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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
TIPS-3: Polypill provides meaningful primary cardiovascular prevention
A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.
And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.
“Aspirin contributes importantly to the benefits,” Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.
The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.
“If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally,” according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.
“This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020,” added Dr. Pais of St. John’s Research Institute in Bangalore, India.
TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.
They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.
During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.
The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.
Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.
Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study’s end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination’s likely real-world performance.
Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.
“If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous,” said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.
However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.
“I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk,” the cardiologist said.
Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, “You’re seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events.”
While TIPS-3 was conducted mainly in low- and middle-income countries, it’s important to recognize that’s where 75% of cardiovascular events and cardiovascular deaths now occur.
“This is very much a disease that has emerged in the developing world,” commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.
He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.
Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.
Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.
SOURCE: Yusuf, S. AHA 2020. Session LBS.02.
A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.
And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.
“Aspirin contributes importantly to the benefits,” Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.
The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.
“If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally,” according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.
“This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020,” added Dr. Pais of St. John’s Research Institute in Bangalore, India.
TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.
They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.
During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.
The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.
Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.
Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study’s end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination’s likely real-world performance.
Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.
“If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous,” said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.
However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.
“I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk,” the cardiologist said.
Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, “You’re seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events.”
While TIPS-3 was conducted mainly in low- and middle-income countries, it’s important to recognize that’s where 75% of cardiovascular events and cardiovascular deaths now occur.
“This is very much a disease that has emerged in the developing world,” commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.
He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.
Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.
Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.
SOURCE: Yusuf, S. AHA 2020. Session LBS.02.
A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.
And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.
“Aspirin contributes importantly to the benefits,” Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.
The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.
“If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally,” according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.
“This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020,” added Dr. Pais of St. John’s Research Institute in Bangalore, India.
TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.
They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.
During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.
The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.
Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.
Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study’s end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination’s likely real-world performance.
Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.
“If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous,” said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.
However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.
“I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk,” the cardiologist said.
Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, “You’re seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events.”
While TIPS-3 was conducted mainly in low- and middle-income countries, it’s important to recognize that’s where 75% of cardiovascular events and cardiovascular deaths now occur.
“This is very much a disease that has emerged in the developing world,” commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.
He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.
Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.
Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.
SOURCE: Yusuf, S. AHA 2020. Session LBS.02.
REPORTING 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.
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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
New reports guide return to play in athletes with COVID-19
Increasingly, clinicians are being called upon to advise athletes who have recovered from COVID-19 on when it is safe for them to return to play.
Now, they have two reports that offer more insights into the cardiotoxic effects of COVID-19 on the athletic heart.
In the first report, researchers report a high prevalence of pericardial involvement in college-student athletes who have recovered from COVID-19 and give their practical advice on how to let these athletes return to play safely.
In the second report, an expert panel of sports cardiologists provides a comprehensive guide to the appropriate imaging of athletes who may have cardiovascular complications from COVID-19.
Both are published in JACC: Cardiovascular Imaging.
“We were asked by the editors of JACC to submit this paper, and the impetus for it was the fact that there are so many athletes returning after being infected with COVID-19, we need to try and give guidance to cardiologists as to how best to evaluate these athletes,” Dermot Phelan, MD, PhD, Sanger Heart and Vascular Institute, Atrium Health, Charlotte, N.C., and lead author of the consensus statement, said in an interview.
The consensus statement acknowledges that information about the cardiovascular complications of COVID-19 continues to evolve. Meanwhile, pathologies such as myocarditis, pericarditis, and right ventricular dysfunction, in the absence of significant clinical symptoms, in athletes who have been affected by COVID-19 remain of considerable concern.
It also emphasizes the unique challenges the average cardiologist faces in distinguishing between what is normal for an athlete’s heart and what is true pathology after COVID-19 infection; details how different imaging modalities can help in screening, evaluating, and monitoring athletes with suspected cardiovascular complications of COVID-19 infection; and discusses the strengths and limitations of these modalities.
Finally, the consensus statement provides some well-needed guidance on return-to-play decision-making, for both the athlete and the clinician.
Athletic remodeling or covid-19 damage?
Athletes can develop certain cardiovascular characteristics because of their athletic activity, and sometimes, this can cloud the diagnostic picture.
“Is this change due to the effects of COVID-19, or is it just because this is an athlete’s heart? This was an international expert consensus, made up of sports cardiologists from all over the world who have a lot of experience in dealing with athletes,” Dr. Phelan said. “We were trying to relay the important information to the cardiologist who is not used to dealing with athletes on a day-to-day basis, as to what they might expect to find in that athlete, and what is not an expected finding and should be tested further.”
Phelan, a sports cardiologist, is familiar with what is normal for an athlete’s heart and what is pathology.
“We know that athletes, particularly long-term endurance athletes, develop changes in the heart that can affect not only the electrics but the structure of the heart, and sometimes, that overlaps with abnormalities with pathology. This can be a challenge for the nonsports cardiologist to differentiate,” he said.
Phelan and his group have written two other consensus documents on the management of cardiovascular problems that develop in some athletes who have been infected with COVID-19.
The first was published in May in JAMA Cardiology, and the second, which revised some of the original recommendations made in the first document, was published online Oct. 26 in JAMA Cardiology.
The first set of recommendations called for imaging studies to be done in all athletes, but the second set states that athletes who recover and are asymptomatic do not need extensive (and expensive) imaging tests.
“These two papers work hand in hand,” Dr. Phelan said. “In May, we had very little experience with COVID, and there was a lot of concern about hospitalized patients having a very high incidence of heart disease. We published those recommendations, but we recognized at the time that we had very little data and that we would reconsider once we had more experience with data.
“This current set of recommendations that we have put forth here are for those athletes who do need to get further testing, so it’s a step beyond,” Dr. Phelan added. “So the second iteration states that young athletes who had mild or no symptoms didn’t need to go through all of that cardiac testing, but others do need it.”
To do widespread cardiovascular imaging for many individuals would be very costly. Realistically, there are not that many centers in the United States that have all the sophisticated equipment required to do such testing, Dr. Phelan noted.
“One of our major points is difficulty obtaining the test, but also the cost; these are very expensive tests. There are limitations. They are useful when used in the correct context,” he said.
To play or not to play, that is the question
Partho P. Sengupta, MD, DM, had to answer that question for more than 50 young athletes who were returning to college at West Virginia University, anxious to be back with their teams and on the playing field. They had been infected with COVID-19 and needed to know when they could return to play.
Dr. Sengupta, who is also an author for the Phelan et al consensus statement on imaging, said there was a lot of pressure – from all the various stakeholders, and from anxious parents, worried college athletes, their teammates, and the university – to determine if the youngsters could return to play.
The fear was that COVID-19 infection left the young athlete’s heart vulnerable to myocarditis and, thus, sudden death on the playing field after strenuous activity.
“At the time we were doing this imaging, there was a lot of concern in the media, and papers were coming out reporting a lot of cardiac involvement or myocarditis associated with COVID-19. Nobody really knew what to do,” he explained.
“There were all kinds of questions, concerns. The parents were putting pressure on us, the athletes wanted to know, the teams, the university. So we put together a team and completed all of the examinations, including testing of blood markers, within a 2-week period. These young athletes, they’re scared, they’re worried and anxious, they don’t know what’s going to happen with their scholarship, so there was some urgency to this work,” Dr. Sengupta said.
“We had to screen all comers within a very short period. We had 54 consecutive patients, gave them full screening, full battery of tests, blood tests, all in a 2-week period,” he said.
Speed was of the essence, and Dr. Sengupta and his team rolled up their sleeves and got to work “We had to know who was safe to clear to return to play and who might need extra follow-up.”
Screening echocardiograms
They performed screening echocardiograms on 54 consecutive college athletes who had tested positive for COVID-19 on reverse transcription polymerase chain reaction nasal swab testing or who showed that they had IgG antibodies against COVID-19. The screening echocardiograms were done after the athletes had quarantined for at least 14 days and were no longer infectious.
Most (85%) were male, and the mean age was 19 years. A total of 16 (30%) athletes were asymptomatic, 36 (66%) reported mild COVID-19 related symptoms, and two (4%) reported moderate symptoms.
Of the 54 athletes who were initially screened with echocardiography, 48 (11 asymptomatic, 37 symptomatic), went on to have cardiac magnetic resonance imaging.
Results showed that more than half the athletes (27; 56.3%), showed some cardiac abnormality. The most common was pericardial late enhancement with associated pericardial effusion, affecting 19 (39.5%) athletes.
Of these, six (12.5%) had reduced global longitudinal strain (GLS) or an increased native T1.
One patient showed myocardial enhancement.
Additionally, seven athletes (14.6%) had reduced left ventricular ejection fraction or reduced GLS with or without increased native T1. Native T2 levels were normal in all subjects and no specific imaging features of myocardial inflammation were identified.
Participants were brought back to receive the results of their tests and to get an individualized plan about their safe return to play 3 to 5 weeks after they had ceased to be infectious with COVID-19.
“We saw pericardial inflammation that was resolving. We did not see any blood biomarkers to suggest that there was active inflammation going on,” he said. “We also did not see any muscle inflammation, but we did see pockets of fluid in over a third of our athletes.”
Fortunately, most were deemed able to get back to playing safely, despite having evidence of pericardial inflammation.
This was on strict condition that they be monitored very closely for any adverse events that might occur as they began to exercise again.
“Once they go back to the field to start exercising and practicing, it is under great supervision. We instructed all of our sports physicians and other team managers that these people need to be observed very carefully. So as long as they were asymptomatic, even though the signs of pericardial inflammation were there, if there were no signs of inflammation in the blood, we let them go back to play, closely monitored,” Dr. Sengupta said.
A small number remained very symptomatic at the end of the 5 weeks and were referred to cardiac rehabilitation, Dr. Sengupta said. “They were tired, fatigued, short of breath, even 5 weeks after they got over COVID, so we sent them for cardiac rehab to help them get conditioned again.”
The researchers plan to reevaluate and reimage all of the athletes in another 3 months to monitor their cardiac health.
Dr. Sengupta acknowledged the limitations of this single-center, nonrandomized, controlled report, but insists reports such as this add a bit more to what we are learning about COVID-19 every day.
“These kids were coming to us and asking questions. You have to use the best science you have available to you at that point in time. Some people ask why we did not have a control group, but how do you design a control population in the midst of a pandemic? The science may or may not be perfect, I agree, but the information we obtained is important,” he said.
“Right now, I don’t think we have enough science, and we are still learning. It is very difficult to predict who will develop the heart muscle disease or the pericardial disease,” Dr. Sengupta said. “We had to do our work quickly to give answers to the young athletes, their parents, their teammates, their university, as soon as possible, and we were doing this under pandemic conditions.”
The work was supported by the National Science Foundation National Institute of General Medical Sciences of the National Institutes of Health. Dr. Phelan reported no relevant financial relationships. Dr. Sengupta reported that he is a consultant for HeartSciences, Kencor Health, and Ultromics.
This article first appeared on Medscape.com.
Increasingly, clinicians are being called upon to advise athletes who have recovered from COVID-19 on when it is safe for them to return to play.
Now, they have two reports that offer more insights into the cardiotoxic effects of COVID-19 on the athletic heart.
In the first report, researchers report a high prevalence of pericardial involvement in college-student athletes who have recovered from COVID-19 and give their practical advice on how to let these athletes return to play safely.
In the second report, an expert panel of sports cardiologists provides a comprehensive guide to the appropriate imaging of athletes who may have cardiovascular complications from COVID-19.
Both are published in JACC: Cardiovascular Imaging.
“We were asked by the editors of JACC to submit this paper, and the impetus for it was the fact that there are so many athletes returning after being infected with COVID-19, we need to try and give guidance to cardiologists as to how best to evaluate these athletes,” Dermot Phelan, MD, PhD, Sanger Heart and Vascular Institute, Atrium Health, Charlotte, N.C., and lead author of the consensus statement, said in an interview.
The consensus statement acknowledges that information about the cardiovascular complications of COVID-19 continues to evolve. Meanwhile, pathologies such as myocarditis, pericarditis, and right ventricular dysfunction, in the absence of significant clinical symptoms, in athletes who have been affected by COVID-19 remain of considerable concern.
It also emphasizes the unique challenges the average cardiologist faces in distinguishing between what is normal for an athlete’s heart and what is true pathology after COVID-19 infection; details how different imaging modalities can help in screening, evaluating, and monitoring athletes with suspected cardiovascular complications of COVID-19 infection; and discusses the strengths and limitations of these modalities.
Finally, the consensus statement provides some well-needed guidance on return-to-play decision-making, for both the athlete and the clinician.
Athletic remodeling or covid-19 damage?
Athletes can develop certain cardiovascular characteristics because of their athletic activity, and sometimes, this can cloud the diagnostic picture.
“Is this change due to the effects of COVID-19, or is it just because this is an athlete’s heart? This was an international expert consensus, made up of sports cardiologists from all over the world who have a lot of experience in dealing with athletes,” Dr. Phelan said. “We were trying to relay the important information to the cardiologist who is not used to dealing with athletes on a day-to-day basis, as to what they might expect to find in that athlete, and what is not an expected finding and should be tested further.”
Phelan, a sports cardiologist, is familiar with what is normal for an athlete’s heart and what is pathology.
“We know that athletes, particularly long-term endurance athletes, develop changes in the heart that can affect not only the electrics but the structure of the heart, and sometimes, that overlaps with abnormalities with pathology. This can be a challenge for the nonsports cardiologist to differentiate,” he said.
Phelan and his group have written two other consensus documents on the management of cardiovascular problems that develop in some athletes who have been infected with COVID-19.
The first was published in May in JAMA Cardiology, and the second, which revised some of the original recommendations made in the first document, was published online Oct. 26 in JAMA Cardiology.
The first set of recommendations called for imaging studies to be done in all athletes, but the second set states that athletes who recover and are asymptomatic do not need extensive (and expensive) imaging tests.
“These two papers work hand in hand,” Dr. Phelan said. “In May, we had very little experience with COVID, and there was a lot of concern about hospitalized patients having a very high incidence of heart disease. We published those recommendations, but we recognized at the time that we had very little data and that we would reconsider once we had more experience with data.
“This current set of recommendations that we have put forth here are for those athletes who do need to get further testing, so it’s a step beyond,” Dr. Phelan added. “So the second iteration states that young athletes who had mild or no symptoms didn’t need to go through all of that cardiac testing, but others do need it.”
To do widespread cardiovascular imaging for many individuals would be very costly. Realistically, there are not that many centers in the United States that have all the sophisticated equipment required to do such testing, Dr. Phelan noted.
“One of our major points is difficulty obtaining the test, but also the cost; these are very expensive tests. There are limitations. They are useful when used in the correct context,” he said.
To play or not to play, that is the question
Partho P. Sengupta, MD, DM, had to answer that question for more than 50 young athletes who were returning to college at West Virginia University, anxious to be back with their teams and on the playing field. They had been infected with COVID-19 and needed to know when they could return to play.
Dr. Sengupta, who is also an author for the Phelan et al consensus statement on imaging, said there was a lot of pressure – from all the various stakeholders, and from anxious parents, worried college athletes, their teammates, and the university – to determine if the youngsters could return to play.
The fear was that COVID-19 infection left the young athlete’s heart vulnerable to myocarditis and, thus, sudden death on the playing field after strenuous activity.
“At the time we were doing this imaging, there was a lot of concern in the media, and papers were coming out reporting a lot of cardiac involvement or myocarditis associated with COVID-19. Nobody really knew what to do,” he explained.
“There were all kinds of questions, concerns. The parents were putting pressure on us, the athletes wanted to know, the teams, the university. So we put together a team and completed all of the examinations, including testing of blood markers, within a 2-week period. These young athletes, they’re scared, they’re worried and anxious, they don’t know what’s going to happen with their scholarship, so there was some urgency to this work,” Dr. Sengupta said.
“We had to screen all comers within a very short period. We had 54 consecutive patients, gave them full screening, full battery of tests, blood tests, all in a 2-week period,” he said.
Speed was of the essence, and Dr. Sengupta and his team rolled up their sleeves and got to work “We had to know who was safe to clear to return to play and who might need extra follow-up.”
Screening echocardiograms
They performed screening echocardiograms on 54 consecutive college athletes who had tested positive for COVID-19 on reverse transcription polymerase chain reaction nasal swab testing or who showed that they had IgG antibodies against COVID-19. The screening echocardiograms were done after the athletes had quarantined for at least 14 days and were no longer infectious.
Most (85%) were male, and the mean age was 19 years. A total of 16 (30%) athletes were asymptomatic, 36 (66%) reported mild COVID-19 related symptoms, and two (4%) reported moderate symptoms.
Of the 54 athletes who were initially screened with echocardiography, 48 (11 asymptomatic, 37 symptomatic), went on to have cardiac magnetic resonance imaging.
Results showed that more than half the athletes (27; 56.3%), showed some cardiac abnormality. The most common was pericardial late enhancement with associated pericardial effusion, affecting 19 (39.5%) athletes.
Of these, six (12.5%) had reduced global longitudinal strain (GLS) or an increased native T1.
One patient showed myocardial enhancement.
Additionally, seven athletes (14.6%) had reduced left ventricular ejection fraction or reduced GLS with or without increased native T1. Native T2 levels were normal in all subjects and no specific imaging features of myocardial inflammation were identified.
Participants were brought back to receive the results of their tests and to get an individualized plan about their safe return to play 3 to 5 weeks after they had ceased to be infectious with COVID-19.
“We saw pericardial inflammation that was resolving. We did not see any blood biomarkers to suggest that there was active inflammation going on,” he said. “We also did not see any muscle inflammation, but we did see pockets of fluid in over a third of our athletes.”
Fortunately, most were deemed able to get back to playing safely, despite having evidence of pericardial inflammation.
This was on strict condition that they be monitored very closely for any adverse events that might occur as they began to exercise again.
“Once they go back to the field to start exercising and practicing, it is under great supervision. We instructed all of our sports physicians and other team managers that these people need to be observed very carefully. So as long as they were asymptomatic, even though the signs of pericardial inflammation were there, if there were no signs of inflammation in the blood, we let them go back to play, closely monitored,” Dr. Sengupta said.
A small number remained very symptomatic at the end of the 5 weeks and were referred to cardiac rehabilitation, Dr. Sengupta said. “They were tired, fatigued, short of breath, even 5 weeks after they got over COVID, so we sent them for cardiac rehab to help them get conditioned again.”
The researchers plan to reevaluate and reimage all of the athletes in another 3 months to monitor their cardiac health.
Dr. Sengupta acknowledged the limitations of this single-center, nonrandomized, controlled report, but insists reports such as this add a bit more to what we are learning about COVID-19 every day.
“These kids were coming to us and asking questions. You have to use the best science you have available to you at that point in time. Some people ask why we did not have a control group, but how do you design a control population in the midst of a pandemic? The science may or may not be perfect, I agree, but the information we obtained is important,” he said.
“Right now, I don’t think we have enough science, and we are still learning. It is very difficult to predict who will develop the heart muscle disease or the pericardial disease,” Dr. Sengupta said. “We had to do our work quickly to give answers to the young athletes, their parents, their teammates, their university, as soon as possible, and we were doing this under pandemic conditions.”
The work was supported by the National Science Foundation National Institute of General Medical Sciences of the National Institutes of Health. Dr. Phelan reported no relevant financial relationships. Dr. Sengupta reported that he is a consultant for HeartSciences, Kencor Health, and Ultromics.
This article first appeared on Medscape.com.
Increasingly, clinicians are being called upon to advise athletes who have recovered from COVID-19 on when it is safe for them to return to play.
Now, they have two reports that offer more insights into the cardiotoxic effects of COVID-19 on the athletic heart.
In the first report, researchers report a high prevalence of pericardial involvement in college-student athletes who have recovered from COVID-19 and give their practical advice on how to let these athletes return to play safely.
In the second report, an expert panel of sports cardiologists provides a comprehensive guide to the appropriate imaging of athletes who may have cardiovascular complications from COVID-19.
Both are published in JACC: Cardiovascular Imaging.
“We were asked by the editors of JACC to submit this paper, and the impetus for it was the fact that there are so many athletes returning after being infected with COVID-19, we need to try and give guidance to cardiologists as to how best to evaluate these athletes,” Dermot Phelan, MD, PhD, Sanger Heart and Vascular Institute, Atrium Health, Charlotte, N.C., and lead author of the consensus statement, said in an interview.
The consensus statement acknowledges that information about the cardiovascular complications of COVID-19 continues to evolve. Meanwhile, pathologies such as myocarditis, pericarditis, and right ventricular dysfunction, in the absence of significant clinical symptoms, in athletes who have been affected by COVID-19 remain of considerable concern.
It also emphasizes the unique challenges the average cardiologist faces in distinguishing between what is normal for an athlete’s heart and what is true pathology after COVID-19 infection; details how different imaging modalities can help in screening, evaluating, and monitoring athletes with suspected cardiovascular complications of COVID-19 infection; and discusses the strengths and limitations of these modalities.
Finally, the consensus statement provides some well-needed guidance on return-to-play decision-making, for both the athlete and the clinician.
Athletic remodeling or covid-19 damage?
Athletes can develop certain cardiovascular characteristics because of their athletic activity, and sometimes, this can cloud the diagnostic picture.
“Is this change due to the effects of COVID-19, or is it just because this is an athlete’s heart? This was an international expert consensus, made up of sports cardiologists from all over the world who have a lot of experience in dealing with athletes,” Dr. Phelan said. “We were trying to relay the important information to the cardiologist who is not used to dealing with athletes on a day-to-day basis, as to what they might expect to find in that athlete, and what is not an expected finding and should be tested further.”
Phelan, a sports cardiologist, is familiar with what is normal for an athlete’s heart and what is pathology.
“We know that athletes, particularly long-term endurance athletes, develop changes in the heart that can affect not only the electrics but the structure of the heart, and sometimes, that overlaps with abnormalities with pathology. This can be a challenge for the nonsports cardiologist to differentiate,” he said.
Phelan and his group have written two other consensus documents on the management of cardiovascular problems that develop in some athletes who have been infected with COVID-19.
The first was published in May in JAMA Cardiology, and the second, which revised some of the original recommendations made in the first document, was published online Oct. 26 in JAMA Cardiology.
The first set of recommendations called for imaging studies to be done in all athletes, but the second set states that athletes who recover and are asymptomatic do not need extensive (and expensive) imaging tests.
“These two papers work hand in hand,” Dr. Phelan said. “In May, we had very little experience with COVID, and there was a lot of concern about hospitalized patients having a very high incidence of heart disease. We published those recommendations, but we recognized at the time that we had very little data and that we would reconsider once we had more experience with data.
“This current set of recommendations that we have put forth here are for those athletes who do need to get further testing, so it’s a step beyond,” Dr. Phelan added. “So the second iteration states that young athletes who had mild or no symptoms didn’t need to go through all of that cardiac testing, but others do need it.”
To do widespread cardiovascular imaging for many individuals would be very costly. Realistically, there are not that many centers in the United States that have all the sophisticated equipment required to do such testing, Dr. Phelan noted.
“One of our major points is difficulty obtaining the test, but also the cost; these are very expensive tests. There are limitations. They are useful when used in the correct context,” he said.
To play or not to play, that is the question
Partho P. Sengupta, MD, DM, had to answer that question for more than 50 young athletes who were returning to college at West Virginia University, anxious to be back with their teams and on the playing field. They had been infected with COVID-19 and needed to know when they could return to play.
Dr. Sengupta, who is also an author for the Phelan et al consensus statement on imaging, said there was a lot of pressure – from all the various stakeholders, and from anxious parents, worried college athletes, their teammates, and the university – to determine if the youngsters could return to play.
The fear was that COVID-19 infection left the young athlete’s heart vulnerable to myocarditis and, thus, sudden death on the playing field after strenuous activity.
“At the time we were doing this imaging, there was a lot of concern in the media, and papers were coming out reporting a lot of cardiac involvement or myocarditis associated with COVID-19. Nobody really knew what to do,” he explained.
“There were all kinds of questions, concerns. The parents were putting pressure on us, the athletes wanted to know, the teams, the university. So we put together a team and completed all of the examinations, including testing of blood markers, within a 2-week period. These young athletes, they’re scared, they’re worried and anxious, they don’t know what’s going to happen with their scholarship, so there was some urgency to this work,” Dr. Sengupta said.
“We had to screen all comers within a very short period. We had 54 consecutive patients, gave them full screening, full battery of tests, blood tests, all in a 2-week period,” he said.
Speed was of the essence, and Dr. Sengupta and his team rolled up their sleeves and got to work “We had to know who was safe to clear to return to play and who might need extra follow-up.”
Screening echocardiograms
They performed screening echocardiograms on 54 consecutive college athletes who had tested positive for COVID-19 on reverse transcription polymerase chain reaction nasal swab testing or who showed that they had IgG antibodies against COVID-19. The screening echocardiograms were done after the athletes had quarantined for at least 14 days and were no longer infectious.
Most (85%) were male, and the mean age was 19 years. A total of 16 (30%) athletes were asymptomatic, 36 (66%) reported mild COVID-19 related symptoms, and two (4%) reported moderate symptoms.
Of the 54 athletes who were initially screened with echocardiography, 48 (11 asymptomatic, 37 symptomatic), went on to have cardiac magnetic resonance imaging.
Results showed that more than half the athletes (27; 56.3%), showed some cardiac abnormality. The most common was pericardial late enhancement with associated pericardial effusion, affecting 19 (39.5%) athletes.
Of these, six (12.5%) had reduced global longitudinal strain (GLS) or an increased native T1.
One patient showed myocardial enhancement.
Additionally, seven athletes (14.6%) had reduced left ventricular ejection fraction or reduced GLS with or without increased native T1. Native T2 levels were normal in all subjects and no specific imaging features of myocardial inflammation were identified.
Participants were brought back to receive the results of their tests and to get an individualized plan about their safe return to play 3 to 5 weeks after they had ceased to be infectious with COVID-19.
“We saw pericardial inflammation that was resolving. We did not see any blood biomarkers to suggest that there was active inflammation going on,” he said. “We also did not see any muscle inflammation, but we did see pockets of fluid in over a third of our athletes.”
Fortunately, most were deemed able to get back to playing safely, despite having evidence of pericardial inflammation.
This was on strict condition that they be monitored very closely for any adverse events that might occur as they began to exercise again.
“Once they go back to the field to start exercising and practicing, it is under great supervision. We instructed all of our sports physicians and other team managers that these people need to be observed very carefully. So as long as they were asymptomatic, even though the signs of pericardial inflammation were there, if there were no signs of inflammation in the blood, we let them go back to play, closely monitored,” Dr. Sengupta said.
A small number remained very symptomatic at the end of the 5 weeks and were referred to cardiac rehabilitation, Dr. Sengupta said. “They were tired, fatigued, short of breath, even 5 weeks after they got over COVID, so we sent them for cardiac rehab to help them get conditioned again.”
The researchers plan to reevaluate and reimage all of the athletes in another 3 months to monitor their cardiac health.
Dr. Sengupta acknowledged the limitations of this single-center, nonrandomized, controlled report, but insists reports such as this add a bit more to what we are learning about COVID-19 every day.
“These kids were coming to us and asking questions. You have to use the best science you have available to you at that point in time. Some people ask why we did not have a control group, but how do you design a control population in the midst of a pandemic? The science may or may not be perfect, I agree, but the information we obtained is important,” he said.
“Right now, I don’t think we have enough science, and we are still learning. It is very difficult to predict who will develop the heart muscle disease or the pericardial disease,” Dr. Sengupta said. “We had to do our work quickly to give answers to the young athletes, their parents, their teammates, their university, as soon as possible, and we were doing this under pandemic conditions.”
The work was supported by the National Science Foundation National Institute of General Medical Sciences of the National Institutes of Health. Dr. Phelan reported no relevant financial relationships. Dr. Sengupta reported that he is a consultant for HeartSciences, Kencor Health, and Ultromics.
This article first appeared on Medscape.com.
Methotrexate and hydroxychloroquine split on cardiovascular outcomes in RA
No significant differences in major adverse cardiovascular events (MACE) emerged between methotrexate and hydroxychloroquine (HCQ) treatment in a comparison of adults 65 years or older with rheumatoid arthritis. However, researchers reported some elevation in risk for stroke in the methotrexate group and for myocardial infarction and heart failure in the HCQ group.
The primary outcome, a composite of MI, stroke, or cardiovascular death, had an incidence of 23.39 per 1,000 person-years in the methotrexate group versus 24.33 in the HCQ group in this observational study of nearly 60,000 people.
“These results suggest an importance of looking at different individual events of cardiovascular disease rather than the whole ‘CV’ disease only,” Seoyoung Kim, MD, said in an interview. “The other important thing is that the mortality was not significantly different between the two groups.”
For example, the researchers reported 256 cardiovascular-related deaths in the methotrexate group and 263 such deaths in the HCQ cohort.
Addressing a recognized risk
“It is well known that patients with rheumatoid arthritis have excessive morbidity and mortality,” Dr. Kim, of the division of rheumatology at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School in Boston, said at the virtual annual meeting of the American College of Rheumatology.
Among prior studies in this area, the Cardiovascular Inflammation Reduction Trial (CIRT) found no significant reduction in cardiovascular events among people taking methotrexate versus placebo. However, the study of 4,786 people was not specific to RA, Dr. Kim said. The lack of efficacy on this endpoint prompted researchers to stop CIRT early.
“So what does the conclusion of the CIRT trial mean for rheumatoid arthritis patients?” Dr. Kim asked.
To find out, she and colleagues compared risk of MACE among participants newly starting either methotrexate or HCQ. The study included 59,329 people aged 65 and older who were identified through Medicare claims data from 2008 to 2016. Mean age was 74 years, and 80% were women.
The investigators used propensity score matching to control for multiple covariates for demographics, other medications, and comorbidities. Use of other medications was similar between groups, including glucocorticoids, NSAIDs, and statins. Baseline cardiovascular morbidities likewise were well balanced, Dr. Kim said.
The hazard ratio for the primary MACE outcome was 0.96 (95% confidence interval, 0.86-1.08).
Secondary outcomes
MI was less common in the methotrexate group, for example, with an incidence of 8.49 per 1,000 person-years versus 10.68 per 1,000 person-years in the HCQ cohort. This finding was statically significant, Dr. Kim said, with a hazard ratio of 0.80 favoring methotrexate.
Heart failure also occurred less often in the methotrexate cohort, with an incidence rate of 8.57 per 1,000 person-years versus a rate of 14.24 in the HCQ group. The hazard ratio again favored methotrexate at 0.60.
In contrast, strokes were more common with methotrexate than with (incidence of 7.94 vs. 6.01 per 1,000 person-years).
Another secondary outcome, all-cause mortality, was not significantly different between groups. There were 821 deaths in the methotrexate group (28.65 per 1,000 person-years) and 796 deaths in the HCQ group (31.33 per 1,000 person-years).
Studying causality next?
Session moderator Maya Buch, MD, PhD, professor of rheumatology at the University of Manchester (England), asked Dr. Kim why she found significant differences in some secondary outcomes but not the primary composite endpoint.
“When we think of cardiovascular diseases, we tend to think of them all developing through the same mechanism. But perhaps the exact mechanism might not be identical,” Dr. Kim replied. The findings do not suggest causality because the study was observational, she added, “but maybe this will lead to a randomized, controlled trial.”
When asked for comment, Dr. Buch said that the study was “interesting” and “suggestive of differences in type of MACE between the two drugs evaluated,” but that there should be caution in interpreting the findings because of the lack of detailed information on RA disease and activity in claims databases, in addition to other factors, even though the investigators made adjustments for known differences through propensity score matching.
The division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital supported the study. Dr. Kim has received support for Brigham and Women’s Hospital for unrelated research from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb. Several other coauthors reported having financial relationships with pharmaceutical companies that make drugs for RA. Dr. Buch had no relevant disclosures.
SOURCE: He M et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 1993.
No significant differences in major adverse cardiovascular events (MACE) emerged between methotrexate and hydroxychloroquine (HCQ) treatment in a comparison of adults 65 years or older with rheumatoid arthritis. However, researchers reported some elevation in risk for stroke in the methotrexate group and for myocardial infarction and heart failure in the HCQ group.
The primary outcome, a composite of MI, stroke, or cardiovascular death, had an incidence of 23.39 per 1,000 person-years in the methotrexate group versus 24.33 in the HCQ group in this observational study of nearly 60,000 people.
“These results suggest an importance of looking at different individual events of cardiovascular disease rather than the whole ‘CV’ disease only,” Seoyoung Kim, MD, said in an interview. “The other important thing is that the mortality was not significantly different between the two groups.”
For example, the researchers reported 256 cardiovascular-related deaths in the methotrexate group and 263 such deaths in the HCQ cohort.
Addressing a recognized risk
“It is well known that patients with rheumatoid arthritis have excessive morbidity and mortality,” Dr. Kim, of the division of rheumatology at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School in Boston, said at the virtual annual meeting of the American College of Rheumatology.
Among prior studies in this area, the Cardiovascular Inflammation Reduction Trial (CIRT) found no significant reduction in cardiovascular events among people taking methotrexate versus placebo. However, the study of 4,786 people was not specific to RA, Dr. Kim said. The lack of efficacy on this endpoint prompted researchers to stop CIRT early.
“So what does the conclusion of the CIRT trial mean for rheumatoid arthritis patients?” Dr. Kim asked.
To find out, she and colleagues compared risk of MACE among participants newly starting either methotrexate or HCQ. The study included 59,329 people aged 65 and older who were identified through Medicare claims data from 2008 to 2016. Mean age was 74 years, and 80% were women.
The investigators used propensity score matching to control for multiple covariates for demographics, other medications, and comorbidities. Use of other medications was similar between groups, including glucocorticoids, NSAIDs, and statins. Baseline cardiovascular morbidities likewise were well balanced, Dr. Kim said.
The hazard ratio for the primary MACE outcome was 0.96 (95% confidence interval, 0.86-1.08).
Secondary outcomes
MI was less common in the methotrexate group, for example, with an incidence of 8.49 per 1,000 person-years versus 10.68 per 1,000 person-years in the HCQ cohort. This finding was statically significant, Dr. Kim said, with a hazard ratio of 0.80 favoring methotrexate.
Heart failure also occurred less often in the methotrexate cohort, with an incidence rate of 8.57 per 1,000 person-years versus a rate of 14.24 in the HCQ group. The hazard ratio again favored methotrexate at 0.60.
In contrast, strokes were more common with methotrexate than with (incidence of 7.94 vs. 6.01 per 1,000 person-years).
Another secondary outcome, all-cause mortality, was not significantly different between groups. There were 821 deaths in the methotrexate group (28.65 per 1,000 person-years) and 796 deaths in the HCQ group (31.33 per 1,000 person-years).
Studying causality next?
Session moderator Maya Buch, MD, PhD, professor of rheumatology at the University of Manchester (England), asked Dr. Kim why she found significant differences in some secondary outcomes but not the primary composite endpoint.
“When we think of cardiovascular diseases, we tend to think of them all developing through the same mechanism. But perhaps the exact mechanism might not be identical,” Dr. Kim replied. The findings do not suggest causality because the study was observational, she added, “but maybe this will lead to a randomized, controlled trial.”
When asked for comment, Dr. Buch said that the study was “interesting” and “suggestive of differences in type of MACE between the two drugs evaluated,” but that there should be caution in interpreting the findings because of the lack of detailed information on RA disease and activity in claims databases, in addition to other factors, even though the investigators made adjustments for known differences through propensity score matching.
The division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital supported the study. Dr. Kim has received support for Brigham and Women’s Hospital for unrelated research from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb. Several other coauthors reported having financial relationships with pharmaceutical companies that make drugs for RA. Dr. Buch had no relevant disclosures.
SOURCE: He M et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 1993.
No significant differences in major adverse cardiovascular events (MACE) emerged between methotrexate and hydroxychloroquine (HCQ) treatment in a comparison of adults 65 years or older with rheumatoid arthritis. However, researchers reported some elevation in risk for stroke in the methotrexate group and for myocardial infarction and heart failure in the HCQ group.
The primary outcome, a composite of MI, stroke, or cardiovascular death, had an incidence of 23.39 per 1,000 person-years in the methotrexate group versus 24.33 in the HCQ group in this observational study of nearly 60,000 people.
“These results suggest an importance of looking at different individual events of cardiovascular disease rather than the whole ‘CV’ disease only,” Seoyoung Kim, MD, said in an interview. “The other important thing is that the mortality was not significantly different between the two groups.”
For example, the researchers reported 256 cardiovascular-related deaths in the methotrexate group and 263 such deaths in the HCQ cohort.
Addressing a recognized risk
“It is well known that patients with rheumatoid arthritis have excessive morbidity and mortality,” Dr. Kim, of the division of rheumatology at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School in Boston, said at the virtual annual meeting of the American College of Rheumatology.
Among prior studies in this area, the Cardiovascular Inflammation Reduction Trial (CIRT) found no significant reduction in cardiovascular events among people taking methotrexate versus placebo. However, the study of 4,786 people was not specific to RA, Dr. Kim said. The lack of efficacy on this endpoint prompted researchers to stop CIRT early.
“So what does the conclusion of the CIRT trial mean for rheumatoid arthritis patients?” Dr. Kim asked.
To find out, she and colleagues compared risk of MACE among participants newly starting either methotrexate or HCQ. The study included 59,329 people aged 65 and older who were identified through Medicare claims data from 2008 to 2016. Mean age was 74 years, and 80% were women.
The investigators used propensity score matching to control for multiple covariates for demographics, other medications, and comorbidities. Use of other medications was similar between groups, including glucocorticoids, NSAIDs, and statins. Baseline cardiovascular morbidities likewise were well balanced, Dr. Kim said.
The hazard ratio for the primary MACE outcome was 0.96 (95% confidence interval, 0.86-1.08).
Secondary outcomes
MI was less common in the methotrexate group, for example, with an incidence of 8.49 per 1,000 person-years versus 10.68 per 1,000 person-years in the HCQ cohort. This finding was statically significant, Dr. Kim said, with a hazard ratio of 0.80 favoring methotrexate.
Heart failure also occurred less often in the methotrexate cohort, with an incidence rate of 8.57 per 1,000 person-years versus a rate of 14.24 in the HCQ group. The hazard ratio again favored methotrexate at 0.60.
In contrast, strokes were more common with methotrexate than with (incidence of 7.94 vs. 6.01 per 1,000 person-years).
Another secondary outcome, all-cause mortality, was not significantly different between groups. There were 821 deaths in the methotrexate group (28.65 per 1,000 person-years) and 796 deaths in the HCQ group (31.33 per 1,000 person-years).
Studying causality next?
Session moderator Maya Buch, MD, PhD, professor of rheumatology at the University of Manchester (England), asked Dr. Kim why she found significant differences in some secondary outcomes but not the primary composite endpoint.
“When we think of cardiovascular diseases, we tend to think of them all developing through the same mechanism. But perhaps the exact mechanism might not be identical,” Dr. Kim replied. The findings do not suggest causality because the study was observational, she added, “but maybe this will lead to a randomized, controlled trial.”
When asked for comment, Dr. Buch said that the study was “interesting” and “suggestive of differences in type of MACE between the two drugs evaluated,” but that there should be caution in interpreting the findings because of the lack of detailed information on RA disease and activity in claims databases, in addition to other factors, even though the investigators made adjustments for known differences through propensity score matching.
The division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital supported the study. Dr. Kim has received support for Brigham and Women’s Hospital for unrelated research from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb. Several other coauthors reported having financial relationships with pharmaceutical companies that make drugs for RA. Dr. Buch had no relevant disclosures.
SOURCE: He M et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 1993.
FROM ACR 2020
Virtual AHA 2020 may influence template for postpandemic scientific sessions
Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.
With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.
Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.
The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.
“I can’t commit to exactly what AHA sessions will look like next November; I think that’s still being looked at,” the organization’s president-elect Donald M. Lloyd-Jones, MD, ScM, chair of the AHA Committee on Scientific Sessions Programming, told theheart.org | Medscape Cardiology.
There’s no debating that a live conference is valuable “for career networking and other opportunities, so I don’t think we can do without it. That has to be an important part of it,” he said. “When we can safely, of course.”
Still, “the virtual platform democratizes, right? I mean, it just allows greater access for a broader audience, and I think that’s important, too,” said Lloyd-Jones, MD, Northwestern University Feinberg School of Medicine, Chicago.
“I don’t think we’ll ever go completely back to it being all in-person,” he said. “I think the world has changed, and we’ll have to adapt our platforms to recognize that.”
Online, at least, meeting registrants will get a better look at Anthony Fauci, MD, than one might from the middle rows of a vast ballroom-turned-auditorium. Fauci is scheduled to speak on “Public Health and Scientific Challenges” during the Main Event Session “Latest Insights on COVID 19 and Cardiovascular Disease,” slated for the meeting’s final day.
Fauci has directed the National Institute of Allergy and Infectious Diseases (NIAID) since 1984, and has been celebrated for his leadership roles in the battles against AIDS and Ebola virus. Today, his name is close to a household word for his service as a prominent though embattled member of the White House Coronavirus Task Force.
The virtual AHA sessions will feature a core collection of LBS presentations from often high-profile clinical trials and other studies the organization deems worthy of special attention. There are nine such presentations arrayed across the meeting’s five days — from Friday, November 13 to Tuesday, November 17 — at times listed in this story and throughout the AHA Scientific Session program synched with the Central Standard Time (CST) zone of the AHA’s home office in Dallas.
Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST
The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).
In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.
Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.
Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.
The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST
Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.
The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.
The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.
In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST
The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.
Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.
The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.
The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.
This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).
About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST
The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.
SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.
The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.
Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.
The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.
The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.
The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST
Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST
The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.
Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care
The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.
Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST
In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.
Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.
In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.
Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.
In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.
Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.
In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.
At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).
The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.
SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.
Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST
Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.
Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.
The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.
INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.
The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST
The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.
The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.
Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.
MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”
Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.
The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.
The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.
Lloyd-Jones and Fauci declared no conflicts.
This article first appeared on Medscape.com.
Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.
With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.
Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.
The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.
“I can’t commit to exactly what AHA sessions will look like next November; I think that’s still being looked at,” the organization’s president-elect Donald M. Lloyd-Jones, MD, ScM, chair of the AHA Committee on Scientific Sessions Programming, told theheart.org | Medscape Cardiology.
There’s no debating that a live conference is valuable “for career networking and other opportunities, so I don’t think we can do without it. That has to be an important part of it,” he said. “When we can safely, of course.”
Still, “the virtual platform democratizes, right? I mean, it just allows greater access for a broader audience, and I think that’s important, too,” said Lloyd-Jones, MD, Northwestern University Feinberg School of Medicine, Chicago.
“I don’t think we’ll ever go completely back to it being all in-person,” he said. “I think the world has changed, and we’ll have to adapt our platforms to recognize that.”
Online, at least, meeting registrants will get a better look at Anthony Fauci, MD, than one might from the middle rows of a vast ballroom-turned-auditorium. Fauci is scheduled to speak on “Public Health and Scientific Challenges” during the Main Event Session “Latest Insights on COVID 19 and Cardiovascular Disease,” slated for the meeting’s final day.
Fauci has directed the National Institute of Allergy and Infectious Diseases (NIAID) since 1984, and has been celebrated for his leadership roles in the battles against AIDS and Ebola virus. Today, his name is close to a household word for his service as a prominent though embattled member of the White House Coronavirus Task Force.
The virtual AHA sessions will feature a core collection of LBS presentations from often high-profile clinical trials and other studies the organization deems worthy of special attention. There are nine such presentations arrayed across the meeting’s five days — from Friday, November 13 to Tuesday, November 17 — at times listed in this story and throughout the AHA Scientific Session program synched with the Central Standard Time (CST) zone of the AHA’s home office in Dallas.
Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST
The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).
In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.
Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.
Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.
The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST
Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.
The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.
The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.
In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST
The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.
Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.
The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.
The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.
This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).
About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST
The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.
SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.
The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.
Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.
The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.
The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.
The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST
Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST
The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.
Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care
The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.
Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST
In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.
Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.
In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.
Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.
In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.
Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.
In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.
At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).
The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.
SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.
Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST
Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.
Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.
The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.
INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.
The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST
The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.
The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.
Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.
MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”
Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.
The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.
The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.
Lloyd-Jones and Fauci declared no conflicts.
This article first appeared on Medscape.com.
Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.
With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.
Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.
The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.
“I can’t commit to exactly what AHA sessions will look like next November; I think that’s still being looked at,” the organization’s president-elect Donald M. Lloyd-Jones, MD, ScM, chair of the AHA Committee on Scientific Sessions Programming, told theheart.org | Medscape Cardiology.
There’s no debating that a live conference is valuable “for career networking and other opportunities, so I don’t think we can do without it. That has to be an important part of it,” he said. “When we can safely, of course.”
Still, “the virtual platform democratizes, right? I mean, it just allows greater access for a broader audience, and I think that’s important, too,” said Lloyd-Jones, MD, Northwestern University Feinberg School of Medicine, Chicago.
“I don’t think we’ll ever go completely back to it being all in-person,” he said. “I think the world has changed, and we’ll have to adapt our platforms to recognize that.”
Online, at least, meeting registrants will get a better look at Anthony Fauci, MD, than one might from the middle rows of a vast ballroom-turned-auditorium. Fauci is scheduled to speak on “Public Health and Scientific Challenges” during the Main Event Session “Latest Insights on COVID 19 and Cardiovascular Disease,” slated for the meeting’s final day.
Fauci has directed the National Institute of Allergy and Infectious Diseases (NIAID) since 1984, and has been celebrated for his leadership roles in the battles against AIDS and Ebola virus. Today, his name is close to a household word for his service as a prominent though embattled member of the White House Coronavirus Task Force.
The virtual AHA sessions will feature a core collection of LBS presentations from often high-profile clinical trials and other studies the organization deems worthy of special attention. There are nine such presentations arrayed across the meeting’s five days — from Friday, November 13 to Tuesday, November 17 — at times listed in this story and throughout the AHA Scientific Session program synched with the Central Standard Time (CST) zone of the AHA’s home office in Dallas.
Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST
The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).
In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.
Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.
Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.
The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST
Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.
The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.
The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.
In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST
The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.
Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.
The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.
The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.
This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).
About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST
The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.
SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.
The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.
Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.
The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.
The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.
The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST
Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST
The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.
Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care
The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.
Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST
In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.
Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.
In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.
Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.
In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.
Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.
In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.
At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).
The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.
SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.
Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST
Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.
Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.
The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.
INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.
The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST
The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.
The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.
Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.
MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”
Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.
The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.
The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.
Lloyd-Jones and Fauci declared no conflicts.
This article first appeared on Medscape.com.
90-year-old man • dyspnea • lower extremity edema • limitations in daily activities • Dx?
THE CASE
An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.
The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.
The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.
Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.
The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).
THE DIAGNOSIS
The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.
Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.1 Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.1 (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.1) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.1 Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.
Continue to: Within 5 days...
Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.
DISCUSSION
There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.2
What the evidence shows. The TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.3 Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.3 Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).4 The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.5 Torsemide has also been shown to improve quality of life compared to furosemide.6
Preliminary results from the TORNADO trial,7 a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.8 The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).8 A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.8
A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.9
Continue to: Our patient
Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.
On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.
The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.
THE TAKEAWAY
A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.
A growing body of literature9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.
CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]
1. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-239.
2. Buggey J, Mentz RJ, Pitt B, et al. A reappraisal of loop diuretic choice in heart failure patients. Am Heart J. 2015;169:323-333.
3. Cosín J, Díez J; TORIC investigators. Torasemide in chronic heart failure: results of the TORIC study. Eur J Heart Fail. 2002;4:507-513.
4. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-520.
5. Mentz RJ, Hasselblad V, DeVore AD, et al. Torsemide versus furosemide in patients with acute heart failure (from the ASCEND-HF Trial). Am J Cardiol. 2016;117:404-411.
6. Müller K, Gamba G, Jaquet F, et al. Torasemide vs furosemide in primary care patients with chronic heart failure NYHA II to IV—efficacy and quality of life. Eur J Heart Fail. 2003;5:793-801.
7. Balsam P, Ozierański K, Tymińska A, et al. The impact of torasemide on haemodynamic and neurohormonal stress, and cardiac remodelling in heart failure—TORNADO: a study protocol for a randomized controlled trial. Trials. 2017;18:36.
8. Balsam P, Ozierański K, Marchel M, et al. Comparative effectiveness of torasemide versus furosemide in symptomatic therapy in heart failure patients: preliminary results from the randomized TORNADO trial. Cardiol J. 2019;26:661-668.
9. Abraham B, Megaly M, Sous M, et al. Meta-analysis comparing torsemide versus furosemide in patients with heart failure. Am J Cardiol. 2020;125:92-99.
10. Balsam P, Ozierański K, Kapłon-Cieślicka A, et al. Comparative analysis of long-term outcomes of torasemide and furosemide in heart failure patients in heart failure registries of the European Society of Cardiology. Cardiovasc Drugs Ther. 2019;33:77-86.
11. Täger T, Fröhlich H, Grundtvig M, et al. Comparative effectiveness of loop diuretics on mortality in the treatment of patients with chronic heart failure—a multicenter propensity score matched analysis. Int J Cardiol. 2019;289:83-90.
THE CASE
An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.
The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.
The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.
Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.
The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).
THE DIAGNOSIS
The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.
Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.1 Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.1 (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.1) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.1 Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.
Continue to: Within 5 days...
Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.
DISCUSSION
There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.2
What the evidence shows. The TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.3 Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.3 Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).4 The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.5 Torsemide has also been shown to improve quality of life compared to furosemide.6
Preliminary results from the TORNADO trial,7 a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.8 The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).8 A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.8
A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.9
Continue to: Our patient
Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.
On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.
The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.
THE TAKEAWAY
A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.
A growing body of literature9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.
CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]
THE CASE
An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.
The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.
The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.
Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.
The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).
THE DIAGNOSIS
The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.
Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.1 Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.1 (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.1) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.1 Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.
Continue to: Within 5 days...
Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.
DISCUSSION
There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.2
What the evidence shows. The TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.3 Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.3 Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).4 The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.5 Torsemide has also been shown to improve quality of life compared to furosemide.6
Preliminary results from the TORNADO trial,7 a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.8 The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).8 A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.8
A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.9
Continue to: Our patient
Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.
On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.
The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.
THE TAKEAWAY
A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.
A growing body of literature9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.
CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]
1. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-239.
2. Buggey J, Mentz RJ, Pitt B, et al. A reappraisal of loop diuretic choice in heart failure patients. Am Heart J. 2015;169:323-333.
3. Cosín J, Díez J; TORIC investigators. Torasemide in chronic heart failure: results of the TORIC study. Eur J Heart Fail. 2002;4:507-513.
4. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-520.
5. Mentz RJ, Hasselblad V, DeVore AD, et al. Torsemide versus furosemide in patients with acute heart failure (from the ASCEND-HF Trial). Am J Cardiol. 2016;117:404-411.
6. Müller K, Gamba G, Jaquet F, et al. Torasemide vs furosemide in primary care patients with chronic heart failure NYHA II to IV—efficacy and quality of life. Eur J Heart Fail. 2003;5:793-801.
7. Balsam P, Ozierański K, Tymińska A, et al. The impact of torasemide on haemodynamic and neurohormonal stress, and cardiac remodelling in heart failure—TORNADO: a study protocol for a randomized controlled trial. Trials. 2017;18:36.
8. Balsam P, Ozierański K, Marchel M, et al. Comparative effectiveness of torasemide versus furosemide in symptomatic therapy in heart failure patients: preliminary results from the randomized TORNADO trial. Cardiol J. 2019;26:661-668.
9. Abraham B, Megaly M, Sous M, et al. Meta-analysis comparing torsemide versus furosemide in patients with heart failure. Am J Cardiol. 2020;125:92-99.
10. Balsam P, Ozierański K, Kapłon-Cieślicka A, et al. Comparative analysis of long-term outcomes of torasemide and furosemide in heart failure patients in heart failure registries of the European Society of Cardiology. Cardiovasc Drugs Ther. 2019;33:77-86.
11. Täger T, Fröhlich H, Grundtvig M, et al. Comparative effectiveness of loop diuretics on mortality in the treatment of patients with chronic heart failure—a multicenter propensity score matched analysis. Int J Cardiol. 2019;289:83-90.
1. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-239.
2. Buggey J, Mentz RJ, Pitt B, et al. A reappraisal of loop diuretic choice in heart failure patients. Am Heart J. 2015;169:323-333.
3. Cosín J, Díez J; TORIC investigators. Torasemide in chronic heart failure: results of the TORIC study. Eur J Heart Fail. 2002;4:507-513.
4. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-520.
5. Mentz RJ, Hasselblad V, DeVore AD, et al. Torsemide versus furosemide in patients with acute heart failure (from the ASCEND-HF Trial). Am J Cardiol. 2016;117:404-411.
6. Müller K, Gamba G, Jaquet F, et al. Torasemide vs furosemide in primary care patients with chronic heart failure NYHA II to IV—efficacy and quality of life. Eur J Heart Fail. 2003;5:793-801.
7. Balsam P, Ozierański K, Tymińska A, et al. The impact of torasemide on haemodynamic and neurohormonal stress, and cardiac remodelling in heart failure—TORNADO: a study protocol for a randomized controlled trial. Trials. 2017;18:36.
8. Balsam P, Ozierański K, Marchel M, et al. Comparative effectiveness of torasemide versus furosemide in symptomatic therapy in heart failure patients: preliminary results from the randomized TORNADO trial. Cardiol J. 2019;26:661-668.
9. Abraham B, Megaly M, Sous M, et al. Meta-analysis comparing torsemide versus furosemide in patients with heart failure. Am J Cardiol. 2020;125:92-99.
10. Balsam P, Ozierański K, Kapłon-Cieślicka A, et al. Comparative analysis of long-term outcomes of torasemide and furosemide in heart failure patients in heart failure registries of the European Society of Cardiology. Cardiovasc Drugs Ther. 2019;33:77-86.
11. Täger T, Fröhlich H, Grundtvig M, et al. Comparative effectiveness of loop diuretics on mortality in the treatment of patients with chronic heart failure—a multicenter propensity score matched analysis. Int J Cardiol. 2019;289:83-90.
Rethinking daily aspirin for primary prevention
ILLUSTRATIVE CASE
A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.
Should this patient continue taking a daily aspirin for primary prevention of CVD?
Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).2 This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.3 (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.
STUDY SUMMARY
No reduction in risk, increased chance of bleeding
Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.1 The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and nonfatal ischemic stroke.
Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.
Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I2 = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.
WHAT’S NEW?
Study is emblematic of a shift away from daily aspirin
Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.
Continue to: The USPSTF guidelines...
The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.2
The 2019 American College of Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of bleeding should not be started on a daily aspirin.4
CAVEATS
Jury is still out regarding very high-risk patients
While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.
CHALLENGES TO IMPLEMENTATION
Patients may not be eager to give up an accepted practice
Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Mahmoud AN, Gad MM, Elgendy AY, et al. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J. 2019;40:607-617.
2. Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836-845.
3. Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized controlled trials. Lancet. 2009;373:1849-1860.
4. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74:e177-e232.
ILLUSTRATIVE CASE
A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.
Should this patient continue taking a daily aspirin for primary prevention of CVD?
Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).2 This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.3 (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.
STUDY SUMMARY
No reduction in risk, increased chance of bleeding
Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.1 The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and nonfatal ischemic stroke.
Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.
Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I2 = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.
WHAT’S NEW?
Study is emblematic of a shift away from daily aspirin
Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.
Continue to: The USPSTF guidelines...
The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.2
The 2019 American College of Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of bleeding should not be started on a daily aspirin.4
CAVEATS
Jury is still out regarding very high-risk patients
While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.
CHALLENGES TO IMPLEMENTATION
Patients may not be eager to give up an accepted practice
Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.
Should this patient continue taking a daily aspirin for primary prevention of CVD?
Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).2 This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.3 (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.
STUDY SUMMARY
No reduction in risk, increased chance of bleeding
Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.1 The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and nonfatal ischemic stroke.
Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.
Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I2 = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.
WHAT’S NEW?
Study is emblematic of a shift away from daily aspirin
Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.
Continue to: The USPSTF guidelines...
The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.2
The 2019 American College of Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of bleeding should not be started on a daily aspirin.4
CAVEATS
Jury is still out regarding very high-risk patients
While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.
CHALLENGES TO IMPLEMENTATION
Patients may not be eager to give up an accepted practice
Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Mahmoud AN, Gad MM, Elgendy AY, et al. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J. 2019;40:607-617.
2. Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836-845.
3. Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized controlled trials. Lancet. 2009;373:1849-1860.
4. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74:e177-e232.
1. Mahmoud AN, Gad MM, Elgendy AY, et al. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J. 2019;40:607-617.
2. Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836-845.
3. Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized controlled trials. Lancet. 2009;373:1849-1860.
4. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74:e177-e232.
PRACTICE CHANGER
Do not routinely use aspirin for primary prevention of cardiovascular disease (CVD). There is no identifiable mortality benefit for those without established CVD—regardless of risk factors. And aspirin therapy increases the risk of major bleeding.
STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis of 11 randomized trials involving 157,248 patients who received aspirin for primary prevention.1
Mahmoud AN, Gad MM, Elgendy AY, et al. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J. 2019;40:607-617.
