabetes who may or may not be performing fingerstick glucose monitoring, but if they are, they still aren’t using the information to guide management.
“This isn’t about handing out devices and letting patients get on about it on their own accord. This is really about supporting those individuals,” Faz Chowdhury, MD, Nemaura’s chief executive officer, said in an interview.
He pointed to studies showing improvements in glycemic control in patients with type 2 diabetes who were instructed to perform fingerstick blood glucose testing seven times a day for 3-4 days a month and given advice about how to respond to the data.
“This is well established. We’re saying we can make that process a lot more scalable and affordable and convenient for the patient. ... The behavior change side is digitized,” Dr. Chowdhury said. “We want to provide a program to help people reverse their diabetes or at least stabilize it as much as possible.”
Nicholas Argento, MD, diabetes technology director at Maryland Endocrine and Diabetes, Columbia, said in an interview: “It’s interesting. They’re taking a very different approach. I think there’s a lot of validity to what they’re looking at because we have great CGMs right now, but because of the price point it’s not accessible to a lot of people.
“I think they’re onto something that could prove to be useful to a larger group of patients,” he added.
Worn a few days per month and accurate despite being noninvasive
Instead of inserting a catheter under the skin with a needle, as do current CGMs, the device comprises a small rechargeable transmitter and adhesive patch with a sensor that sits on the top of the skin, typically the upper arm. Glucose molecules are drawn out of the interstitial fluid just below the skin and into a chamber where the transmitter measures the glucose level and transmits the data every 5 minutes via Bluetooth to a smartphone app.
Despite this noninvasive approach, the device appears to be about as accurate as traditional CGMs, with comparable mean absolute relative difference (MARD) from a gold standard glucose measure of about 11%-12% with once-daily calibration versus 10%-11% for the Abbott FreeStyle Libre.
Unlike traditional CGMs, SugarBEAT is meant to be worn for only 14 hours at a time during the day and for 2-4 days per month rather than every day.
It’s not aimed at patients with type 1 diabetes or those with type 2 diabetes who are at high risk for hypoglycemia. It requires once-daily fingerstick calibration and is not indicated to replace fingersticks for treatment decisions.
SugarBEAT received a CE Mark in Europe as a Class IIb medical device in May 2019. That version provides real-time glucose values visible to the wearer. In the United States the company submitted a premarketing approval application for the device to the Food and Drug Administration in July 2020, which awaits a decision.
However, FDA is allowing it to enter the U.S. market as a “wellness” device that won’t deliver real-time values for now but instead will generate retroactive reports available to the physician and the patient.
And last month, U.K.-based Neumara launched the BEATdiabetes site, which allows users to sign in and link to the device once it becomes available.
The site provides “scientifically validated, personalized coaching” based on a program developed at the Joslin Diabetes Clinic in Syracuse, N.Y., and will ultimately include monitoring of other cardiovascular risk factors with digital connectivity to a variety of wearables.
Fingerstick monitoring in type 2 diabetes is only so useful
“Fingerstick monitoring for type 2 diabetes is only so useful,” Dr. Argento said in an interview.
“It’s difficult to get people to monitor in a meaningful way.” If patients perform them only in the morning or at other sporadic times of the day, he said, “Then you get a one-dimensional picture ... and they don’t know what to do with the information anyway, so they stop doing it.”
In contrast, with SugarBEAT and BEATDiabetes, “I think it does address a need that fingerstick monitoring doesn’t.”
Dr. Argento did express a few caveats about the device, however. For one, it still requires one fingerstick a day for calibration. “If people don’t like needles, that might be a disincentive.”
Also, despite the apparently comparable mean absolute relative difference with that of conventional CGMs, that measure can still “hide” values that may be consistently either above or below target range.
“MARD is like A1c in that it’s useful but limited. ... It doesn’t tell you about variability or systemic bias,” he said.
Dr. Argento also said that he’d like to see data on the lag time between the interstitial fluid and blood glucose measures with this noninvasive method as compared with that of a subcutaneous catheter.
However, he acknowledged that these potentials for error would be less important for patients with type 2 diabetes who aren’t generally taking medications that increase their risk for hypoglycemia.
In all, he said, “stay tuned. I think this is part of a movement going away from point-in-time to looking at trends and wearables and data to enrich decision-making…There are still some unanswered questions I have but I think they’re onto a concept that’s useful for a broader population.”
Dr. Chowdhury is an employee of Neumara. Dr. Argento consults for Senseonics and Dexcom, and is also a speaker for Dexcom.
This article first appeared on Medscape.com.
New AHA scientific statement on menopause and CVD risk
Changes in hormones, body composition, lipids, and vascular health during the menopause transition can increase a woman’s chance of developing cardiovascular disease (CVD) after menopause, the American Heart Association said in a scientific statement.
“This statement aims to raise awareness of both healthcare providers and women about the menopause transition as a time of increasing heart disease risk,” Samar R. El Khoudary, PhD, MPH, who chaired the writing group, said in an interview.
“As such, it emphasizes the importance of monitoring women’s health during midlife and targeting this stage as a critical window for applying early intervention strategies that aim to maintain a healthy heart and reduce the risk of heart disease,” said Dr. El Khoudary, of the University of Pittsburgh.
The statement was published online Nov. 30 in Circulation.
Evolution in knowledge
During the past 20 years, knowledge of how menopause might contribute to CVD has evolved “dramatically,” Dr. El Khoudary noted. The accumulated data consistently point to the menopause transition as a time of change in heart health.
“Importantly,” she said, the latest AHA guidelines for CVD prevention in women, published in 2011, do not include data now available on the menopause transition as a time of increased CVD risk.
“As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” said Dr. El Khoudary.
The statement provides a contemporary synthesis of the existing data on menopause and how it relates to CVD, the leading cause of death of U.S. women.
Earlier age at natural menopause has generally been found to be a marker of greater CVD risk. Iatrogenically induced menopause (bilateral oophorectomy) during the premenopausal period is also associated with higher CVD risk, the data suggest.
Vasomotor symptoms are associated with worse levels of CVD risk factors and measures of subclinical atherosclerosis. Sleep disturbance has also been linked to greater risk for subclinical CVD and worse CV health indexes in women during midlife.
Increases in central/visceral fat and decreases in lean muscle mass are more pronounced during the menopause transition. This increased central adiposity is associated with increased risk for mortality, even among those with normal body mass index, the writing group found.
Increases in lipid levels (LDL cholesterol and apolipoprotein B), metabolic syndrome risk, and vascular remodeling at midlife are driven by the menopause transition more than aging, whereas increases in blood pressure, insulin level, and glucose level are likely more influenced by chronological aging, they reported.
Lifestyle interventions
The writing group noted that, because of the increase in overall life expectancy in the United States, a significant proportion of women will spend up to 40% of their lives after menopause.
Yet data suggest that only 7.2% of women transitioning to menopause are meeting physical activity guidelines and that fewer than 20% of those women are consistently maintaining a healthy diet.
Limited data from randomized, controlled trials suggest that a multidimensional lifestyle intervention during the menopause transition can prevent weight gain and reduce blood pressure and levels of triglycerides, blood glucose, and insulin and reduce the incidence of subclinical carotid atherosclerosis, they pointed out.
“Novel data” indicate a reversal in the associations of HDL cholesterol with CVD risk over the menopause transition, suggesting that higher HDL cholesterol levels may not consistently reflect good cardiovascular health in middle-aged women, the group noted.
There are also data suggesting that starting menopause hormone therapy when younger than 60 years or within 10 years of menopause is associated with reduced CVD risk.
The group said further research is needed into the cardiometabolic effects of menopause hormone therapy, including effects associated with form, route, and duration of administration, in women traversing menopause.
They also noted that data for the primary and secondary prevention of atherosclerotic CVD and improved survival with lipid-lowering interventions “remain elusive” for women and that further study is needed to develop evidence-based recommendations tailored specifically to women.
The research had no commercial funding. Dr. El Khoudary has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Changes in hormones, body composition, lipids, and vascular health during the menopause transition can increase a woman’s chance of developing cardiovascular disease (CVD) after menopause, the American Heart Association said in a scientific statement.
“This statement aims to raise awareness of both healthcare providers and women about the menopause transition as a time of increasing heart disease risk,” Samar R. El Khoudary, PhD, MPH, who chaired the writing group, said in an interview.
“As such, it emphasizes the importance of monitoring women’s health during midlife and targeting this stage as a critical window for applying early intervention strategies that aim to maintain a healthy heart and reduce the risk of heart disease,” said Dr. El Khoudary, of the University of Pittsburgh.
The statement was published online Nov. 30 in Circulation.
Evolution in knowledge
During the past 20 years, knowledge of how menopause might contribute to CVD has evolved “dramatically,” Dr. El Khoudary noted. The accumulated data consistently point to the menopause transition as a time of change in heart health.
“Importantly,” she said, the latest AHA guidelines for CVD prevention in women, published in 2011, do not include data now available on the menopause transition as a time of increased CVD risk.
“As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” said Dr. El Khoudary.
The statement provides a contemporary synthesis of the existing data on menopause and how it relates to CVD, the leading cause of death of U.S. women.
Earlier age at natural menopause has generally been found to be a marker of greater CVD risk. Iatrogenically induced menopause (bilateral oophorectomy) during the premenopausal period is also associated with higher CVD risk, the data suggest.
Vasomotor symptoms are associated with worse levels of CVD risk factors and measures of subclinical atherosclerosis. Sleep disturbance has also been linked to greater risk for subclinical CVD and worse CV health indexes in women during midlife.
Increases in central/visceral fat and decreases in lean muscle mass are more pronounced during the menopause transition. This increased central adiposity is associated with increased risk for mortality, even among those with normal body mass index, the writing group found.
Increases in lipid levels (LDL cholesterol and apolipoprotein B), metabolic syndrome risk, and vascular remodeling at midlife are driven by the menopause transition more than aging, whereas increases in blood pressure, insulin level, and glucose level are likely more influenced by chronological aging, they reported.
Lifestyle interventions
The writing group noted that, because of the increase in overall life expectancy in the United States, a significant proportion of women will spend up to 40% of their lives after menopause.
Yet data suggest that only 7.2% of women transitioning to menopause are meeting physical activity guidelines and that fewer than 20% of those women are consistently maintaining a healthy diet.
Limited data from randomized, controlled trials suggest that a multidimensional lifestyle intervention during the menopause transition can prevent weight gain and reduce blood pressure and levels of triglycerides, blood glucose, and insulin and reduce the incidence of subclinical carotid atherosclerosis, they pointed out.
“Novel data” indicate a reversal in the associations of HDL cholesterol with CVD risk over the menopause transition, suggesting that higher HDL cholesterol levels may not consistently reflect good cardiovascular health in middle-aged women, the group noted.
There are also data suggesting that starting menopause hormone therapy when younger than 60 years or within 10 years of menopause is associated with reduced CVD risk.
The group said further research is needed into the cardiometabolic effects of menopause hormone therapy, including effects associated with form, route, and duration of administration, in women traversing menopause.
They also noted that data for the primary and secondary prevention of atherosclerotic CVD and improved survival with lipid-lowering interventions “remain elusive” for women and that further study is needed to develop evidence-based recommendations tailored specifically to women.
The research had no commercial funding. Dr. El Khoudary has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Changes in hormones, body composition, lipids, and vascular health during the menopause transition can increase a woman’s chance of developing cardiovascular disease (CVD) after menopause, the American Heart Association said in a scientific statement.
“This statement aims to raise awareness of both healthcare providers and women about the menopause transition as a time of increasing heart disease risk,” Samar R. El Khoudary, PhD, MPH, who chaired the writing group, said in an interview.
“As such, it emphasizes the importance of monitoring women’s health during midlife and targeting this stage as a critical window for applying early intervention strategies that aim to maintain a healthy heart and reduce the risk of heart disease,” said Dr. El Khoudary, of the University of Pittsburgh.
The statement was published online Nov. 30 in Circulation.
Evolution in knowledge
During the past 20 years, knowledge of how menopause might contribute to CVD has evolved “dramatically,” Dr. El Khoudary noted. The accumulated data consistently point to the menopause transition as a time of change in heart health.
“Importantly,” she said, the latest AHA guidelines for CVD prevention in women, published in 2011, do not include data now available on the menopause transition as a time of increased CVD risk.
“As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” said Dr. El Khoudary.
The statement provides a contemporary synthesis of the existing data on menopause and how it relates to CVD, the leading cause of death of U.S. women.
Earlier age at natural menopause has generally been found to be a marker of greater CVD risk. Iatrogenically induced menopause (bilateral oophorectomy) during the premenopausal period is also associated with higher CVD risk, the data suggest.
Vasomotor symptoms are associated with worse levels of CVD risk factors and measures of subclinical atherosclerosis. Sleep disturbance has also been linked to greater risk for subclinical CVD and worse CV health indexes in women during midlife.
Increases in central/visceral fat and decreases in lean muscle mass are more pronounced during the menopause transition. This increased central adiposity is associated with increased risk for mortality, even among those with normal body mass index, the writing group found.
Increases in lipid levels (LDL cholesterol and apolipoprotein B), metabolic syndrome risk, and vascular remodeling at midlife are driven by the menopause transition more than aging, whereas increases in blood pressure, insulin level, and glucose level are likely more influenced by chronological aging, they reported.
Lifestyle interventions
The writing group noted that, because of the increase in overall life expectancy in the United States, a significant proportion of women will spend up to 40% of their lives after menopause.
Yet data suggest that only 7.2% of women transitioning to menopause are meeting physical activity guidelines and that fewer than 20% of those women are consistently maintaining a healthy diet.
Limited data from randomized, controlled trials suggest that a multidimensional lifestyle intervention during the menopause transition can prevent weight gain and reduce blood pressure and levels of triglycerides, blood glucose, and insulin and reduce the incidence of subclinical carotid atherosclerosis, they pointed out.
“Novel data” indicate a reversal in the associations of HDL cholesterol with CVD risk over the menopause transition, suggesting that higher HDL cholesterol levels may not consistently reflect good cardiovascular health in middle-aged women, the group noted.
There are also data suggesting that starting menopause hormone therapy when younger than 60 years or within 10 years of menopause is associated with reduced CVD risk.
The group said further research is needed into the cardiometabolic effects of menopause hormone therapy, including effects associated with form, route, and duration of administration, in women traversing menopause.
They also noted that data for the primary and secondary prevention of atherosclerotic CVD and improved survival with lipid-lowering interventions “remain elusive” for women and that further study is needed to develop evidence-based recommendations tailored specifically to women.
The research had no commercial funding. Dr. El Khoudary has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
First SGLT1/2 inhibitor shows ‘spectacular’ phase 3 safety and efficacy in T2D
Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.
Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.
They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m2; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).
These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.
All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m2.
“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.
“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”
The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.
“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
A dual SGLT inhibitor
What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.
The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m2 at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.
“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”
The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.
“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
First-ever HFpEF benefit
In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.
First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m2, excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.
The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.
Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.
“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
Also safe soon after acute heart failure decompensation
The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.
“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.
SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.
Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.
“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.
Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.
The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.
Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.
Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.
They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m2; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).
These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.
All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m2.
“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.
“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”
The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.
“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
A dual SGLT inhibitor
What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.
The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m2 at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.
“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”
The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.
“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
First-ever HFpEF benefit
In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.
First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m2, excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.
The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.
Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.
“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
Also safe soon after acute heart failure decompensation
The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.
“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.
SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.
Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.
“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.
Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.
The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.
Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.
Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.
They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m2; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).
These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.
All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m2.
“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.
“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”
The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.
“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
A dual SGLT inhibitor
What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.
The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m2 at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.
“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”
The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.
“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
First-ever HFpEF benefit
In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.
First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m2, excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.
The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.
Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.
“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
Also safe soon after acute heart failure decompensation
The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.
“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.
SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.
Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.
“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.
Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.
The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.
FROM AHA 2020
Clopidogrel bests ticagrelor head-to-head for elective PCI in ALPHEUS
Ticagrelor failed to unseat clopidogrel as the guideline-recommended P2Y12 inhibitor of choice in patients undergoing elective percutaneous coronary intervention for stable CAD in the randomized ALPHEUS trial.
“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” reported Johanne Silvain, MD, PhD, professor of cardiology at the Sorbonne University and director of the ICU at Pitie-Salpetriere Hospital, Paris, at the virtual American Heart Association scientific sessions.
Ticagrelor did, however, result in a significantly higher rate of nuisance or minor bleeding than clopidogrel within 30 days post PCI, as well as more frequent dyspnea and treatment discontinuation.
ALPHEUS was an open-label, randomized trial including 1,883 patients undergoing elective PCI for stable coronary disease at 49 French or Czech PCI centers. All participants were either troponin-negative or had a modestly elevated but declining high-sensitivity troponin level. They possessed an average of 3.2 procedure-related or patient-related high-risk features, among the most common of which were multivessel disease, long lesions requiring multiple stents, and diabetes. Patients were randomized to a 300- or 600-mg loading dose of clopidogrel (Kengreal) or 180 mg of ticagrelor (Brilinta) prior to PCI. Afterwards they continued on 90 mg of ticagrelor twice daily or 75 mg of clopidogrel once daily for 30 days. Everyone was also on aspirin.
Myonecrosis hypothesis falls flat
The primary endpoint was the occurrence of major myocardial injury, defined as a periprocedural troponin elevated greater than 5 times the upper limit of normal within 48 hours of PCI; type 4a MI, defined as major myocardial injury plus signs or symptoms of ischemia; or stent thrombosis.
The rates were closely similar: 35.5% with ticagrelor, 36.2% with clopidogrel. The bulk of events consisted of major myocardial injury, with an incidence of 26.7% in the ticagrelor group and 27.7% with clopidogrel. Stent thrombosis occurred in 0.3% of patients in each group. Type 4a MI occurred in 8.5% of the ticagrelor group and 8.2% of patients on clopidogrel.
The study hypothesis was that a substantial portion of periprocedural myonecrosis may be thrombotic in nature, and that a stronger P2Y12 inhibitor could reduce the occurrence of these mini-infarcts and thus provide patient benefit. But the hypothesis was not borne out.
“We don’t know if these events are a risk factor or just a marker of risk,” Dr. Silvain said.
There were no between-group differences in major bleeding events at 48 hours or 30 days. However, the rate of nuisance or minor bleeding at 30 days was 11.2% in the ticagrelor arm, significantly higher than the 7.5% incidence with clopidogrel. Moreover, dyspnea occurred in 11.2% of patients on ticagrelor, compared to 0.2% with clopidogrel. Study drug discontinuation was more frequent in the ticagrelor arm: 2.2%, versus 0.4%.
Dr. Silvain also presented a pooled analysis of the 1,883 patients in ALPHEUS plus 781 from the similarly designed SASSICAIA trial, which compared prasugrel (Effient) to clopidogrel. Neither of the more potent P2Y12 inhibitors showed superiority over clopidogrel.
Discussant Stephen D. Wiviott, MD, summed things up: “With no evidence for ischemic benefit and higher rates of low-severity bleeding, this trial does not support the use of more potent P2Y12 antagonists for elective PCI. Based on these results, and consistent with SASSICAIA, aspirin with clopidogrel should remain the standard of care in this population.”
Troponin response may vary
A striking finding in ALPHEUS was the discrepancy between very high rates of periprocedural troponin elevation and very low rates of clinical events through 30 days of follow-up. “When you look at these modest elevations of troponin it appears that there is a lot of noise here,” said Dr. Wiviott, vice president for clinical trials research and administration at Massachusetts General Hospital and Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
Troponin elevations in stable coronary patients undergoing PCI may have a different underlying mechanism than elevated troponins in patients undergoing PCI for an acute coronary syndrome, he added. In stable CAD patients, the phenomenon may be more related to atherosclerosis than to platelet activation and thrombosis.
During a panel discussion, Sunil V. Rao, MD, said cardiologists are “probably going to have to go back to the drawing board and think about what kinds of events are really, really important.”
“It’s incumbent on our profession to figure out whether periprocedural MI should continue to be a component of the composite endpoint in PCI trials, because it’s highly dependent on the definition that’s being used,” observed Dr. Rao, professor of medicine at Duke University, Durham, N.C.
Dr. Silvain reported receiving institutional research funding and consulting fees from AstraZeneca, which funded the ALPHEUS trial. He serves as a consultant to a handful of other pharmaceutical companies as well.
Simultaneously with Dr. Silvain’s presentation at AHA 2020, the ALPHEUS results were published online in The Lancet.
SOURCE: Silvain J. AHA 2020. Session LBS 3.
Ticagrelor failed to unseat clopidogrel as the guideline-recommended P2Y12 inhibitor of choice in patients undergoing elective percutaneous coronary intervention for stable CAD in the randomized ALPHEUS trial.
“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” reported Johanne Silvain, MD, PhD, professor of cardiology at the Sorbonne University and director of the ICU at Pitie-Salpetriere Hospital, Paris, at the virtual American Heart Association scientific sessions.
Ticagrelor did, however, result in a significantly higher rate of nuisance or minor bleeding than clopidogrel within 30 days post PCI, as well as more frequent dyspnea and treatment discontinuation.
ALPHEUS was an open-label, randomized trial including 1,883 patients undergoing elective PCI for stable coronary disease at 49 French or Czech PCI centers. All participants were either troponin-negative or had a modestly elevated but declining high-sensitivity troponin level. They possessed an average of 3.2 procedure-related or patient-related high-risk features, among the most common of which were multivessel disease, long lesions requiring multiple stents, and diabetes. Patients were randomized to a 300- or 600-mg loading dose of clopidogrel (Kengreal) or 180 mg of ticagrelor (Brilinta) prior to PCI. Afterwards they continued on 90 mg of ticagrelor twice daily or 75 mg of clopidogrel once daily for 30 days. Everyone was also on aspirin.
Myonecrosis hypothesis falls flat
The primary endpoint was the occurrence of major myocardial injury, defined as a periprocedural troponin elevated greater than 5 times the upper limit of normal within 48 hours of PCI; type 4a MI, defined as major myocardial injury plus signs or symptoms of ischemia; or stent thrombosis.
The rates were closely similar: 35.5% with ticagrelor, 36.2% with clopidogrel. The bulk of events consisted of major myocardial injury, with an incidence of 26.7% in the ticagrelor group and 27.7% with clopidogrel. Stent thrombosis occurred in 0.3% of patients in each group. Type 4a MI occurred in 8.5% of the ticagrelor group and 8.2% of patients on clopidogrel.
The study hypothesis was that a substantial portion of periprocedural myonecrosis may be thrombotic in nature, and that a stronger P2Y12 inhibitor could reduce the occurrence of these mini-infarcts and thus provide patient benefit. But the hypothesis was not borne out.
“We don’t know if these events are a risk factor or just a marker of risk,” Dr. Silvain said.
There were no between-group differences in major bleeding events at 48 hours or 30 days. However, the rate of nuisance or minor bleeding at 30 days was 11.2% in the ticagrelor arm, significantly higher than the 7.5% incidence with clopidogrel. Moreover, dyspnea occurred in 11.2% of patients on ticagrelor, compared to 0.2% with clopidogrel. Study drug discontinuation was more frequent in the ticagrelor arm: 2.2%, versus 0.4%.
Dr. Silvain also presented a pooled analysis of the 1,883 patients in ALPHEUS plus 781 from the similarly designed SASSICAIA trial, which compared prasugrel (Effient) to clopidogrel. Neither of the more potent P2Y12 inhibitors showed superiority over clopidogrel.
Discussant Stephen D. Wiviott, MD, summed things up: “With no evidence for ischemic benefit and higher rates of low-severity bleeding, this trial does not support the use of more potent P2Y12 antagonists for elective PCI. Based on these results, and consistent with SASSICAIA, aspirin with clopidogrel should remain the standard of care in this population.”
Troponin response may vary
A striking finding in ALPHEUS was the discrepancy between very high rates of periprocedural troponin elevation and very low rates of clinical events through 30 days of follow-up. “When you look at these modest elevations of troponin it appears that there is a lot of noise here,” said Dr. Wiviott, vice president for clinical trials research and administration at Massachusetts General Hospital and Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
Troponin elevations in stable coronary patients undergoing PCI may have a different underlying mechanism than elevated troponins in patients undergoing PCI for an acute coronary syndrome, he added. In stable CAD patients, the phenomenon may be more related to atherosclerosis than to platelet activation and thrombosis.
During a panel discussion, Sunil V. Rao, MD, said cardiologists are “probably going to have to go back to the drawing board and think about what kinds of events are really, really important.”
“It’s incumbent on our profession to figure out whether periprocedural MI should continue to be a component of the composite endpoint in PCI trials, because it’s highly dependent on the definition that’s being used,” observed Dr. Rao, professor of medicine at Duke University, Durham, N.C.
Dr. Silvain reported receiving institutional research funding and consulting fees from AstraZeneca, which funded the ALPHEUS trial. He serves as a consultant to a handful of other pharmaceutical companies as well.
Simultaneously with Dr. Silvain’s presentation at AHA 2020, the ALPHEUS results were published online in The Lancet.
SOURCE: Silvain J. AHA 2020. Session LBS 3.
Ticagrelor failed to unseat clopidogrel as the guideline-recommended P2Y12 inhibitor of choice in patients undergoing elective percutaneous coronary intervention for stable CAD in the randomized ALPHEUS trial.
“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” reported Johanne Silvain, MD, PhD, professor of cardiology at the Sorbonne University and director of the ICU at Pitie-Salpetriere Hospital, Paris, at the virtual American Heart Association scientific sessions.
Ticagrelor did, however, result in a significantly higher rate of nuisance or minor bleeding than clopidogrel within 30 days post PCI, as well as more frequent dyspnea and treatment discontinuation.
ALPHEUS was an open-label, randomized trial including 1,883 patients undergoing elective PCI for stable coronary disease at 49 French or Czech PCI centers. All participants were either troponin-negative or had a modestly elevated but declining high-sensitivity troponin level. They possessed an average of 3.2 procedure-related or patient-related high-risk features, among the most common of which were multivessel disease, long lesions requiring multiple stents, and diabetes. Patients were randomized to a 300- or 600-mg loading dose of clopidogrel (Kengreal) or 180 mg of ticagrelor (Brilinta) prior to PCI. Afterwards they continued on 90 mg of ticagrelor twice daily or 75 mg of clopidogrel once daily for 30 days. Everyone was also on aspirin.
Myonecrosis hypothesis falls flat
The primary endpoint was the occurrence of major myocardial injury, defined as a periprocedural troponin elevated greater than 5 times the upper limit of normal within 48 hours of PCI; type 4a MI, defined as major myocardial injury plus signs or symptoms of ischemia; or stent thrombosis.
The rates were closely similar: 35.5% with ticagrelor, 36.2% with clopidogrel. The bulk of events consisted of major myocardial injury, with an incidence of 26.7% in the ticagrelor group and 27.7% with clopidogrel. Stent thrombosis occurred in 0.3% of patients in each group. Type 4a MI occurred in 8.5% of the ticagrelor group and 8.2% of patients on clopidogrel.
The study hypothesis was that a substantial portion of periprocedural myonecrosis may be thrombotic in nature, and that a stronger P2Y12 inhibitor could reduce the occurrence of these mini-infarcts and thus provide patient benefit. But the hypothesis was not borne out.
“We don’t know if these events are a risk factor or just a marker of risk,” Dr. Silvain said.
There were no between-group differences in major bleeding events at 48 hours or 30 days. However, the rate of nuisance or minor bleeding at 30 days was 11.2% in the ticagrelor arm, significantly higher than the 7.5% incidence with clopidogrel. Moreover, dyspnea occurred in 11.2% of patients on ticagrelor, compared to 0.2% with clopidogrel. Study drug discontinuation was more frequent in the ticagrelor arm: 2.2%, versus 0.4%.
Dr. Silvain also presented a pooled analysis of the 1,883 patients in ALPHEUS plus 781 from the similarly designed SASSICAIA trial, which compared prasugrel (Effient) to clopidogrel. Neither of the more potent P2Y12 inhibitors showed superiority over clopidogrel.
Discussant Stephen D. Wiviott, MD, summed things up: “With no evidence for ischemic benefit and higher rates of low-severity bleeding, this trial does not support the use of more potent P2Y12 antagonists for elective PCI. Based on these results, and consistent with SASSICAIA, aspirin with clopidogrel should remain the standard of care in this population.”
Troponin response may vary
A striking finding in ALPHEUS was the discrepancy between very high rates of periprocedural troponin elevation and very low rates of clinical events through 30 days of follow-up. “When you look at these modest elevations of troponin it appears that there is a lot of noise here,” said Dr. Wiviott, vice president for clinical trials research and administration at Massachusetts General Hospital and Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
Troponin elevations in stable coronary patients undergoing PCI may have a different underlying mechanism than elevated troponins in patients undergoing PCI for an acute coronary syndrome, he added. In stable CAD patients, the phenomenon may be more related to atherosclerosis than to platelet activation and thrombosis.
During a panel discussion, Sunil V. Rao, MD, said cardiologists are “probably going to have to go back to the drawing board and think about what kinds of events are really, really important.”
“It’s incumbent on our profession to figure out whether periprocedural MI should continue to be a component of the composite endpoint in PCI trials, because it’s highly dependent on the definition that’s being used,” observed Dr. Rao, professor of medicine at Duke University, Durham, N.C.
Dr. Silvain reported receiving institutional research funding and consulting fees from AstraZeneca, which funded the ALPHEUS trial. He serves as a consultant to a handful of other pharmaceutical companies as well.
Simultaneously with Dr. Silvain’s presentation at AHA 2020, the ALPHEUS results were published online in The Lancet.
SOURCE: Silvain J. AHA 2020. Session LBS 3.
REPORTING FROM AHA 2020
Intravenous iron reduces HF readmissions: AFFIRM-AHF
Iron supplementation reduces heart failure (HF) readmissions in iron-deficient patients hospitalized for acute HF, according to results of the AFFIRM-AHF trial.
After 52 weeks, intravenous ferric carboxymaltose (Ferinject) reduced the risk of total HF hospitalizations and cardiovascular (CV) death by 21% compared with placebo (293 vs 372 events; rate ratio [RR] 0.79; 95% CI, 0.62 - 1.01).
Although the composite primary endpoint failed to achieve statistical significance, it was driven by a significant 26% reduction in the risk of total HF hospital readmissions (P = .013) without an effect on CV mortality (P =.809).
Because the management and follow-up of patients was affected by the COVID-19 pandemic, a prespecified sensitivity analysis was performed that censored patients in each country at the date when its first COVID-19 patient was reported, explained principal investigator Piotr Ponikowski, MD, PhD, Wroclaw Medical University, Wroclaw, Poland.
That analysis revealed a significant 30% reduction in total HF readmissions (P = .005) in patients receiving ferric carboxymaltose (FCM), as well as significant benefits on the primary composite and secondary endpoints.
Notably, 80% of patients required only one or two injections and HF hospitalizations were reduced irrespective of anemia status.
“Iron deficiency should be searched in patients hospitalized with acute heart failure — assessed using a simple blood test — and is now an important therapeutic target,” Ponikowski said at the virtual American Heart Association (AHA) Scientific Sessions 2020.
The results were also published simultaneously in The Lancet.
Iron deficiency is present in up to 70% of patients with acute HF and a predictor of poor outcome, independent of anemia and ejection fraction, he noted.
The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials demonstrated that IV iron supplementation improves exercise capacity, symptoms, and quality of life in iron-deficient HF patients.
However, no such benefit was seen with oral IV in the IRONOUT trial. “So it seems if we are to replace iron, it needs to be done using intravenous therapy,” said John McMurray, MD, University of Glasgow, Scotland, who was invited to discuss the results.
He observed that the reduction in HF hospitalizations in AFFIRM-AHF were relatively modest and that the trial was never expected to show a benefit on CV mortality. Also, the COVID-19 sensitivity analysis providing more convincing effects is a valid approach and one recommended by regulators.
Further, the findings are supported by independent evidence in chronic kidney disease, from the PIVOTAL trial, that intravenous iron reduces HF hospitalizations, McMurray said.
“The million-dollar question, of course, is what will the results of this study mean for the guidelines: I think they probably will change the guidelines,” he said. “Certainly, I hope they will change the US guidelines, which have really given a very lukewarm recommendation for intravenous iron and I think that should probably be stronger.”
In a class IIb recommendation, the 2017 American College of Cardiology/AHA/Heart Failure Society of America heart failure guidelines say intravenous iron “might be reasonable” to improve functional status and quality of life in New York Heart Association class II and III patients with iron deficiency.
The 2016 European Society of Cardiology guidelines include a class IIa recommendation that IV iron “should be considered” in iron-deficient patients with symptomatic HF with reduced ejection fraction.
“This is the first large-scale [trial] of IV supplementation that could potentially change the way we approach patients, particularly those with hospitalized heart failure,” past AHA president Clyde Yancy, MD, MSc, Northwestern University Feinberg School of Medicine in Chicago, said during an earlier press briefing.
He pointed out that clinicians have been circumspect about the early IV iron data. “I have to congratulate you because you’ve changed the narrative,” Yancy said. “We have to start thinking about iron deficiency; we have to think about how we incorporate this in treatment protocols.”
Press briefing panelist Marc Pfeffer, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School in Boston, acknowledged he was among those circumspect.
“I’m no longer a skeptic and I want to congratulate them for showing it’s a risk factor,” he said. “It’s one thing to have a risk factor; it’s another to be a modifiable risk factor and I think that’s what’s so exciting about this.”
The double-blind, phase 4 AFFIRM-AHF trial randomly assigned 1132 patients to receive a bolus injection of ferric carboxymaltose or normal saline before hospital discharge for an acute HF episode. Subsequent treatment was given, as needed, up to 24 weeks post-randomization.
At admission, all patients had left ventricular ejection fractions less than 50% and iron deficiency (serum ferritin <100 ng/mL or serum ferritin 100-299 ng/mL if transferrin saturation <20%).
The modified intention-to-treat (mITT) analysis included 558 FCM patients and 550 controls in whom study treatment was started and for whom at least one post-randomization value was available.
Press briefing discussant Nancy Sweitzer, MD, PhD, director of the University of Arizona’s Sarver Heart Center in Tucson, said AFFIRM-AHF is an “important trial likely to change guidelines” and “targeted one of the highest risk populations we have in heart failure.”
Patients with iron deficiency tend to be elderly with more comorbidities, have longer hospital lengths of stay, and higher readmission rates. “So impacting hospitalizations in this population is incredibly impactful,” she said.
“Awareness and assessment of iron deficiency are an important part of inpatient care of patients with ejection fractions less than or equal to 50% and acute decompensated heart failure, and I think all of us in the community need to pay much more attention to this issue.”
As with any new therapy, there are implementation challenges such as how to monitor patients and deliver the therapy in a cost-effective way, Sweitzer said.
The trial focused on the most vulnerable period for HF patients, but these patients should be rechecked every 3 to 4 months for iron deficiency, Ponikowski observed during the briefing.
“This is a modifiable risk factor,” he said. “We only need to remember, we only need to assess it, and we have a very, very simple tool in our hands. We just need to measure two biomarkers, transferrin saturation and ferritin — that’s all.”
Unanswered questions include the mechanism behind the reduction in hospitalization, the relationship of benefit to hemoglobin levels, and whether there is a differential benefit based on age, presence of ischemia, or sex, especially as women tend to be more severely affected by iron deficiency, Sweitzer said.
During the formal presentation, Ponikowski said the primary endpoint was consistent in subgroup analyses across baseline hemoglobin, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide levels, HF etiology, ejection fraction, and whether HF was diagnosed prior to the index hospitalization.
Treatment with FCM was safe, with no significant differences between the FCM and placebo groups in serious adverse events (45% vs 51%) or adverse events leading to study discontinuation (18% vs 17%), he reported. The most common adverse events were cardiac disorders (40.1% vs 44.3%) and infections (18.2% vs 22%).
AFFIRM-AHF is the first of three ongoing mortality and morbidity trials in heart failure with intravenous ferric carboxymaltose; the others are FAIR-HF2 and HEART-FID. Additional insights are also expected next year on intravenous iron isomaltoside from the Scottish-based IRONMAN trial in 1300 HF patients with iron deficiency.
The study was sponsored by Vifor International. Ponikowski has received research grants and personal fees from Vifor Pharma; and personal fees from Amgen, Bayer, Novartis, Abbott Vascular, Boehringer Ingelheim, Merck, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, Renal Guard Solutions Bristol-Myers Squibb, and Impulse Dynamics.
Pfeffer reported honoraria from AstraZeneca, Corvidia, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Roche, Sanofi, and Servier; other relationships with DalCor and Novo Nordisk; research grants from Novartis; and an ownership interest in DalCor. Sweitzer reported research payments from Merck and Novartis; and consulting fees from Myocardia.
McMurray reported relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, and Servier. Yancy reported a relationship with Abbott and JAMA Network.
Lancet. Published online November 13, 2020. Full text
American Heart Association Scientific Sessions 2020: Presented November 13, 2020.
A version of this article originally appeared on Medscape.com.
Iron supplementation reduces heart failure (HF) readmissions in iron-deficient patients hospitalized for acute HF, according to results of the AFFIRM-AHF trial.
After 52 weeks, intravenous ferric carboxymaltose (Ferinject) reduced the risk of total HF hospitalizations and cardiovascular (CV) death by 21% compared with placebo (293 vs 372 events; rate ratio [RR] 0.79; 95% CI, 0.62 - 1.01).
Although the composite primary endpoint failed to achieve statistical significance, it was driven by a significant 26% reduction in the risk of total HF hospital readmissions (P = .013) without an effect on CV mortality (P =.809).
Because the management and follow-up of patients was affected by the COVID-19 pandemic, a prespecified sensitivity analysis was performed that censored patients in each country at the date when its first COVID-19 patient was reported, explained principal investigator Piotr Ponikowski, MD, PhD, Wroclaw Medical University, Wroclaw, Poland.
That analysis revealed a significant 30% reduction in total HF readmissions (P = .005) in patients receiving ferric carboxymaltose (FCM), as well as significant benefits on the primary composite and secondary endpoints.
Notably, 80% of patients required only one or two injections and HF hospitalizations were reduced irrespective of anemia status.
“Iron deficiency should be searched in patients hospitalized with acute heart failure — assessed using a simple blood test — and is now an important therapeutic target,” Ponikowski said at the virtual American Heart Association (AHA) Scientific Sessions 2020.
The results were also published simultaneously in The Lancet.
Iron deficiency is present in up to 70% of patients with acute HF and a predictor of poor outcome, independent of anemia and ejection fraction, he noted.
The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials demonstrated that IV iron supplementation improves exercise capacity, symptoms, and quality of life in iron-deficient HF patients.
However, no such benefit was seen with oral IV in the IRONOUT trial. “So it seems if we are to replace iron, it needs to be done using intravenous therapy,” said John McMurray, MD, University of Glasgow, Scotland, who was invited to discuss the results.
He observed that the reduction in HF hospitalizations in AFFIRM-AHF were relatively modest and that the trial was never expected to show a benefit on CV mortality. Also, the COVID-19 sensitivity analysis providing more convincing effects is a valid approach and one recommended by regulators.
Further, the findings are supported by independent evidence in chronic kidney disease, from the PIVOTAL trial, that intravenous iron reduces HF hospitalizations, McMurray said.
“The million-dollar question, of course, is what will the results of this study mean for the guidelines: I think they probably will change the guidelines,” he said. “Certainly, I hope they will change the US guidelines, which have really given a very lukewarm recommendation for intravenous iron and I think that should probably be stronger.”
In a class IIb recommendation, the 2017 American College of Cardiology/AHA/Heart Failure Society of America heart failure guidelines say intravenous iron “might be reasonable” to improve functional status and quality of life in New York Heart Association class II and III patients with iron deficiency.
The 2016 European Society of Cardiology guidelines include a class IIa recommendation that IV iron “should be considered” in iron-deficient patients with symptomatic HF with reduced ejection fraction.
“This is the first large-scale [trial] of IV supplementation that could potentially change the way we approach patients, particularly those with hospitalized heart failure,” past AHA president Clyde Yancy, MD, MSc, Northwestern University Feinberg School of Medicine in Chicago, said during an earlier press briefing.
He pointed out that clinicians have been circumspect about the early IV iron data. “I have to congratulate you because you’ve changed the narrative,” Yancy said. “We have to start thinking about iron deficiency; we have to think about how we incorporate this in treatment protocols.”
Press briefing panelist Marc Pfeffer, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School in Boston, acknowledged he was among those circumspect.
“I’m no longer a skeptic and I want to congratulate them for showing it’s a risk factor,” he said. “It’s one thing to have a risk factor; it’s another to be a modifiable risk factor and I think that’s what’s so exciting about this.”
The double-blind, phase 4 AFFIRM-AHF trial randomly assigned 1132 patients to receive a bolus injection of ferric carboxymaltose or normal saline before hospital discharge for an acute HF episode. Subsequent treatment was given, as needed, up to 24 weeks post-randomization.
At admission, all patients had left ventricular ejection fractions less than 50% and iron deficiency (serum ferritin <100 ng/mL or serum ferritin 100-299 ng/mL if transferrin saturation <20%).
The modified intention-to-treat (mITT) analysis included 558 FCM patients and 550 controls in whom study treatment was started and for whom at least one post-randomization value was available.
Press briefing discussant Nancy Sweitzer, MD, PhD, director of the University of Arizona’s Sarver Heart Center in Tucson, said AFFIRM-AHF is an “important trial likely to change guidelines” and “targeted one of the highest risk populations we have in heart failure.”
Patients with iron deficiency tend to be elderly with more comorbidities, have longer hospital lengths of stay, and higher readmission rates. “So impacting hospitalizations in this population is incredibly impactful,” she said.
“Awareness and assessment of iron deficiency are an important part of inpatient care of patients with ejection fractions less than or equal to 50% and acute decompensated heart failure, and I think all of us in the community need to pay much more attention to this issue.”
As with any new therapy, there are implementation challenges such as how to monitor patients and deliver the therapy in a cost-effective way, Sweitzer said.
The trial focused on the most vulnerable period for HF patients, but these patients should be rechecked every 3 to 4 months for iron deficiency, Ponikowski observed during the briefing.
“This is a modifiable risk factor,” he said. “We only need to remember, we only need to assess it, and we have a very, very simple tool in our hands. We just need to measure two biomarkers, transferrin saturation and ferritin — that’s all.”
Unanswered questions include the mechanism behind the reduction in hospitalization, the relationship of benefit to hemoglobin levels, and whether there is a differential benefit based on age, presence of ischemia, or sex, especially as women tend to be more severely affected by iron deficiency, Sweitzer said.
During the formal presentation, Ponikowski said the primary endpoint was consistent in subgroup analyses across baseline hemoglobin, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide levels, HF etiology, ejection fraction, and whether HF was diagnosed prior to the index hospitalization.
Treatment with FCM was safe, with no significant differences between the FCM and placebo groups in serious adverse events (45% vs 51%) or adverse events leading to study discontinuation (18% vs 17%), he reported. The most common adverse events were cardiac disorders (40.1% vs 44.3%) and infections (18.2% vs 22%).
AFFIRM-AHF is the first of three ongoing mortality and morbidity trials in heart failure with intravenous ferric carboxymaltose; the others are FAIR-HF2 and HEART-FID. Additional insights are also expected next year on intravenous iron isomaltoside from the Scottish-based IRONMAN trial in 1300 HF patients with iron deficiency.
The study was sponsored by Vifor International. Ponikowski has received research grants and personal fees from Vifor Pharma; and personal fees from Amgen, Bayer, Novartis, Abbott Vascular, Boehringer Ingelheim, Merck, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, Renal Guard Solutions Bristol-Myers Squibb, and Impulse Dynamics.
Pfeffer reported honoraria from AstraZeneca, Corvidia, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Roche, Sanofi, and Servier; other relationships with DalCor and Novo Nordisk; research grants from Novartis; and an ownership interest in DalCor. Sweitzer reported research payments from Merck and Novartis; and consulting fees from Myocardia.
McMurray reported relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, and Servier. Yancy reported a relationship with Abbott and JAMA Network.
Lancet. Published online November 13, 2020. Full text
American Heart Association Scientific Sessions 2020: Presented November 13, 2020.
A version of this article originally appeared on Medscape.com.
Iron supplementation reduces heart failure (HF) readmissions in iron-deficient patients hospitalized for acute HF, according to results of the AFFIRM-AHF trial.
After 52 weeks, intravenous ferric carboxymaltose (Ferinject) reduced the risk of total HF hospitalizations and cardiovascular (CV) death by 21% compared with placebo (293 vs 372 events; rate ratio [RR] 0.79; 95% CI, 0.62 - 1.01).
Although the composite primary endpoint failed to achieve statistical significance, it was driven by a significant 26% reduction in the risk of total HF hospital readmissions (P = .013) without an effect on CV mortality (P =.809).
Because the management and follow-up of patients was affected by the COVID-19 pandemic, a prespecified sensitivity analysis was performed that censored patients in each country at the date when its first COVID-19 patient was reported, explained principal investigator Piotr Ponikowski, MD, PhD, Wroclaw Medical University, Wroclaw, Poland.
That analysis revealed a significant 30% reduction in total HF readmissions (P = .005) in patients receiving ferric carboxymaltose (FCM), as well as significant benefits on the primary composite and secondary endpoints.
Notably, 80% of patients required only one or two injections and HF hospitalizations were reduced irrespective of anemia status.
“Iron deficiency should be searched in patients hospitalized with acute heart failure — assessed using a simple blood test — and is now an important therapeutic target,” Ponikowski said at the virtual American Heart Association (AHA) Scientific Sessions 2020.
The results were also published simultaneously in The Lancet.
Iron deficiency is present in up to 70% of patients with acute HF and a predictor of poor outcome, independent of anemia and ejection fraction, he noted.
The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials demonstrated that IV iron supplementation improves exercise capacity, symptoms, and quality of life in iron-deficient HF patients.
However, no such benefit was seen with oral IV in the IRONOUT trial. “So it seems if we are to replace iron, it needs to be done using intravenous therapy,” said John McMurray, MD, University of Glasgow, Scotland, who was invited to discuss the results.
He observed that the reduction in HF hospitalizations in AFFIRM-AHF were relatively modest and that the trial was never expected to show a benefit on CV mortality. Also, the COVID-19 sensitivity analysis providing more convincing effects is a valid approach and one recommended by regulators.
Further, the findings are supported by independent evidence in chronic kidney disease, from the PIVOTAL trial, that intravenous iron reduces HF hospitalizations, McMurray said.
“The million-dollar question, of course, is what will the results of this study mean for the guidelines: I think they probably will change the guidelines,” he said. “Certainly, I hope they will change the US guidelines, which have really given a very lukewarm recommendation for intravenous iron and I think that should probably be stronger.”
In a class IIb recommendation, the 2017 American College of Cardiology/AHA/Heart Failure Society of America heart failure guidelines say intravenous iron “might be reasonable” to improve functional status and quality of life in New York Heart Association class II and III patients with iron deficiency.
The 2016 European Society of Cardiology guidelines include a class IIa recommendation that IV iron “should be considered” in iron-deficient patients with symptomatic HF with reduced ejection fraction.
“This is the first large-scale [trial] of IV supplementation that could potentially change the way we approach patients, particularly those with hospitalized heart failure,” past AHA president Clyde Yancy, MD, MSc, Northwestern University Feinberg School of Medicine in Chicago, said during an earlier press briefing.
He pointed out that clinicians have been circumspect about the early IV iron data. “I have to congratulate you because you’ve changed the narrative,” Yancy said. “We have to start thinking about iron deficiency; we have to think about how we incorporate this in treatment protocols.”
Press briefing panelist Marc Pfeffer, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School in Boston, acknowledged he was among those circumspect.
“I’m no longer a skeptic and I want to congratulate them for showing it’s a risk factor,” he said. “It’s one thing to have a risk factor; it’s another to be a modifiable risk factor and I think that’s what’s so exciting about this.”
The double-blind, phase 4 AFFIRM-AHF trial randomly assigned 1132 patients to receive a bolus injection of ferric carboxymaltose or normal saline before hospital discharge for an acute HF episode. Subsequent treatment was given, as needed, up to 24 weeks post-randomization.
At admission, all patients had left ventricular ejection fractions less than 50% and iron deficiency (serum ferritin <100 ng/mL or serum ferritin 100-299 ng/mL if transferrin saturation <20%).
The modified intention-to-treat (mITT) analysis included 558 FCM patients and 550 controls in whom study treatment was started and for whom at least one post-randomization value was available.
Press briefing discussant Nancy Sweitzer, MD, PhD, director of the University of Arizona’s Sarver Heart Center in Tucson, said AFFIRM-AHF is an “important trial likely to change guidelines” and “targeted one of the highest risk populations we have in heart failure.”
Patients with iron deficiency tend to be elderly with more comorbidities, have longer hospital lengths of stay, and higher readmission rates. “So impacting hospitalizations in this population is incredibly impactful,” she said.
“Awareness and assessment of iron deficiency are an important part of inpatient care of patients with ejection fractions less than or equal to 50% and acute decompensated heart failure, and I think all of us in the community need to pay much more attention to this issue.”
As with any new therapy, there are implementation challenges such as how to monitor patients and deliver the therapy in a cost-effective way, Sweitzer said.
The trial focused on the most vulnerable period for HF patients, but these patients should be rechecked every 3 to 4 months for iron deficiency, Ponikowski observed during the briefing.
“This is a modifiable risk factor,” he said. “We only need to remember, we only need to assess it, and we have a very, very simple tool in our hands. We just need to measure two biomarkers, transferrin saturation and ferritin — that’s all.”
Unanswered questions include the mechanism behind the reduction in hospitalization, the relationship of benefit to hemoglobin levels, and whether there is a differential benefit based on age, presence of ischemia, or sex, especially as women tend to be more severely affected by iron deficiency, Sweitzer said.
During the formal presentation, Ponikowski said the primary endpoint was consistent in subgroup analyses across baseline hemoglobin, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide levels, HF etiology, ejection fraction, and whether HF was diagnosed prior to the index hospitalization.
Treatment with FCM was safe, with no significant differences between the FCM and placebo groups in serious adverse events (45% vs 51%) or adverse events leading to study discontinuation (18% vs 17%), he reported. The most common adverse events were cardiac disorders (40.1% vs 44.3%) and infections (18.2% vs 22%).
AFFIRM-AHF is the first of three ongoing mortality and morbidity trials in heart failure with intravenous ferric carboxymaltose; the others are FAIR-HF2 and HEART-FID. Additional insights are also expected next year on intravenous iron isomaltoside from the Scottish-based IRONMAN trial in 1300 HF patients with iron deficiency.
The study was sponsored by Vifor International. Ponikowski has received research grants and personal fees from Vifor Pharma; and personal fees from Amgen, Bayer, Novartis, Abbott Vascular, Boehringer Ingelheim, Merck, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, Renal Guard Solutions Bristol-Myers Squibb, and Impulse Dynamics.
Pfeffer reported honoraria from AstraZeneca, Corvidia, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Roche, Sanofi, and Servier; other relationships with DalCor and Novo Nordisk; research grants from Novartis; and an ownership interest in DalCor. Sweitzer reported research payments from Merck and Novartis; and consulting fees from Myocardia.
McMurray reported relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, and Servier. Yancy reported a relationship with Abbott and JAMA Network.
Lancet. Published online November 13, 2020. Full text
American Heart Association Scientific Sessions 2020: Presented November 13, 2020.
A version of this article originally appeared on Medscape.com.
FROM AHA 2020
GALACTIC-HF: New ‘myotropic’ drug class shows modest HFrEF benefit
Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.
“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.
Omecamtiv mecarbil (OM) treatment produced a positive result for the study’s primary endpoint, with a 2.1% absolute cut in the combined rate of cardiovascular death, first heart failure hospitalization, or first urgent visit for heart failure compared with placebo during a median follow-up of about 22 months This represented an 8% relative risk reduction, reported John R. Teerlink, MD, at the meeting, and broke down as a 0.6% absolute drop in cardiovascular death compared with the placebo arm, a 0.7% cut in heart failure hospitalization, and a 0.8% drop in urgent outpatient visits for heart failure. Dr. Teerlink and his associates called this benefit “modest” in their simultaneous publication in the New England Journal of Medicine.
Room for a fifth HFrEF drug?
In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.
Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.
The new evidence for OM’s efficacy is “not compelling” when compared with what dapagliflozin and empagliflozin each showed in recent trials, with the SGLT2 inhibitors producing about a 25% cut compared with placebo in a primary outcome that was similar to the one used in the OM trial, commented Douglas L. Mann, MD, a heart failure physician and professor of medicine at Washington University School of Medicine in St. Louis. “Would OM still show a benefit with an SGLT2 inhibitor? That’s not known” on the basis of the available data, he said in an interview.
A related factor that could influence potential use of OM in routine practice is that with four established, foundational drug classes, adding a fifth drug that will only be available in a branded formulation raises issues of incremental cost and compliance issues, Dr. Mann noted.
The positives of omecamtiv mercarbil
But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.
This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.
“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.
If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.
The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.
Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.
Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.
This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.
The world’s first myotropic drug
Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.
“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.
But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.
The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.
GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.
[email protected]
On Twitter @mitchelzoler
Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.
“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.
Omecamtiv mecarbil (OM) treatment produced a positive result for the study’s primary endpoint, with a 2.1% absolute cut in the combined rate of cardiovascular death, first heart failure hospitalization, or first urgent visit for heart failure compared with placebo during a median follow-up of about 22 months This represented an 8% relative risk reduction, reported John R. Teerlink, MD, at the meeting, and broke down as a 0.6% absolute drop in cardiovascular death compared with the placebo arm, a 0.7% cut in heart failure hospitalization, and a 0.8% drop in urgent outpatient visits for heart failure. Dr. Teerlink and his associates called this benefit “modest” in their simultaneous publication in the New England Journal of Medicine.
Room for a fifth HFrEF drug?
In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.
Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.
The new evidence for OM’s efficacy is “not compelling” when compared with what dapagliflozin and empagliflozin each showed in recent trials, with the SGLT2 inhibitors producing about a 25% cut compared with placebo in a primary outcome that was similar to the one used in the OM trial, commented Douglas L. Mann, MD, a heart failure physician and professor of medicine at Washington University School of Medicine in St. Louis. “Would OM still show a benefit with an SGLT2 inhibitor? That’s not known” on the basis of the available data, he said in an interview.
A related factor that could influence potential use of OM in routine practice is that with four established, foundational drug classes, adding a fifth drug that will only be available in a branded formulation raises issues of incremental cost and compliance issues, Dr. Mann noted.
The positives of omecamtiv mercarbil
But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.
This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.
“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.
If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.
The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.
Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.
Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.
This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.
The world’s first myotropic drug
Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.
“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.
But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.
The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.
GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.
[email protected]
On Twitter @mitchelzoler
Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.
“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.
Omecamtiv mecarbil (OM) treatment produced a positive result for the study’s primary endpoint, with a 2.1% absolute cut in the combined rate of cardiovascular death, first heart failure hospitalization, or first urgent visit for heart failure compared with placebo during a median follow-up of about 22 months This represented an 8% relative risk reduction, reported John R. Teerlink, MD, at the meeting, and broke down as a 0.6% absolute drop in cardiovascular death compared with the placebo arm, a 0.7% cut in heart failure hospitalization, and a 0.8% drop in urgent outpatient visits for heart failure. Dr. Teerlink and his associates called this benefit “modest” in their simultaneous publication in the New England Journal of Medicine.
Room for a fifth HFrEF drug?
In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.
Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.
The new evidence for OM’s efficacy is “not compelling” when compared with what dapagliflozin and empagliflozin each showed in recent trials, with the SGLT2 inhibitors producing about a 25% cut compared with placebo in a primary outcome that was similar to the one used in the OM trial, commented Douglas L. Mann, MD, a heart failure physician and professor of medicine at Washington University School of Medicine in St. Louis. “Would OM still show a benefit with an SGLT2 inhibitor? That’s not known” on the basis of the available data, he said in an interview.
A related factor that could influence potential use of OM in routine practice is that with four established, foundational drug classes, adding a fifth drug that will only be available in a branded formulation raises issues of incremental cost and compliance issues, Dr. Mann noted.
The positives of omecamtiv mercarbil
But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.
This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.
“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.
If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.
The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.
Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.
Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.
This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.
The world’s first myotropic drug
Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.
“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.
But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.
The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.
GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.
[email protected]
On Twitter @mitchelzoler
FROM AHA 2020
Don’t miss cardiovascular risk factors in transgender patients
Cardiovascular disease risk is elevated among transgender individuals seeking gender-affirming hormone therapy, according to a retrospective study in 427 patients.
The transgender population often experiences socioeconomic and health disparities, including reduced access to care, Kara J. Denby, MD, said in an interview.
Previous research suggests that the use of gender-affirming hormone therapy (GAHT) may place transgender persons at increased cardiovascular risk, she said.
To identify the potential risk for transgender individuals, the researchers identified baseline cardiovascular risk in patients who had not yet undergone GAHT. Study participants were enrolled in a multidisciplinary transgender program, and the researchers collected data on demographics, medical history, vitals, medications, and laboratory results. The average age of the participants was 26 years, 172 identified as men, 236 as women, and 20 as nonbinary.
Overall, 55% of the participants had a chronic medical condition at baseline. Of these, 74 patients had hypertension, 41 had hyperlipidemia, 2 had a history of stroke, 7 had coronary artery disease, and 4 had chronic obstructive pulmonary disease.
For all patients who did not have documented atherosclerotic cardiovascular disease, their American College of Cardiology/American Heart Association ASCVD and QRISK3 risk scores were calculated. “The incidence of undiagnosed hypertension and hyperlipidemia was 6.8% and 11.3% respectively, and of these cases, only 64% and 24% were on appropriate therapies,” noted Dr. Denby of the Cleveland (Ohio) Clinic.
She reported the results Nov. 13 in a presentation at the at the virtual American Heart Association scientific sessions.
The findings were limited by the observational nature of the study.
However, the results suggest that transgender patients “appear to be at higher risk than their age-matched historical cohorts regardless of gender,” said Dr. Denby. More research is needed, but cardiovascular disease–prevention efforts may be inadequate in the transgender population given the elevated risk observed in this study, she concluded.
Growing transgender population is medically underserved
The transgender population is growing in the United States and internationally, said Dr. Denby. “This group has a history of being marginalized as a result of their transgender status with socioeconomic and health repercussions,” she said. “It is well known that transgender patients are less likely to have access to health care or utilize health care for a variety of reasons, including stigma and fear of mistreatment. This often leads transgender individuals to present to care late in disease processes which makes their disease harder to treat and often leads to emergent medical conditions,” she added.
“Transgender men and women are at high risk for cardiovascular disease and often aren’t screened at recommended intervals because of decreased health care use compared to their cisgender counterparts,” she said. “This may lead to untreated diseases that make them even more likely to suffer poor health outcomes.”
The current study is important because there are “almost no prior data regarding the cardiovascular health status of this population prior to gender-affirming care,” Dr. Denby emphasized. “There are data that gay, lesbian, and bisexual individuals are at higher risk for poor cardiovascular outcomes, but the same data are lacking in the transgender group,” she said.
“As transgender individuals have frequent physician visits while on hormonal therapy, this seems like the opportune time to screen for cardiovascular risk factors and treat previously undiagnosed diseases that can lead to poor health outcomes in the future,” Dr. Denby explained. “If we are able to intervene at an earlier age, perhaps we can help prevent poor health outcomes down the road,” she said.
Additional research can inform practice
Dr. Denby said she was not surprised by the findings. “This is a very high-risk population that often doesn’t follow closely in the health care system,” she said. “These data are very important in thinking holistically about transgender patients.” Clinicians can “use the opportunities we have when they present for gender-affirming care to optimize their overall health status, promote long-term health, and reduce the risks associated with hormonal therapy and gender-affirming surgeries,” she noted. “We hope to use this information to change our practice at the Cleveland Clinic and nationally as well. Transgender patients should be screened and aggressively treated for cardiovascular disease and risk factors,” she said.
Key barriers to overcome include determining the best way to reach out to transgender individuals and then making them feel comfortable in the clinical setting, Dr. Denby said. “This means that we must set up clinics that are approachable and safe for all comers. The lack of laws in many states that protect this vulnerable population also contributes to lack of access to care,” she added.
“We hope to continue research in this arena about how to effectively screen and treat transgender patients as they present to care, not only in the transgender clinic, but also to primary care providers (ob.gyn., internal medicine, family medicine, pediatrics) who also care for this population” since no specific guidelines currently exist to direct the screening for cardiovascular patients in particular, she said.
Findings offer foundation for LGBTQ cardiovascular studies
“This [study] provides us with a good rationale for why we should be considering cardiovascular health in transgender adults,” Billy A. Caceres, PhD, RN, of Columbia University School of Nursing, New York, said in an interview. “It is largely descriptive, but I think that that’s a good step in terms of at least understanding the magnitude of this problem. In addition, I think that what this abstract might do is help lead to future research that examines potentially the associations between not only gender-affirming hormone therapies but other potential social determinants like discrimination or poverty on the cardiovascular health of transgender people,” he noted.
Dr. Caceres served as chair of the writing group for the recent American Heart Association Scientific Statement: LGBTQ Heart Health published in Circulation. He had no financial conflicts to disclose.
The study received no outside funding. Dr. Denby had no financial conflicts to disclose.
SOURCE: Denby KJ et al. AHA 2020, Presentation P2274.
Cardiovascular disease risk is elevated among transgender individuals seeking gender-affirming hormone therapy, according to a retrospective study in 427 patients.
The transgender population often experiences socioeconomic and health disparities, including reduced access to care, Kara J. Denby, MD, said in an interview.
Previous research suggests that the use of gender-affirming hormone therapy (GAHT) may place transgender persons at increased cardiovascular risk, she said.
To identify the potential risk for transgender individuals, the researchers identified baseline cardiovascular risk in patients who had not yet undergone GAHT. Study participants were enrolled in a multidisciplinary transgender program, and the researchers collected data on demographics, medical history, vitals, medications, and laboratory results. The average age of the participants was 26 years, 172 identified as men, 236 as women, and 20 as nonbinary.
Overall, 55% of the participants had a chronic medical condition at baseline. Of these, 74 patients had hypertension, 41 had hyperlipidemia, 2 had a history of stroke, 7 had coronary artery disease, and 4 had chronic obstructive pulmonary disease.
For all patients who did not have documented atherosclerotic cardiovascular disease, their American College of Cardiology/American Heart Association ASCVD and QRISK3 risk scores were calculated. “The incidence of undiagnosed hypertension and hyperlipidemia was 6.8% and 11.3% respectively, and of these cases, only 64% and 24% were on appropriate therapies,” noted Dr. Denby of the Cleveland (Ohio) Clinic.
She reported the results Nov. 13 in a presentation at the at the virtual American Heart Association scientific sessions.
The findings were limited by the observational nature of the study.
However, the results suggest that transgender patients “appear to be at higher risk than their age-matched historical cohorts regardless of gender,” said Dr. Denby. More research is needed, but cardiovascular disease–prevention efforts may be inadequate in the transgender population given the elevated risk observed in this study, she concluded.
Growing transgender population is medically underserved
The transgender population is growing in the United States and internationally, said Dr. Denby. “This group has a history of being marginalized as a result of their transgender status with socioeconomic and health repercussions,” she said. “It is well known that transgender patients are less likely to have access to health care or utilize health care for a variety of reasons, including stigma and fear of mistreatment. This often leads transgender individuals to present to care late in disease processes which makes their disease harder to treat and often leads to emergent medical conditions,” she added.
“Transgender men and women are at high risk for cardiovascular disease and often aren’t screened at recommended intervals because of decreased health care use compared to their cisgender counterparts,” she said. “This may lead to untreated diseases that make them even more likely to suffer poor health outcomes.”
The current study is important because there are “almost no prior data regarding the cardiovascular health status of this population prior to gender-affirming care,” Dr. Denby emphasized. “There are data that gay, lesbian, and bisexual individuals are at higher risk for poor cardiovascular outcomes, but the same data are lacking in the transgender group,” she said.
“As transgender individuals have frequent physician visits while on hormonal therapy, this seems like the opportune time to screen for cardiovascular risk factors and treat previously undiagnosed diseases that can lead to poor health outcomes in the future,” Dr. Denby explained. “If we are able to intervene at an earlier age, perhaps we can help prevent poor health outcomes down the road,” she said.
Additional research can inform practice
Dr. Denby said she was not surprised by the findings. “This is a very high-risk population that often doesn’t follow closely in the health care system,” she said. “These data are very important in thinking holistically about transgender patients.” Clinicians can “use the opportunities we have when they present for gender-affirming care to optimize their overall health status, promote long-term health, and reduce the risks associated with hormonal therapy and gender-affirming surgeries,” she noted. “We hope to use this information to change our practice at the Cleveland Clinic and nationally as well. Transgender patients should be screened and aggressively treated for cardiovascular disease and risk factors,” she said.
Key barriers to overcome include determining the best way to reach out to transgender individuals and then making them feel comfortable in the clinical setting, Dr. Denby said. “This means that we must set up clinics that are approachable and safe for all comers. The lack of laws in many states that protect this vulnerable population also contributes to lack of access to care,” she added.
“We hope to continue research in this arena about how to effectively screen and treat transgender patients as they present to care, not only in the transgender clinic, but also to primary care providers (ob.gyn., internal medicine, family medicine, pediatrics) who also care for this population” since no specific guidelines currently exist to direct the screening for cardiovascular patients in particular, she said.
Findings offer foundation for LGBTQ cardiovascular studies
“This [study] provides us with a good rationale for why we should be considering cardiovascular health in transgender adults,” Billy A. Caceres, PhD, RN, of Columbia University School of Nursing, New York, said in an interview. “It is largely descriptive, but I think that that’s a good step in terms of at least understanding the magnitude of this problem. In addition, I think that what this abstract might do is help lead to future research that examines potentially the associations between not only gender-affirming hormone therapies but other potential social determinants like discrimination or poverty on the cardiovascular health of transgender people,” he noted.
Dr. Caceres served as chair of the writing group for the recent American Heart Association Scientific Statement: LGBTQ Heart Health published in Circulation. He had no financial conflicts to disclose.
The study received no outside funding. Dr. Denby had no financial conflicts to disclose.
SOURCE: Denby KJ et al. AHA 2020, Presentation P2274.
Cardiovascular disease risk is elevated among transgender individuals seeking gender-affirming hormone therapy, according to a retrospective study in 427 patients.
The transgender population often experiences socioeconomic and health disparities, including reduced access to care, Kara J. Denby, MD, said in an interview.
Previous research suggests that the use of gender-affirming hormone therapy (GAHT) may place transgender persons at increased cardiovascular risk, she said.
To identify the potential risk for transgender individuals, the researchers identified baseline cardiovascular risk in patients who had not yet undergone GAHT. Study participants were enrolled in a multidisciplinary transgender program, and the researchers collected data on demographics, medical history, vitals, medications, and laboratory results. The average age of the participants was 26 years, 172 identified as men, 236 as women, and 20 as nonbinary.
Overall, 55% of the participants had a chronic medical condition at baseline. Of these, 74 patients had hypertension, 41 had hyperlipidemia, 2 had a history of stroke, 7 had coronary artery disease, and 4 had chronic obstructive pulmonary disease.
For all patients who did not have documented atherosclerotic cardiovascular disease, their American College of Cardiology/American Heart Association ASCVD and QRISK3 risk scores were calculated. “The incidence of undiagnosed hypertension and hyperlipidemia was 6.8% and 11.3% respectively, and of these cases, only 64% and 24% were on appropriate therapies,” noted Dr. Denby of the Cleveland (Ohio) Clinic.
She reported the results Nov. 13 in a presentation at the at the virtual American Heart Association scientific sessions.
The findings were limited by the observational nature of the study.
However, the results suggest that transgender patients “appear to be at higher risk than their age-matched historical cohorts regardless of gender,” said Dr. Denby. More research is needed, but cardiovascular disease–prevention efforts may be inadequate in the transgender population given the elevated risk observed in this study, she concluded.
Growing transgender population is medically underserved
The transgender population is growing in the United States and internationally, said Dr. Denby. “This group has a history of being marginalized as a result of their transgender status with socioeconomic and health repercussions,” she said. “It is well known that transgender patients are less likely to have access to health care or utilize health care for a variety of reasons, including stigma and fear of mistreatment. This often leads transgender individuals to present to care late in disease processes which makes their disease harder to treat and often leads to emergent medical conditions,” she added.
“Transgender men and women are at high risk for cardiovascular disease and often aren’t screened at recommended intervals because of decreased health care use compared to their cisgender counterparts,” she said. “This may lead to untreated diseases that make them even more likely to suffer poor health outcomes.”
The current study is important because there are “almost no prior data regarding the cardiovascular health status of this population prior to gender-affirming care,” Dr. Denby emphasized. “There are data that gay, lesbian, and bisexual individuals are at higher risk for poor cardiovascular outcomes, but the same data are lacking in the transgender group,” she said.
“As transgender individuals have frequent physician visits while on hormonal therapy, this seems like the opportune time to screen for cardiovascular risk factors and treat previously undiagnosed diseases that can lead to poor health outcomes in the future,” Dr. Denby explained. “If we are able to intervene at an earlier age, perhaps we can help prevent poor health outcomes down the road,” she said.
Additional research can inform practice
Dr. Denby said she was not surprised by the findings. “This is a very high-risk population that often doesn’t follow closely in the health care system,” she said. “These data are very important in thinking holistically about transgender patients.” Clinicians can “use the opportunities we have when they present for gender-affirming care to optimize their overall health status, promote long-term health, and reduce the risks associated with hormonal therapy and gender-affirming surgeries,” she noted. “We hope to use this information to change our practice at the Cleveland Clinic and nationally as well. Transgender patients should be screened and aggressively treated for cardiovascular disease and risk factors,” she said.
Key barriers to overcome include determining the best way to reach out to transgender individuals and then making them feel comfortable in the clinical setting, Dr. Denby said. “This means that we must set up clinics that are approachable and safe for all comers. The lack of laws in many states that protect this vulnerable population also contributes to lack of access to care,” she added.
“We hope to continue research in this arena about how to effectively screen and treat transgender patients as they present to care, not only in the transgender clinic, but also to primary care providers (ob.gyn., internal medicine, family medicine, pediatrics) who also care for this population” since no specific guidelines currently exist to direct the screening for cardiovascular patients in particular, she said.
Findings offer foundation for LGBTQ cardiovascular studies
“This [study] provides us with a good rationale for why we should be considering cardiovascular health in transgender adults,” Billy A. Caceres, PhD, RN, of Columbia University School of Nursing, New York, said in an interview. “It is largely descriptive, but I think that that’s a good step in terms of at least understanding the magnitude of this problem. In addition, I think that what this abstract might do is help lead to future research that examines potentially the associations between not only gender-affirming hormone therapies but other potential social determinants like discrimination or poverty on the cardiovascular health of transgender people,” he noted.
Dr. Caceres served as chair of the writing group for the recent American Heart Association Scientific Statement: LGBTQ Heart Health published in Circulation. He had no financial conflicts to disclose.
The study received no outside funding. Dr. Denby had no financial conflicts to disclose.
SOURCE: Denby KJ et al. AHA 2020, Presentation P2274.
FROM AHA 2020