Anuradha Lala, MD, Associate Professor of Medicine, Cardiology, Associate Professor, Population Health Science and Policy at Icahn School of Medicine at Mount Sinai. Robert John Mentz, MD, Associate Professor of MedicineAssociate Professor in Population Health Sciences, Member in the Duke Clinical Research Institute at Duke University. In this video, she speaks about the article #WordsMatter Continued: Moving from “Candidacy” To “Benefit Derived”.
As professionals who care for patients suffering from heart failure, we are all too familiar with such phrases.
Consider yourself a patient who has been told that you are not a "candidate" for a particular therapy. Is this language likely to make you feel marginalized? Ill-fated? Denied? Such difficulties have recently come to light in relation to the need for COVID-19 vaccination prior to being listed for heart transplantation.
The definition of the candidate, according to Merriam-Webster Dictionary, covers the following:
a:
one who wants to, is nominated for, or qualifies for a position, membership, or honor
b:
one who is likely to go through or be chosen for something specific
Complex integrated decision-making, as is prevalent in clinical practice, contributes to our patients' "fate." However, this is another important proof of how much our #wordsmatter. Our goal is not to determine fate. It is not to favor one patient over another or to refuse anyone life-saving treatment. Rather, our aim and role are to serve as resource stewards while also assisting in determining the amount to which a patient will benefit from a certain therapy (based on aggregated experience and data).
So we've been debating... Why not phrase it that way if that is the intention?
Consider the following phrase in place of the preceding:
"Mr. X is unlikely to benefit from heart transplantation at this time due to active colon cancer (which would grow due to post-transplant immunosuppression)."
Or
"Ms. Y is unlikely to benefit appreciably from sustained LVAD installation at this time due to past stroke, severe peripheral vascular disease, and recurrent gastrointestinal bleeding, all of which put her at high risk of post-surgical complications and mortality."
These rephrasing issues also apply to medical therapies:
"The patient is unlikely to benefit from sacubitril/valsartan at this time due to significant symptomatic hypotension - which may worsen after medication administration."
Articulating why an individual may or may not benefit from therapy at a certain time allows us to communicate more effectively - not only with patients and their loved ones but also among physicians. Furthermore, rather than conveying judgmental feelings, this approach emphasizes nonmaleficence, in which decisions are balanced against all benefits, risks, and consequences. Circumstances change, and assessments based on the current level of expected benefit from a therapy might be evaluated at individualized intervals.
Heart failure is a disease with unacceptably high morbidity and fatality rates. Let us focus on how we relay and convey information as we attempt to enhance therapeutic outcomes. At JCF, we know that our #wordsmatter — to patients, their families, each other, and the communities we serve – whether it's changing "failure" to "function", replacing "non-compliance" with "barriers to adherence", or shifting from "candidacy" to "extent of benefit obtained."
Scott Wright, MD, Professor of Medicine, Chair of the IRB at the Mayo Clinic. In this video, he speaks about the Phase III ORION-9,10, and 11 Studies.
In summary:
This is a placebo-controlled, double-blind, randomized Phase III research in patients with ASCVD with increased LDL-C despite the maximum tolerated dose of LDL-C lowering treatments to assess the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection (s). The study will be conducted in multiple locations across the United States.
Jonathan P. Piccini, MD, Associate Professor at Duke University. In this video, he speaks about the Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study.
Summarization:
Backstory -
The use of direct-acting oral anticoagulants for stroke prevention in atrial fibrillation is restricted due to bleeding concerns. Asundexian, a new oral small molecule activated coagulation factor XIa (FXIa) inhibitor, has the potential to minimize thrombosis while having no effect on haemostasis. In individuals with atrial fibrillation, we wanted to find the best dose of asundexian and compare the risk of bleeding to that of apixaban.
Techniques -
We compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and an increased bleeding risk in this randomised, double-blind, phase 2 dose-finding study. The research was carried out at 93 sites across 14 nations, including 12 in Europe, Canada, and Japan. Using an interactive web response system, participants were randomly assigned (1:1:1) to a treatment group, with randomization stratified by whether patients were using a direct-acting oral anticoagulant prior to the study's start. A double-dummy design was used to achieve masking, with participants receiving both the assigned treatment and a placebo that mimicked the non-assigned therapy. The primary outcome was a composite of major or clinically relevant non-major bleeding based on International Society of Thrombosis and Haemostasis criteria, which was examined in all patients who received at least one dose of study medication. This study is listed on ClinicalTrials.gov as NCT04218266 and EudraCT as 2019-002365-35.
Results -
862 patients were registered between January 30, 2020, and June 21, 2021. 755 individuals were randomized to treatment at random. Because two participants (assigned to asundexian 20 mg) did not take any trial medicine, 753 patients were included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The participants' mean age was 737 years (SD 83), 309 (41%) were women, 216 (29%) had chronic renal disease, and the mean CHA2DS2-VASc score was 39 (13%). Asundexian 20 mg inhibited FXIa activity by 81 percent at trough concentrations and 90 percent at peak concentrations; asundexian 50 mg inhibited FXIa activity by 92 percent at trough concentrations and 94 percent at peak concentrations. The incidence proportions for the primary endpoint were 050 (90 percent confidence interval 014–168) for asundexian 20 mg (three events), 016 (001–099) for asundexian 50 mg (one event), and 033 (009–097) for pooled asundexian (four occurrences) against apixaban (six events). Any adverse event occurred at the same rate in all three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban.
Explanation -
In patients with atrial fibrillation, the FXIa inhibitor asundexian at dosages of 20 mg and 50 mg once daily led in decreased rates of bleeding compared to normal apixaban treatment, with near-complete in vivo FXIa suppression.
Jean Marie Ruddy, MD, Vascular surgeon with clinical interests in lower extremity venous insufficiency and atherosclerotic disease of the abdominal aorta, carotid artery, and extremity vessels at Medical University of South Carolina. Anne Kroman DO, PhD, Cardiac Electrophysiologist at Medical University of South Carolina. Ryan Tedford, MD, Dr. Peter C. Gazes Endowed Chair in Heart Failure; Professor of Medicine at Medical University of South Carolina; Chief, Heart Failure; Medical Director, Cardiac Transplantation; Director, AHFTX Fellowship Program. In this video, she and her colleagues speak about the article MUSC doctors first at academic medical center to perform ‘game-changing’ new heart failure device procedure.
Two MUSC Health doctors are the first at an academic medical center and just the second in the world to employ a new, minimally invasive procedure to implant a heart failure therapy device – and, in an unusual turn of events, they're both women in traditionally male-dominated specialties.
Jean Marie Ruddy, M.D., a vascular surgeon, is the lead investigator at the MUSC site for the testing of this innovative implantation procedure for Barostim. Anne Kroman, D.O., Ph.D., a cardiac electrophysiologist, is the site co-principal investigator for the BATwire percutaneous implant research employing the Barostim Neo System.
Following successful trials headed by MUSC Health cardiologist Michael Zile, M.D., Barostim received breakthrough device approval from the US Food and Drug Administration in 2019. The device stimulates the nerve that regulates blood pressure with electrical impulses, causing the blood arteries to relax.
Although the gadget cannot cure heart failure, it can significantly enhance patients' quality of life. According to cardiologist Ryan Tedford, M.D., section chief of heart failure, medical director of cardiac transplantation, and professor in the College of Medicine, it's intended for patients who aren't getting enough benefit from medication but aren't sick enough for a heart pump or heart transplant.
On Thursday, his patient became the first at MUSC Health to undergo the innovative type of implantation.
To insert the electrode, the first method of implantation required a vascular surgeon to create an incision in the patient's neck. However, in a "engineering achievement," the new approach being investigated would allow the device to be implanted through a wire, according to Ruddy. Kroman explained that it is comparable to how pacemaker wires are now implanted.
Instead, the surgeons used ultrasound to locate the region of the blood vessel where the proper nerve is located, then advanced a needle into place to guide the wire through. The whole thing took around an hour and a half. Although it is believed that this will become an outpatient treatment, participants must be hospitalized overnight for the duration of the experiment.
Patients who have already had the device implanted have reported an improvement in their quality of life, according to Ruddy and Kroman. Patients are typically short of breath before the treatment, even while walking about, and may have given up cherished activities – Ruddy noted one patient who was eager to return to fishing.
According to Tedford, there are a substantial number of people who could benefit from this type of treatment, either because they aren't sick enough for more serious procedures or because they don't match the criteria for those surgeries.
Prakriti Gaba, MD, Cardiology Fellow at Harvard Medical School. In this video, she speaks about the Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.
Outline
Origins:
REDUCE-IT was a double-blind experiment in which 8,179 statin-treated individuals with reduced low-density lipoprotein cholesterol and moderately increased triglycerides were randomly assigned to icosapent ethyl (IPE) or placebo. The primary objective, including death from cardiovascular (CV) causes, was significantly reduced. It was uncertain what effect IPE has on people who had previously had a myocardial infarction (MI).
Goals:
In REDUCE-IT, we wanted to look at the effect of IPE on ischemic events in patients who had previously had a MI.
Methodology:
We conducted post-hoc analysis on patients who had previously experienced MI. CV mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina were the primary endpoints. The most important secondary outcome was CV death, MI, or stroke.
Outcomes:
A total of 3,693 patients had a previous MI. With IPE vs placebo, the primary endpoint was lowered from 26.1 percent to 20.2 percent; HR: 0.74 (95 percent CI: 0.65-0.85; P = 0.00001). The main secondary endpoint was lowered from 18.0% to 13.3%; HR: 0.71 (95 percent CI: 0.61-0.84; P = 0.00006). There was also a substantial 35% relative risk reduction in total ischemia events (P = 0.0000001), 34% reduction in MI (P = 0.00009), 30% reduction in CV death (P = 0.01), and a 20% reduction in all-cause mortality (P = 0.054), despite a modest rise in atrial fibrillation. Sudden cardiac death and cardiac arrest were also drastically reduced by 40% and 56%, respectively.
Inferences:
Patients in REDUCE-IT with a history of recent MI who were treated with IPE had large and significant relative and absolute risk reductions in ischemic events, including CV mortality. (AMR101 Study to Assess Its Ability to Reduce Cardiovascular Events in High-Risk Patients With Hypertriglyceridemia and Statin Use. The primary goal is to assess the effect of 4 g/day AMR101 on the occurrence of a first major cardiovascular event. NCT01492361; [REDUCE-IT])
Andrea Natale M.D., F.A.C.C., F.H.R.S., F.E.S.C., Executive Medical Director, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center at Texas Cardiac Arrhythmia. In this video, he speaks about Endocardial Scar-Homogenization With vs Without Epicardial Ablation in VT Patients With Ischemic Cardiomyopathy.
\n\n
Observation -
\n\n
Goals:
\n\n
The authors of this study compared the success of scar homogeneity with a mixed (epicarddial + endocardial) vs endocardial-only technique for ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) at 5 years of follow-up.
\n\n
Origins:
\n\n
The best ablation strategy for achieving long-term success in VT patients with ICM is unknown.
\n\n
Methodology:
\n\n
Patients with ICM who underwent VT ablation at our center were divided into two groups: endocardial + epicardial scar homogenization and endocardial scar homogenization. Patients who had already undergone open heart surgery were not eligible. Despite the fact that all group 1 patients were noninducible following endocardial ablation, epicardial ablation was done. All patients received bipolar substrate mapping with conventional scar settings of >1.5 mV for normal tissue and 0.5 mV for severe scar. The procedure\'s endpoint in both groups was noninducibility of monomorphic VT. Implantable device interrogations were performed on patients every 4 months for 5 years.
\n\n
Outcomes:
\n\n
The study included 361 participants (n = 70 in group 1 and n = 291 in group 2). At 5 years, 81.4 percent (n = 57/70) of group 1 patients and 66.3 percent (n = 193/291) of group 2 patients were arrhythmia-free (P = 0.01). Anti-arrhythmic medications (AAD) were used by 26 of 57 (45.6 percent) and 172 of 193 (89.1 percent) of the patients in groups 1 and 2 (log-rank P 0.001). Endo-epicarddial scar homogeneity was linked with a substantial reduction in arrhythmia recurrence after controlling for age, gender, and obstructive sleep apnea (HR: 0.48; 95 percent CI: 0.27-0.86; P = 0.02).
\n\n
Observations:
\n\n
Despite being noninducible following endocardial ablation, epicardial substrate was found in all group 1 patients in this series of patients with ICM and VT. Furthermore, when compared to endocardial ablation alone, combined endo-epicarddial scar homogeneity was linked with a much higher success rate at 5 years of follow-up and a significantly lower demand for antiarrhythmic medicines after the treatment.
Michelle M. Kittleson, MD, PhD, Director, Heart Failure Research, Director, Post Graduate Medical Education in Heart Failure and Transplantation, Professor of Medicine at Cedars-Sinai. In this video, she speaks about A Clinician's Guide to the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure.
The American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) 2022 Guideline for the Management of Heart Failure provides clinicians with patient-centered recommendations for preventing, diagnosing, and managing heart failure patients (HF). 1 The document, the result of nearly two years of work by the writing committee's 26 members, includes 159 pages of text (including 40 pages of references), 14 sections, 33 tables, 15 figures, and 192 recommendations—a daunting task for any clinician interested in optimizing the care of patients with HF. What is the best strategy to approach a new policy?
Ibrahim Sultan, MD, Associate Professor of Cardiothoracic Surgery, Director, Center for Thoracic Aortic Disease, Surgical Director, Center for Heart Valve Disease, UPMC Heart and Vascular Institute at UPMC. In this video, he speaks about Transfusion of non–red blood cell blood products does not reduce survival following cardiac surgery.
Outline
Goals:
The evidence suggests that patients undergoing cardiac surgery who receive perioperative packed red blood cell (pRBC) transfusions have an increased risk of death. The current investigation is to determine whether there is a link between non–pRBC blood product transfusions and higher mortality.
Methodology:
Patients who underwent heart surgery between 2010 and 2018 were included in data from our center's Society of Thoracic Surgeons database. Patients requiring pRBC infusions or experiencing circulatory arrest were excluded. Propensity matching (1:1; caliper = 0.2 times the standard deviation of logit of propensity score) was used. Cox regression and Kaplan–Meier estimates were utilized. This study excluded individuals with cardiac transplants, ventricular assist devices, transcatheter aortic valves, and circulatory arrest.
Outcomes:
A total of 8042 patients met the analytic requirements. 395 patients requiring perioperative non–pRBC blood products (platelets, fresh-frozen plasma, and cryoprecipitate) were matched with 395 nontransfusion patients using propensity matching (1:1), resulting in equitable patient cohorts. The median duration of follow-up was 4.5 (3.0-6.4) years. Platelets (327 [82.8 percent]), fresh-frozen plasma (141 [35.7 percent]), and cryoprecipitate were given to patients (60 [15.2 percent ]). There was no statistically significant difference in postoperative mortality (6 [1.5%] vs 4 [1.0%]; P =.52). The transfusion group had higher rates of reoperation (20 [5.0 percent] vs 8 [2.0 percent]; P.02) and prolonged ventilation (36 [9.1 percent] vs 19 [4.8 percent]; P.02). Blood product use was strongly linked with emergent surgery (odds ratio [OR] 2.86 [1.72-4.78]; P.001), intra-aortic balloon pump (OR 3.24 [1.64-6.39]; P.001), and multivalve surgery (OR 4.34 [2.83-6.67]; P.001). Blood product transfusion (hazard ratio: 1.15 [0.89-1.48]; P =.3) was not related with an increased risk of death. There was no significant difference in long-term survival between groups.
Findings:
Those undergoing cardiac surgery who require blood products alone, without pRBC transfusion, have comparable postoperative and long-term survival to patients who do not require blood products. These findings are based on a small number of patients, and further research will help to improve the generalizability of these findings.
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Ibrahim Sultan, MD, Associate Professor of Cardiothoracic Surgery, Director, Center for Thoracic Aortic Disease, Surgical Director, Center for Heart Valve Disease, UPMC Heart and Vascular Institute at UPMC. In this video, he speaks about Transfusion of non–red blood cell blood products does not reduce survival following cardiac surgery.
Outline
Goals:
The evidence suggests that patients undergoing cardiac surgery who receive perioperative packed red blood cell (pRBC) transfusions have an increased risk of death. The current investigation is to determine whether there is a link between non–pRBC blood product transfusions and higher mortality.
Methodology:
Patients who underwent heart surgery between 2010 and 2018 were included in data from our center's Society of Thoracic Surgeons database. Patients requiring pRBC infusions or experiencing circulatory arrest were excluded. Propensity matching (1:1; caliper = 0.2 times the standard deviation of logit of propensity score) was used. Cox regression and Kaplan–Meier estimates were utilized. This study excluded individuals with cardiac transplants, ventricular assist devices, transcatheter aortic valves, and circulatory arrest.
Outcomes:
A total of 8042 patients met the analytic requirements. 395 patients requiring perioperative non–pRBC blood products (platelets, fresh-frozen plasma, and cryoprecipitate) were matched with 395 nontransfusion patients using propensity matching (1:1), resulting in equitable patient cohorts. The median duration of follow-up was 4.5 (3.0-6.4) years. Platelets (327 [82.8 percent]), fresh-frozen plasma (141 [35.7 percent]), and cryoprecipitate were given to patients (60 [15.2 percent ]). There was no statistically significant difference in postoperative mortality (6 [1.5%] vs 4 [1.0%]; P =.52). The transfusion group had higher rates of reoperation (20 [5.0 percent] vs 8 [2.0 percent]; P.02) and prolonged ventilation (36 [9.1 percent] vs 19 [4.8 percent]; P.02). Blood product use was strongly linked with emergent surgery (odds ratio [OR] 2.86 [1.72-4.78]; P.001), intra-aortic balloon pump (OR 3.24 [1.64-6.39]; P.001), and multivalve surgery (OR 4.34 [2.83-6.67]; P.001). Blood product transfusion (hazard ratio: 1.15 [0.89-1.48]; P =.3) was not related with an increased risk of death. There was no significant difference in long-term survival between groups.
Findings:
Those undergoing cardiac surgery who require blood products alone, without pRBC transfusion, have comparable postoperative and long-term survival to patients who do not require blood products. These findings are based on a small number of patients, and further research will help to improve the generalizability of these findings.
Prakriti Gaba, MD, Cardiology Fellow at Harvard Medical School. In this video, she speaks about the Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.
Outline
Origins:
REDUCE-IT was a double-blind experiment in which 8,179 statin-treated individuals with reduced low-density lipoprotein cholesterol and moderately increased triglycerides were randomly assigned to icosapent ethyl (IPE) or placebo. The primary objective, including death from cardiovascular (CV) causes, was significantly reduced. It was uncertain what effect IPE has on people who had previously had a myocardial infarction (MI).
Goals:
In REDUCE-IT, we wanted to look at the effect of IPE on ischemic events in patients who had previously had a MI.
Methodology:
We conducted post-hoc analysis on patients who had previously experienced MI. CV mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina were the primary endpoints. The most important secondary outcome was CV death, MI, or stroke.
Outcomes:
A total of 3,693 patients had a previous MI. With IPE vs placebo, the primary endpoint was lowered from 26.1 percent to 20.2 percent; HR: 0.74 (95 percent CI: 0.65-0.85; P = 0.00001). The main secondary endpoint was lowered from 18.0% to 13.3%; HR: 0.71 (95 percent CI: 0.61-0.84; P = 0.00006). There was also a substantial 35% relative risk reduction in total ischemia events (P = 0.0000001), 34% reduction in MI (P = 0.00009), 30% reduction in CV death (P = 0.01), and a 20% reduction in all-cause mortality (P = 0.054), despite a modest rise in atrial fibrillation. Sudden cardiac death and cardiac arrest were also drastically reduced by 40% and 56%, respectively.
Inferences:
Patients in REDUCE-IT with a history of recent MI who were treated with IPE had large and significant relative and absolute risk reductions in ischemic events, including CV mortality. (AMR101 Study to Assess Its Ability to Reduce Cardiovascular Events in High-Risk Patients With Hypertriglyceridemia and Statin Use. The primary goal is to assess the effect of 4 g/day AMR101 on the occurrence of a first major cardiovascular event. NCT01492361; [REDUCE-IT])
Scott Wright, MD, Professor of Medicine, Chair of the IRB at the Mayo Clinic. In this video, he speaks about the Phase III ORION-9,10, and 11 Studies.
In summary:
This is a placebo-controlled, double-blind, randomized Phase III research in patients with ASCVD with increased LDL-C despite the maximum tolerated dose of LDL-C lowering treatments to assess the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection (s). The study will be conducted in multiple locations across the United States.
Anuradha Lala, MD, Associate Professor of Medicine, Cardiology, Associate Professor, Population Health Science and Policy at Icahn School of Medicine at Mount Sinai. Robert John Mentz, MD, Associate Professor of MedicineAssociate Professor in Population Health Sciences, Member in the Duke Clinical Research Institute at Duke University. In this video, she speaks about the article #WordsMatter Continued: Moving from “Candidacy” To “Benefit Derived”.
As professionals who care for patients suffering from heart failure, we are all too familiar with such phrases.
Consider yourself a patient who has been told that you are not a "candidate" for a particular therapy. Is this language likely to make you feel marginalized? Ill-fated? Denied? Such difficulties have recently come to light in relation to the need for COVID-19 vaccination prior to being listed for heart transplantation.
The definition of the candidate, according to Merriam-Webster Dictionary, covers the following:
a:
one who wants to, is nominated for, or qualifies for a position, membership, or honor
b:
one who is likely to go through or be chosen for something specific
Complex integrated decision-making, as is prevalent in clinical practice, contributes to our patients' "fate." However, this is another important proof of how much our #wordsmatter. Our goal is not to determine fate. It is not to favor one patient over another or to refuse anyone life-saving treatment. Rather, our aim and role are to serve as resource stewards while also assisting in determining the amount to which a patient will benefit from a certain therapy (based on aggregated experience and data).
So we've been debating... Why not phrase it that way if that is the intention?
Consider the following phrase in place of the preceding:
"Mr. X is unlikely to benefit from heart transplantation at this time due to active colon cancer (which would grow due to post-transplant immunosuppression)."
Or
"Ms. Y is unlikely to benefit appreciably from sustained LVAD installation at this time due to past stroke, severe peripheral vascular disease, and recurrent gastrointestinal bleeding, all of which put her at high risk of post-surgical complications and mortality."
These rephrasing issues also apply to medical therapies:
"The patient is unlikely to benefit from sacubitril/valsartan at this time due to significant symptomatic hypotension - which may worsen after medication administration."
Articulating why an individual may or may not benefit from therapy at a certain time allows us to communicate more effectively - not only with patients and their loved ones but also among physicians. Furthermore, rather than conveying judgmental feelings, this approach emphasizes nonmaleficence, in which decisions are balanced against all benefits, risks, and consequences. Circumstances change, and assessments based on the current level of expected benefit from a therapy might be evaluated at individualized intervals.
Heart failure is a disease with unacceptably high morbidity and fatality rates. Let us focus on how we relay and convey information as we attempt to enhance therapeutic outcomes. At JCF, we know that our #wordsmatter — to patients, their families, each other, and the communities we serve – whether it's changing "failure" to "function", replacing "non-compliance" with "barriers to adherence", or shifting from "candidacy" to "extent of benefit obtained."
Jonathan P. Piccini, MD, Associate Professor at Duke University. In this video, he speaks about the Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study.
Summarization:
Backstory -
The use of direct-acting oral anticoagulants for stroke prevention in atrial fibrillation is restricted due to bleeding concerns. Asundexian, a new oral small molecule activated coagulation factor XIa (FXIa) inhibitor, has the potential to minimize thrombosis while having no effect on haemostasis. In individuals with atrial fibrillation, we wanted to find the best dose of asundexian and compare the risk of bleeding to that of apixaban.
Techniques -
We compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and an increased bleeding risk in this randomised, double-blind, phase 2 dose-finding study. The research was carried out at 93 sites across 14 nations, including 12 in Europe, Canada, and Japan. Using an interactive web response system, participants were randomly assigned (1:1:1) to a treatment group, with randomization stratified by whether patients were using a direct-acting oral anticoagulant prior to the study's start. A double-dummy design was used to achieve masking, with participants receiving both the assigned treatment and a placebo that mimicked the non-assigned therapy. The primary outcome was a composite of major or clinically relevant non-major bleeding based on International Society of Thrombosis and Haemostasis criteria, which was examined in all patients who received at least one dose of study medication. This study is listed on ClinicalTrials.gov as NCT04218266 and EudraCT as 2019-002365-35.
Results -
862 patients were registered between January 30, 2020, and June 21, 2021. 755 individuals were randomized to treatment at random. Because two participants (assigned to asundexian 20 mg) did not take any trial medicine, 753 patients were included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The participants' mean age was 737 years (SD 83), 309 (41%) were women, 216 (29%) had chronic renal disease, and the mean CHA2DS2-VASc score was 39 (13%). Asundexian 20 mg inhibited FXIa activity by 81 percent at trough concentrations and 90 percent at peak concentrations; asundexian 50 mg inhibited FXIa activity by 92 percent at trough concentrations and 94 percent at peak concentrations. The incidence proportions for the primary endpoint were 050 (90 percent confidence interval 014–168) for asundexian 20 mg (three events), 016 (001–099) for asundexian 50 mg (one event), and 033 (009–097) for pooled asundexian (four occurrences) against apixaban (six events). Any adverse event occurred at the same rate in all three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban.
Explanation -
In patients with atrial fibrillation, the FXIa inhibitor asundexian at dosages of 20 mg and 50 mg once daily led in decreased rates of bleeding compared to normal apixaban treatment, with near-complete in vivo FXIa suppression.
Andrea Natale M.D., F.A.C.C., F.H.R.S., F.E.S.C., Executive Medical Director, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center at Texas Cardiac Arrhythmia. In this video, he speaks about Endocardial Scar-Homogenization With vs Without Epicardial Ablation in VT Patients With Ischemic Cardiomyopathy.
\n\n
Observation -
\n\n
Goals:
\n\n
The authors of this study compared the success of scar homogeneity with a mixed (epicarddial + endocardial) vs endocardial-only technique for ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) at 5 years of follow-up.
\n\n
Origins:
\n\n
The best ablation strategy for achieving long-term success in VT patients with ICM is unknown.
\n\n
Methodology:
\n\n
Patients with ICM who underwent VT ablation at our center were divided into two groups: endocardial + epicardial scar homogenization and endocardial scar homogenization. Patients who had already undergone open heart surgery were not eligible. Despite the fact that all group 1 patients were noninducible following endocardial ablation, epicardial ablation was done. All patients received bipolar substrate mapping with conventional scar settings of >1.5 mV for normal tissue and 0.5 mV for severe scar. The procedure\'s endpoint in both groups was noninducibility of monomorphic VT. Implantable device interrogations were performed on patients every 4 months for 5 years.
\n\n
Outcomes:
\n\n
The study included 361 participants (n = 70 in group 1 and n = 291 in group 2). At 5 years, 81.4 percent (n = 57/70) of group 1 patients and 66.3 percent (n = 193/291) of group 2 patients were arrhythmia-free (P = 0.01). Anti-arrhythmic medications (AAD) were used by 26 of 57 (45.6 percent) and 172 of 193 (89.1 percent) of the patients in groups 1 and 2 (log-rank P 0.001). Endo-epicarddial scar homogeneity was linked with a substantial reduction in arrhythmia recurrence after controlling for age, gender, and obstructive sleep apnea (HR: 0.48; 95 percent CI: 0.27-0.86; P = 0.02).
\n\n
Observations:
\n\n
Despite being noninducible following endocardial ablation, epicardial substrate was found in all group 1 patients in this series of patients with ICM and VT. Furthermore, when compared to endocardial ablation alone, combined endo-epicarddial scar homogeneity was linked with a much higher success rate at 5 years of follow-up and a significantly lower demand for antiarrhythmic medicines after the treatment.
Jean Marie Ruddy, MD, Vascular surgeon with clinical interests in lower extremity venous insufficiency and atherosclerotic disease of the abdominal aorta, carotid artery, and extremity vessels at Medical University of South Carolina. Anne Kroman DO, PhD, Cardiac Electrophysiologist at Medical University of South Carolina. Ryan Tedford, MD, Dr. Peter C. Gazes Endowed Chair in Heart Failure; Professor of Medicine at Medical University of South Carolina; Chief, Heart Failure; Medical Director, Cardiac Transplantation; Director, AHFTX Fellowship Program. In this video, she and her colleagues speak about the article MUSC doctors first at academic medical center to perform ‘game-changing’ new heart failure device procedure.
Two MUSC Health doctors are the first at an academic medical center and just the second in the world to employ a new, minimally invasive procedure to implant a heart failure therapy device – and, in an unusual turn of events, they're both women in traditionally male-dominated specialties.
Jean Marie Ruddy, M.D., a vascular surgeon, is the lead investigator at the MUSC site for the testing of this innovative implantation procedure for Barostim. Anne Kroman, D.O., Ph.D., a cardiac electrophysiologist, is the site co-principal investigator for the BATwire percutaneous implant research employing the Barostim Neo System.
Following successful trials headed by MUSC Health cardiologist Michael Zile, M.D., Barostim received breakthrough device approval from the US Food and Drug Administration in 2019. The device stimulates the nerve that regulates blood pressure with electrical impulses, causing the blood arteries to relax.
Although the gadget cannot cure heart failure, it can significantly enhance patients' quality of life. According to cardiologist Ryan Tedford, M.D., section chief of heart failure, medical director of cardiac transplantation, and professor in the College of Medicine, it's intended for patients who aren't getting enough benefit from medication but aren't sick enough for a heart pump or heart transplant.
On Thursday, his patient became the first at MUSC Health to undergo the innovative type of implantation.
To insert the electrode, the first method of implantation required a vascular surgeon to create an incision in the patient's neck. However, in a "engineering achievement," the new approach being investigated would allow the device to be implanted through a wire, according to Ruddy. Kroman explained that it is comparable to how pacemaker wires are now implanted.
Instead, the surgeons used ultrasound to locate the region of the blood vessel where the proper nerve is located, then advanced a needle into place to guide the wire through. The whole thing took around an hour and a half. Although it is believed that this will become an outpatient treatment, participants must be hospitalized overnight for the duration of the experiment.
Patients who have already had the device implanted have reported an improvement in their quality of life, according to Ruddy and Kroman. Patients are typically short of breath before the treatment, even while walking about, and may have given up cherished activities – Ruddy noted one patient who was eager to return to fishing.
According to Tedford, there are a substantial number of people who could benefit from this type of treatment, either because they aren't sick enough for more serious procedures or because they don't match the criteria for those surgeries.
Michelle M. Kittleson, MD, PhD, Director, Heart Failure Research, Director, Post Graduate Medical Education in Heart Failure and Transplantation, Professor of Medicine at Cedars-Sinai. In this video, she speaks about A Clinician's Guide to the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure.
The American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) 2022 Guideline for the Management of Heart Failure provides clinicians with patient-centered recommendations for preventing, diagnosing, and managing heart failure patients (HF). 1 The document, the result of nearly two years of work by the writing committee's 26 members, includes 159 pages of text (including 40 pages of references), 14 sections, 33 tables, 15 figures, and 192 recommendations—a daunting task for any clinician interested in optimizing the care of patients with HF. What is the best strategy to approach a new policy?
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Barry H. Greenberg, MD, is a board-certified cardiologist and a pioneer in the field of heart failure internationally. At UC San Diego Health, he is the director of the Advanced Heart Failure Treatment Program. In this podcast Dr. Greenberg discusses the Prognostic Value of Global Longitudinal Strain in Patients With Heart Failure With Improved Ejection Fraction.
https://www.jacc.org/doi/10.1016/j.jchf.2021.08.007
Abstract
The researchers wanted to see if global longitudinal strain (GLS) is linked to the natural history of patients with heart failure (HF) who had a better ejection fraction (HFimpEF).
Background
The ejection fraction (EF) of the left ventricle (LV) generally improves in people who have a low EF. Patients with HFimpEF, on the other hand, have a wide range of clinical outcomes. GLS, a sensitive biomarker of LV systolic function, could help this population estimate the risk of future occurrences.
Methods
Retrospective examination of HF patients with LVEF greater than 40% on index echocardiography who had LVEF less than 40% on initial study and improved by 10%. On index echocardiography, GLS was measured using 2-dimensional speckle-tracking software. The primary outcome was the time it took for cardiovascular death or HF hospitalization/emergency treatment to occur for the first time.
Results
The median absolute values of GLS (aGLS) and LVEF from index echocardiogram were 12.7 percent (IQR: 10.8 percent-14.7 percent) and 52 percent (IQR: 46 percent -58 percent) for the 289 patients with HFimpEF, respectively. The primary endpoint occurred less frequently in patients with aGLS above the median than below it (21 percent vs 34 percent; P = 0.014); HR of 0.51; 95 percent CI: 0.33-0.81; P = 0.004; HR of 0.51; 95 percent CI: 0.33-0.81; P = 0.004; HR of 0.51; 95 percent CI: 0.33-0.81; P = 0.004; HR of 0.51; 95 percent CI: 0.3 When aGLS on index echocardiogram was assessed as a continuous variable, each 1% increase was associated with a lower likelihood of the composite endpoint; HR 0.86; 95 percent CI: 0.79-0.93; P 0.001, an association that persisted after multivariable adjustment; HR 0.90; 95 percent CI: 0.82-0.97; P = 0.01. Lower aGLS was linked to a higher chance of LVEF worsening.
Conclusions
GLS is a powerful predictor of future HF episodes and heart function impairment in patients with HFimpEF.
Dr. Tamer M.A. Mohamed's works as Assistant Professor of Medicine at the University of Louisville. His research has focused on innovative mechanisms and therapeutics for cardiac hypertrophy and heart failure in animal models for the past 12 years. Translation of those results into human medication therapy for cardiac disease is one of Dr. Mohamed's primary focuses. In this video Dr. Mohamed discusses the Transient Cell Cycle Induction in Cardiomyocytes to Treat Subacute Ischemic Heart Failure.
https://www.researchgate.net/publication/358010698_Transient_Cell_Cycle_Induction_in_Cardiomyocytes_to_Treat_Subacute_Ischemic_Heart_Failure
Background: After a myocardial infarction (MI), the heart's regeneration ability is impaired. In vitro and in vivo, ectopic introduction of Cdk1/CyclinB1 and Cdk4/CyclinD1 complexes (4F) stimulates cardiomyocyte proliferation in 15-20% of infected cardiomyocytes and improves cardiac function after MI in mice, according to a prior study. Methods: On a single cell level, we used temporal single-cell RNAseq to identify the essential reprogramming steps during 4F-induced cardiomyocyte growth. We also hoped to begin the first preclinical testing of 4F gene therapy as a candidate for the treatment of ischemia-induced heart failure utilizing rat and pig models of ischemic heart failure. Results: At 48 hours after infection with 4F, full cell cycle reprogramming was observed in 15% of the cardiomyocyte population, which was primarily associated with sarcomere disassembly and metabolic reprogramming (n=3/timepoint/group), as revealed by temporal bulk and single-cell RNAseq and further biochemical validations of mature hiPS-CMs treated with LacZ or 4F adenoviruses. A polycistronic non-integrating lentivirus (NIL) expressing 4F was used to achieve transient overexpression of the protein in cardiomyocytes. Each NIL is directed by the TNNT2 promoter (TNNT2-4Fpolycistronic-NIL). In rats (n=10) and pigs (n=6-7), TNNT2-4Fpolycistronic-NIL or control virus was administered intramyocardially one week after MI. TNNT2-4Fpolycistronic-NIL-treated animals demonstrated a substantial improvement in left ventricular ejection fraction and scar size four weeks after injection when compared to control virus-treated animals. Rats given TNNT2-4Fpolycistronic-NIL demonstrated a persistent improvement in cardiac function four months following therapy, with no signs of cardiac arrhythmias or systemic carcinogenesis (n=10/group). Conclusions: Using an unique transitory and cardiomyocyte-specific viral construct, this study gives mechanistic insights into the process of forced cardiomyocyte proliferation and increases the clinical practicality of this technique by limiting the carcinogenic potential of cell cycle factors.
Dr. Tamer M.A. Mohamed's works as Assistant Professor of Medicine at the University of Louisville. His research has focused on innovative mechanisms and therapeutics for cardiac hypertrophy and heart failure in animal models for the past 12 years. Translation of those results into human medication therapy for cardiac disease is one of Dr. Mohamed's primary focuses. In this podcast Dr. Mohamed discusses the Transient Cell Cycle Induction in Cardiomyocytes to Treat Subacute Ischemic Heart Failure.
https://www.researchgate.net/publication/358010698_Transient_Cell_Cycle_Induction_in_Cardiomyocytes_to_Treat_Subacute_Ischemic_Heart_Failure
Background: After a myocardial infarction (MI), the heart's regeneration ability is impaired. In vitro and in vivo, ectopic introduction of Cdk1/CyclinB1 and Cdk4/CyclinD1 complexes (4F) stimulates cardiomyocyte proliferation in 15-20% of infected cardiomyocytes and improves cardiac function after MI in mice, according to a prior study. Methods: On a single cell level, we used temporal single-cell RNAseq to identify the essential reprogramming steps during 4F-induced cardiomyocyte growth. We also hoped to begin the first preclinical testing of 4F gene therapy as a candidate for the treatment of ischemia-induced heart failure utilizing rat and pig models of ischemic heart failure. Results: At 48 hours after infection with 4F, full cell cycle reprogramming was observed in 15% of the cardiomyocyte population, which was primarily associated with sarcomere disassembly and metabolic reprogramming (n=3/timepoint/group), as revealed by temporal bulk and single-cell RNAseq and further biochemical validations of mature hiPS-CMs treated with LacZ or 4F adenoviruses. A polycistronic non-integrating lentivirus (NIL) expressing 4F was used to achieve transient overexpression of the protein in cardiomyocytes. Each NIL is directed by the TNNT2 promoter (TNNT2-4Fpolycistronic-NIL). In rats (n=10) and pigs (n=6-7), TNNT2-4Fpolycistronic-NIL or control virus was administered intramyocardially one week after MI. TNNT2-4Fpolycistronic-NIL-treated animals demonstrated a substantial improvement in left ventricular ejection fraction and scar size four weeks after injection when compared to control virus-treated animals. Rats given TNNT2-4Fpolycistronic-NIL demonstrated a persistent improvement in cardiac function four months following therapy, with no signs of cardiac arrhythmias or systemic carcinogenesis (n=10/group). Conclusions: Using an unique transitory and cardiomyocyte-specific viral construct, this study gives mechanistic insights into the process of forced cardiomyocyte proliferation and increases the clinical practicality of this technique by limiting the carcinogenic potential of cell cycle factors.
Dr. Oscar M. Westin is a PHd student and a medical doctor at the University Hospital of Copenhagen's Heart Center, Rigshospitalet. In this video Dr. Westin speaks on the Two Decades of Cardiac Amyloidosis: A Danish Nationwide Study.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Cardiac amyloidosis (CA) is linked to a bad prognosis. According to screening studies, CA is often ignored, especially in the elderly. Recent therapy improvements have drawn attention to the condition, although data on CA epidemiology across time is scarce.
Objectives
The goal of this study was to describe all CA patients in Denmark from 1998 to 2017, as well as to look at changes in patient characteristics over time.
Methods
In Danish nationwide registries, all patients with any kind of amyloidosis diagnosed between 1998 and 2017, as well as their comorbidities and medication, were identified. Any diagnosis code for amyloidosis paired with a diagnosis code for heart failure, cardiomyopathy, or atrial fibrillation, or a procedural code for pacemaker installation, regardless of order, was classified as CA. The index date was established as the date on which those criteria were met. By index date, patients were separated into 5-year segments. We also included control subjects (1:4 ratio) from the general population as a comparison.
Results
619 patients met the CA requirements. The median age at baseline grew from 67.4 years (interquartile range [IQR]: 53.9-75.2 years) in 1998-2002 to 72.3 years in 2013-2017. (IQR: 66.0-79.3 years). Male patients grew from 62.1 percent to 66.2 percent of all patients. In the Danish population aged 65 years, the incidence of CA increased from 0.88 to 3.56 per 100,000 person-years, whereas 2-year mortality reduced from 82.6 percent (IQR: 69.9 percent -90.5 percent) to 50.2 percent (IQR: 43.1 percent -56.9 percent ). CA patients had a considerably greater mortality rate than control participants (log-rank test: P 0.0001).
Conclusions
On a nationwide scale, CA, as defined in this study, was becoming more prevalent. The rising number of male patients and median age indicate that wild-type transthyretin amyloidosis is to blame. The fact that earlier, less advanced illnesses are being recognized more often could explain the lower fatality rate.
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