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Dr. Benjamin Hibbert MD. University of Ottawa Heart Institute - Speaks on Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock

Link to Abstract:
https://www.nejm.org/doi/full/10.1056/NEJMoa2026845?query=cardiology


CONTEXT: Cardiogenic shock is linked to a high rate of morbidity and mortality. Although inotropic support is a common part of medical treatment for cardiogenic shock, there is no data to guide inotropic drug selection in clinical practice.

METHODS: In a double-blind study, individuals with cardiogenic shock were randomly randomized to receive milrinone or dobutamine. In-hospital death from any cause, resuscitated cardiac arrest, cardiac transplantation or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke identified by a neurologist, or beginning of renal replacement therapy were the major outcomes. Individual components of the primary composite result were included as secondary outcomes.

RESULTS: A total of 192 people were enrolled (96 in each group). The primary result did not differ substantially between the treatment groups; 47 participants (49%) in the milrinone group and 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95 percent confidence interval [CI], 0.69 to 1.19; P=0.47) experienced a primary outcome event. Secondary outcomes such as in-hospital death (37 percent and 43 percent of participants, respectively; relative risk, 0.85; 95 percent CI, 0.60 to 1.21), resuscitated cardiac arrest (7 percent and 9 percent; hazard ratio, 0.78; 95 percent CI, 0.29 to 2.07), and mechanical circulatory support (12 percent) showed no significant differences between the groups (22 percent and 17 percent ; hazard ratio, 1.39; 95 percent CI, 0.73 to 2.67).

CONCLUSIONS: There was no significant difference between milrinone and dobutamine in individuals with cardiogenic shock in terms of the key composite outcome or crucial secondary outcomes. (Funded by the Ontario Academic Health Sciences Centres Alternative Funding Plan's Innovation Fund; ClinicalTrials.gov number: NCT03207165. opens in new tab.)

Dr. Gary F. Marklin is a pulmonologist in Saint Louis, Missouri, and is affiliated with St. Alexius Hospital-Broadway Campus and Mercy Hospital South.

Dr. Marklin has more than 36 years of experience practicing internal medicine and is a seasoned critical care physician. He has worked as a consulting physician at Saint Anthony's Medical Center in the fields of intensive care, respiratory care, and pulmonary care.

Link to Article: https://clinicaltrials.gov/ct2/show/NCT04415658?cond=Cardiac+Death&phase=23&draw=2&rank=24#contacts


Background: Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid stimulating hormone) may contribute to hemodynamic instability and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy.

Methods: This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12-hours or saline placebo. The primary study hypothesis is that thyroxine treatment results in more hearts transplanted. Additional outcome measures are time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography.

Discussion: This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment for organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether treatment increases hearts transplanted and/or provides other hemodynamic benefits.

June-Wha Rhee, MD, cardiologist with specialized clinical and research training in cardiovascular drug toxicity and pharmacogenomics, from Stanford Hospital and Clinics speaks about Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers (Breast and Prostate) on the Cardiovascular System: Effects and Modifications.

Link to Abstract:
https://www.ahajournals.org/doi/pdf/10.1161/HCG.0000000000000082

Overview:

The main causes of mortality in the United States are cardiovascular disease and cancer, with hormone-dependent tumors (breast and prostate cancer) being the most frequent noncutaneous malignancies in women and men, respectively. The hormonal (endocrine-related) treatments that are used to treat both malignancies enhance survival rates, but they significantly raise cardiovascular morbidity and death in survivors. This consensus statement outlines the dangers of particular hormone treatments used to treat breast and prostate cancer, as well as an evidence-based strategy for preventing and detecting negative cardiovascular events. The cardiovascular effects of various durations of hormonal therapy, the cardiovascular risks associated with combinations of newer generations of more intensive hormonal treatments, and the specific cardiovascular risks that affect individuals of various races/ethnicities are all highlighted as areas of uncertainty.

Finally, a multidisciplinary approach to the application of lifestyle and pharmaceutical treatments for risk reduction and management is emphasized both during and after active therapy.

Prof. Elmir Omerovic, MD- Department of Cardiology, Sahlgrenska University Hospital, University of Gothenburg speaks about Long-term mortality in patients with ischaemic heart failure revascularized with coronary artery bypass grafting or percutaneous coronary intervention: insights from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).


Link to Abstract:
https://academic.oup.com/eurheartj/article/42/27/2657/6282431


Abstract

Aims:
The goal of this study was to evaluate coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) for the treatment of heart failure caused by ischemic heart disease.

Methods and outcomes:
We looked at all-cause mortality after CABG or PCI in patients with heart failure and multivessel disease (coronary artery stenosis >50 percent in two arteries or the left main) who had coronary angiography in Sweden between 2000 and 2018. To account for known and unknown confounders, we utilized propensity score-adjusted logistic and Cox proportional-hazards regressions, as well as an instrumental variable model. In a hierarchical database, multilevel modeling was employed to account for clustering of observations. There were 2509 patients in all, with 82.9 percent of them being men; 35.8% of them had diabetes, and 34.7 percent had experienced a previous myocardial infarction. The average age was 68.1 9.4 years (47.8% were over 70), and 64.9 percent of the participants had three-vessel or left main illness. PCI was the primary indicated therapy in 56.2 percent of cases, while CABG was the primary designated therapy in 43.8 percent. The median period between follow-ups was 3.9 years (range: 1 day to 10 years). There were a total of 1010 deaths. CABG was associated with a decreased risk of death compared to PCI [odds ratio (OR) 0.62; 95 percent confidence interval (CI) 0.41–0.96; P = 0.031]. Death risk increased linearly with quintiles of hospitals where PCI was the preferred revascularization procedure (OR 1.27, 95 percent CI 1.17–1.38, Ptrend 0.001).

Conclusion:
Long-term survival was higher following CABG than after PCI in patients with ischemic heart failure.

Dr. Stefan Anker, MD Charité - From University of Medicine Berlin
Speaks about Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

Link to Abstract: ​
https://www.nejm.org/doi/full/10.1056/NEJMoa2110956?query=cardiology


BACKGROUND: Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has been shown to improve cardiorenal outcomes in patients with stage 3 or 4 chronic kidney disease (CKD) and significant albuminuria, as well as type 2 diabetes. Finerenone's usage in patients with type 2 diabetes and other forms of CKD is unknown.

METHODS:

In this double-blind trial, patients with CKD and type 2 diabetes were randomly randomized to either finerenone or a placebo. Patients with a urinary albumin-to-creatinine ratio of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 of body surface area (stage 2 to (stage 1 or 2 CKD). Patients were given renin–angiotensin system blockers that had been adjusted to the maximal dose on the manufacturer's label that did not cause unacceptable side effects before randomization. The primary outcome was a composite of mortality from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure, as measured by a time-to-event analysis. The first secondary outcome was a composite of kidney failure, a prolonged drop in eGFR of at least 40% from baseline, or death due to renal causes. Adverse occurrences reported by investigators were used to assess safety.

RESULTS:

Randomization was performed on a total of 7437 subjects. During a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and 519 of 3666 patients (14.2%) in the placebo group (hazard ratio, 0.87; 95 percent confidence interval [CI], 0.76 to 0.98; P=0.03), with the benefit driven primarily by a lower incidence of hospitalization for hepatitis C. (hazard ratio, 0.71; 95 percent CI, 0.56 to 0.90). 350 patients (9.5%) in the finerenone group and 395 (10.8%) in the placebo group experienced the secondary composite result (hazard ratio, 0.87; 95 percent CI, 0.76 to 1.01). There was no significant difference in the overall frequency of adverse events across groups. Finerenone (1.2 percent) had a greater rate of hyperkalemia-related trial regimen discontinuation than placebo (0.8 percent) (0.4 percent ).

CONCLUSIONS:

Finerenone medication improved cardiovascular outcomes in patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria when compared to placebo. (Funded by Bayer; NCT02545049 on ClinicalTrials.gov for FIGARO-DKD. opens in new tab.)

Gherardo Finocchiaro, MD Consultant Cardiologist, Inherited Cardiac Conditions, Cardiac Imaging, Sports Cardiology at St George's University Hospitals NHS Foundation Trust speaks about The Labyrinth Of Nomenclature In Cardiology. Eternal Dilemmas And New Challenges On The Horizon In The Personalized Medicine Era.

Link to Article:
https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2088

Introduction
The search for precise terminology and classifications is a continual source of conundrums in medicine and research, and it's especially relevant and contentious in the field of cardiovascular disorders.

The cardiology community is split between customized medicine and imprecise diagnostic categories, which are frequently used to describe non-entities. The exponential expansion in information, which coincides with a continual rise in complexity, has sparked a dispute about the appropriate classifications. The need to capture each individual's fundamental physiological or pathological characteristics may conflict with the need to categorize, as no categorization can fully portray the complexity of reality.

We will explore how terminology and classifications in the field of cardiovascular illnesses originated, as well as the key nomenclature deadlocks, in this perspective. We'll start with the philosophical foundations of this long-running argument before moving on to practical issues, using the topic of cardiomyopathies and heart failure as an illustration (HF).

Classifications and terminologies A lengthy trip through philosophy

The terminology refers to the verbal labels that are linked to an idea, and it has long been a source of conundrums in philosophy, science, and, of course, medicine. Terminology and classifications have been a source of contention since at least the fifth century BC. 1 Plato devotes a large section of his dialogues to the so-called "theory of forms" or "theory of ideas," in which he attempts to answer the central question "What is the essence of things?" He believed that the object was fundamentally the shape and that the phenomena (v: to emerge) were shadows of the form [the difference between essence and phenomena is powerfully depicted in Plato's Republic allegory of the cave].

Aristotle had a more empirical approach to reality. He proposed that abstract ideas are descriptions of objects that have been categorized based on their characteristics. He proposes the concept of characteristics as categories. This perspective rejects Platonic extreme realism in favor of a view of the universal as a characteristic within a thing and everything else that is unique to it. A substance's essence is its substantial form, and as only universals can be defined, substantial forms are universals.

Several philosophers and theologians of the Middle Ages (William of Ockam, Roscellinus, and others) rejected realistic ideas in favor of nominalism. While Plato (and Platonists) believed that distinct objects are the way they are because of the presence of a universal, nominalism holds that only particulars exist and that they are derived from our representational system or language (the way we speak of the world). Human conventions tend to classify objects or ideas into categories that exist because we choose to name them rather than because they are universal abstractions.

Immanuel Kant, more recently, proposed that universals are not actual, but rather concepts in rational persons' minds, basic categories of pure reason organically related to the rationality of the individual making the judgment. Ludwig Wittgenstein, a twentieth-century philosopher, focused his work primarily on the relationship between language and reality, acknowledging the great limitations of terminology, which is highly context-dependent and assumes a private meaning that is understood differently by individuals participating in a conversation.

Modern taxonomy was originally created in the 16th and 17th centuries, long before the 20th-century era of clinical descriptions, such as Standardized Nomenclature of Diseases (SND) and International Classification of Diseases (ICDS) (ICD).

Cardiomyopathies are an example of this.

In an attempt to capture the complex character of cardiomyopathies, several definitions and categories have been proposed. The European Society of Cardiology (ESC) offers a categorization based on a phenotypic expression that supports an empiric approach.

These categories reflect commendable attempts that will undoubtedly give some clarity in the area. Classifications make use of categories and names that should capture the many manifestations of a cardiac ailment while also capturing the core of the disease. This assumption's inherent failure can be described in a variety of ways. The term "hypertrophic cardiomyopathy" (HCM) refers to a pathological condition characterized by cardiac hypertrophy. We're seeing more and more cases where there are signs and symptoms of HCM, such as lateral deep T-wave inversion or a family history of HCM, yet the wall thickness at the left ventricular apex is just 11 or 12 mm (not surpassing the international criterion of 15 mm). We would undoubtedly be reluctant to label the aforementioned ailment HCM if we strictly read rules and the importance of the term. Similar difficulties arise when interpreting post-mortem cardiac findings in decedents of sudden death with (or without) hypertrophy: Some researchers believe that HCM can be diagnosed without hypertrophy but with significant myocardial disarray (a profound derangement of normal myocyte alignment on histology); on the other hand, unexplained hypertrophy in the setting of sudden death should not be considered part of the HCM disease spectrum.

Other cardiomyopathies are in the same boat. The term "arrhythmogenic right ventricular cardiomyopathy" conjures up images of a disease marked by arrhythmias and affecting the right ventricle. Longitudinal investigations have revealed that, while a large number of individuals suffer from arrhythmias, many of them have a fairly steady trajectory. Furthermore, it appears that blaming simply the right ventricle is insufficient, as the left ventricle has lately been found to be damaged as well (or maybe the only chamber affected).

A phenotypic categorization (or nomenclature) has the inherent danger of halting the diagnostic process at first sight and incorrectly classifying a morphologic feature as a particular illness.

Heart failure is one example.

Because HF is a condition rather than a disease, a certain level of nomenclature complexity is usually unavoidable. HF with decreased ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF) are the three categories defined by the ESC recommendations based on left ventricular ejection fraction (HFpEF). This categorization is clear, although it does have some limits. The ejection fraction can not distinguish between aetiologies, thus a patient with a low left ventricular ejection fraction might have ischemic heart disease or hereditary dilated cardiomyopathy.

Even greater causal variability may be seen in the HFpEF group, which could be termed a "nosographic trap." Many randomized clinical trials in people with HFrEF have yielded significant results. The same cannot be true for HFpEF sufferers. Although the causes for this discrepancy are unknown, the nosographic instability that characterizes this condition might be a major factor in clinical trial failure in HFpEF. Indeed, HFpEF is a depiction of a 'non-thing,' not a description of clinical reality. The term 'HFpEF' has the potential to be too broad, including a wide range of clinical entities, each needing unique therapy. This language impasse may be to blame for the failure of clinical trials evaluating the efficacy of various medicines in HFpEF.

Differential diagnosis is a problem.

Differential diagnosis is difficult in the field of HF and cardiomyopathies since distinct disease entities can have the same phenotype and a single illness might have multiple phenotypes. A growing number of research are attempting to evaluate and compare certain characteristics in order to show that they are useful in distinguishing A from B. This experimental method, on the other hand, is based on a dichotomous and mutually exclusive interpretation of reality, and hence assumes that A and B are distinct things. Nature, on the other hand, seldom follows binary laws. The challenge of differential diagnosis between physiological adaptation to exercise and cardiomyopathies is an example. We must acknowledge that an athlete may have cardiomyopathy, and that a patient with cardiomyopathy can be an athlete, and that the phenotypic is a mix of physiological and pathological processes (Figure 2). For instance, the assumption that A and B (for example, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy) are two distinct clinical entities is a postulate: A and B are distinct because we arbitrarily and customarily choose to designate them by different names (following the aforementioned nominalist vision).

Differential diagnosis of athlete's heart and dilated cardiomyopathy (DCM) using a dichotomous approach (A). Because it is possible to combine DCM and physiological adaptation to exercise, a strategy focused on the awareness of "shades of grey" rather than a mutually exclusive interpretation of clinical data would accommodate for the limitations of our knowledge based on empiric reality (phenotype) (B). LBBB, left bundle branch block; LV, left ventricle; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; ECG, electrocardiogram; FH, family history; LBBB, left bundle branch block; LV, left ventricle; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; LVH, left ventricular hypertrophy; LVH, left ventricular hypert RV, right ventricle; RVH, right ventricular hypertrophy; MRI, magnetic resonance imaging SCD is for sudden cardiac death; TWI stands for T-wave inversion; and VO2 stands for oxygen consumption.

Ankeet S. Bhatt, MD and Muthiah Vaduganathan, MD, MPH Division of Cardiology, Brigham and Women's Hospital speaks about Prioritizing Dissemination and Implementation Science in Cardiometabolic Medicine - CONNECTing the Dots.

Link to Article:
https://jamanetwork.com/journals/jama/article-abstract/2782323


Heart failure with a low ejection fraction is a classic example of scientific breakthroughs that have yet to be completely realized in clinical practice. Stepwise development in discovery research has resulted in the release of numerous disease-modifying medicines in recent years. 1 It is predicted that full adoption of modern multidrug regimens will result in considerable increases in lifespan and event-free survival. 2 However, there are still significant gaps in the appropriate use of these treatments. 3 Other common cardiometabolic diseases, such as diabetes, chronic renal disease, atherosclerotic cardiovascular disease, and obesity, have similar implementation gaps. Because of these flaws in execution, the population-level impact that these treatments may provide has been restricted.

Mathilde Vermeer, MS, Ph.D. Student at UMCG Cardiology Research Institute speaks about Publication: Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.


Link to Article:
https://www.jci.org/articles/view/140615

Link to Abstract:
https://www.science.org/doi/10.1126/scitranslmed.abd1817

Abstract:

By skipping the first start codon, the start codon c.1A>G mutation in KLHL24, which encodes the ubiquitin ligase KLHL24, leads in the deletion of 28 N-terminal amino acids (KLHL24-N28). KLHL24-N28 causes gain of function in skin, producing epidermolysis bullosa simplex by overly targeting intermediate filament keratin-14 for proteasomal breakdown (EBS). Dilated cardiomyopathy (DCM) is found in the majority of EBS patients, although the pathogenic process in the heart remains unclear. We predicted that KLHL24-N28 causes excessive desmin degradation, resulting in DCM, because desmin is the cardiac analog of keratin-14. Dynamically loaded engineering heart tissues (dyn-EHTs) were created from cardiomyocytes produced from human induced pluripotent stem cells (hiPSCs) from two patients and three nonfamilial controls. Desmin protein levels were shown to be tenfold lower in patient-derived dyn-EHTs, which corresponded to decreased desmin levels seen in patients' explanted hearts. Tissue dilatation, reduced mitochondrial function, lower force values, and higher cardiomyocyte stress followed this. KLHL24-mediated desmin degradation was verified in HEK293 transfection tests. Desmin protein levels were restored in patient-derived dyn-EHTs via KLHL24 RNA interference or direct desmin overexpression, restoring shape and function. To summarize, the presence of KLHL24-N28 in cardiomyocytes causes excessive desmin degradation, which affects tissue shape and function and may be avoided by restoring desmin protein levels.

Overview:

Inherited cardiomyopathies are common illnesses with a wide range of causes. New causal genes are found on a regular basis. We think we were the first to discover a connection between the KLHL24:c.1A>G mutation (Met1Val), which causes epidermolysis bullosa simplex (EBS) in the skin and dilated cardiomyopathy (DCM) in the heart (1). Around 33 individuals with identical gain-of-function mutations leading to DCM have been documented since our first finding (2, 3). Despite these reports, the causal consequences of KLHL24 gain-of-function mutations in cardiomyopathy have yet to be determined.



The KLHL24:c.1A>G mutation is one of five known methionine start codon mutations in ubiquitin ligase KLHL24 (c.1A>G, c.1A>T, c.2T>C, c.3G>A, and c.3G>T), which results in the loss of 28 N-terminal amino acids (KLHL24-N28) by bypassing the first start codon. KLHL24 acts as a ubiquitin ligase in the epidermis, creating a protein complex with CUL3 and RBX1 to facilitate keratin 14 degradation. Through KLHL24 auto-ubiquitination, this process is kept in check. The mutant protein KLHL24-N28, on the other hand, is unable to perform auto-ubiquitination and hence is more stable. Excessive ubiquitination and, as a result, breakdown of keratin 14 occurs, resulting in skin fragility.

Keratins (KRT) are intermediate filaments (IFs) proteins that are required for the cytoskeletal network of keratinocytes in the skin. When cells are stretched, IFs provide cells with flexibility to minor deformations while also strengthening them (8). EBS and hereditary cardiomyopathies have been linked to mutations in genes encoding various IFs, which play important regulatory functions in stretch-bearing tissues including the skin and the heart (9, 10). In cardiomyocytes and skeletal muscle cells, Desmin (DES) is a crucial IF (11). Desmin filaments connect myofibrils and expand the z-discs, producing a supporting latticework that runs from the sarcolemma to the nuclear envelope. They help to orient, stabilize, and transmit signals between the nucleus, cell membrane, mitochondria, and myofibrils. Mitochondrial dysfunction is one of the first and most visible abnormalities when the IF network in the heart is disrupted. Desmin network failure also causes nuclear delamination and intercalated disc abnormalities, which eventually contribute to heart function loss. Desminopathies have been linked to a number of DES mutations as well as mutations in other genes that impact the desmin network.

We predicted that KLHL24-N28 causes excessive desmin degradation in the heart, resulting in DCM, because desmin belongs to the same highly conserved intermediate filament protein family as keratins (15). We employed human induced pluripotent stem cells (hiPSCs) to differentiate patient-specific KLHL24WT/c.1A>G cardiomyocytes to test this notion. A dynamically loaded engineered heart tissue (dyn-EHT) model was used to investigate the role of KLHL24 in cardiac tissue compliance (i.e., stretching the desmin network) (16). To replicate the stress (preload and afterload) experienced by the heart, a polydimethylsiloxane (PDMS) strip is connected to engineered heart tissues (EHT). Finite element modeling may be used to calculate tissue contractile force by bending the strip (FEM). This system can also be dynamically grown, allowing researchers to see the morphological and functional changes that occur during ventricular dilation, which was crucial in identifying a clinically relevant phenotype in desmoplakin-mutated hiPSC-CMs (16). We show that a gain-of-function mutation in KLHL24, which results in KLHL24-N28 and causes excessive desmin degradation in cardiomyocytes, negatively affecting the shape and function of dyn-EHTs, may be avoided by KLHL24 RNA interference or direct desmin overexpression.

Outcomes:

EBS in families with dilated cardiomyopathy. Two patients of Dutch descent, both carriers of the KLHL24:c gene, were included in this research. Figure 1A, II:3, and III:2 show the 1A>G mutation (1). KLHL24-N28 is a shortened KLHL24 protein caused by this mutation (Figure 1B). Both patients had EBS and exhibited characteristic aplasia cutis congenita and skin fragility that improved with time. Furthermore, at the age of 17, the index patient (II:3) was diagnosed with a fast-progressing type of DCM, for which he had a heart transplant at the age of 18. His son (III:2), who was 18 years old at the time of the research, was still asymptomatic, but his echocardiography revealed clear indications of DCM, including left ventricular (LV) dilatation, decreased LVEF, and impaired global longitudinal systolic strain.

Steffen Desch, MD from the Heart Center Leipzig at the University of Leipzig - Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation.

Link to Abstract:
https://www.nejm.org/doi/full/10.1056/NEJMoa2101909?query=cardiology

Abstract:

BEGINNINGS -

Out-of-hospital cardiac arrest is frequently caused by myocardial infarction. The advantages of Heart Center Leipzig at the University of Leipzig f early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation, on the other hand, remain unknown.

PRIMARY RESEARCH METHODS -

554 patients with successfully resuscitated out-of-hospital cardiac arrest of suspected coronary origin were randomly allocated to either immediate coronary angiography (immediate-angiography group) or initial intensive care evaluation with delayed or selective angiography in this multicenter study (delayed-angiography group). On post-resuscitation electrocardiography, none of the patients showed ST-segment elevation. At 30 days, the primary end objective was death from any cause. At 30 days, a composite of death from any cause or significant neurologic impairment was used as a secondary end objective.

OBJECTIVES -

In the primary analysis, 530 out of 554 patients (95.7 percent) were included. At 30 days, 143 of 265 patients in the immediate-angiography group (54.0%) and 122 of 265 patients (46.0%) in the delayed-angiography group (hazard ratio, 1.28; 95 percent confidence interval [CI], 1.00 to 1.63; P=0.06) had died (hazard ratio, 1.28; 95 percent confidence interval [CI], 1.00 to 1.63; P=0.06). The immediate-angiography group had a higher relative risk of mortality or severe neurologic impairment (164 of 255 patients [64.3 percent ]) than the delayed-angiography group (138 of 248 patients [55.6 percent ]), with a relative risk of 1.16. (95 percent CI, 1.00 to 1.34). The two groups had identical values for peak troponin release, as well as the incidence of moderate or severe bleeding, stroke, and renal replacement therapy.

FINAL THOUGHTS -

Immediate angiography had no benefit over a delayed or selective approach in patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation in terms of the 30-day risk of mortality from any cause. (ToMAHAWK ClinicalTrials.gov number: NCT02750462. opens in a new tab; funded by the German Center for Cardiovascular Research.)

Dr. Gary F. Marklin is a pulmonologist in Saint Louis, Missouri, and is affiliated with St. Alexius Hospital-Broadway Campus and Mercy Hospital South.

Dr. Marklin has more than 36 years of experience practicing internal medicine and is a seasoned critical care physician. He has worked as a consulting physician at Saint Anthony's Medical Center in the fields of intensive care, respiratory care, and pulmonary care.

Link to Article: https://clinicaltrials.gov/ct2/show/NCT04415658?cond=Cardiac+Death&phase=23&draw=2&rank=24#contacts


Background: Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid stimulating hormone) may contribute to hemodynamic instability and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy.

Methods: This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12-hours or saline placebo. The primary study hypothesis is that thyroxine treatment results in more hearts transplanted. Additional outcome measures are time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography.

Discussion: This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment for organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether treatment increases hearts transplanted and/or provides other hemodynamic benefits.

Dr. Mia Ravn Jacobsen, M.D. is a Corresponding Author at Rigshospitalet, Copenhagen University Hospital - Aalborg University Hospital's Department of Cardiology.

Link to Abstract: https://www.internationaljournalofcardiology.com/article/S0167-5273(21)01192-X/fulltext#%20


Abstract\sBackground
To assess the efficacy and safety of clopidogrel, prasugrel, and ticagrelor in people who have had an ST-segment elevation myocardial infarction (STEMI) and to expand on what has been learned from randomized clinical studies.

Methods
The Eastern Danish Heart Registry was used to identify all consecutive STEMI patients admitted to Copenhagen University Hospital, Rigshospitalet, between 2009 and 2016. Claim medicines and end points were gathered through individual linkage to Danish national registers. Patients alive a week after discharge were included in the study, and they were divided into three groups based on whether they were taking clopidogrel, prasugrel, or ticagrelor. They were then monitored for a year. Multivariate Cox proportional-hazards models were used to analyze the effectiveness end point (a composite of all-cause mortality, recurrent myocardial infarction, and ischemic stroke) and the safety end point (a composite of bleedings resulting to hospitalization).

Results
A total of 5123 patients (clopidogrel [1245], prasugrel [1902], ticagrelor [1976]) were enrolled in the study, with a 95 percent therapy persistency rate. Aspirin was taken at the same time in 95% of the cases. Females made up 24% of the population, while the elderly made up 17%. The efficacy endpoint occurred less frequently for ticagrelor (HR 0.50, 95 percent CI 0.35–0.70) and prasugrel (HR 0.48, 95 percent CI 0.33–0.68) as compared to clopidogrel, with no differences in bleedings requiring hospitalization. Prasugrel and ticagrelor have no differences in comparative effectiveness or safety. Similar results were found in sensitivity analyses using time-dependent drug exposure for the years 2011–2015.

Conclusions
When compared to clopidogrel, ticagrelor and prasugrel were linked with a lower incidence of all-cause mortality, recurrent myocardial infarction, and ischemic stroke in STEMI patients without an increase in bleeding that required hospitalization. There were no differences between prasugrel and ticagrelor.

Niklas Nielsen, MD - #HelsingborgHospital #CardiacArrest #Cardiology #Research Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest

Link to Abstract- https://www.nejm.org/doi/full/10.1056/NEJMoa2100591

Abstract

BACKGROUND
Targeted temperature management is indicated for patients who have suffered a cardiac arrest, however the evidence for this is inconclusive.

METHODS In an open-label trial with blinded outcome assessment, we randomly assigned 1900 adults in coma who had an out-of-hospital cardiac arrest of suspected cardiac or unknown cause to targeted hypothermia at 33°C followed by controlled rewarming, or targeted normothermia with early fever treatment (body temperature, 37.8°C). At 6 months, the primary outcome was death from any cause. Functional result at 6 months, as measured by the modified Rankin scale, was a secondary endpoint. Sexe, age, initial cardiac rhythm, time to return to spontaneous circulation, and presence or absence of shock on entry were all used to create subgroups. Pneumonia, sepsis, hemorrhage, arrhythmia resulting in hemodynamic compromise, and skin issues connected to the temperature management device were all pre-specified adverse events.

RESULTS The primary outcome was assessed in a total of 1850 individuals. At 6 months, 465 of the 925 hypothermia patients (50%) had died, compared to 446 of the 925 normothermia patients (48%) (relative risk with hypothermia, 1.04; 95 percent confidence interval [CI], 0.94 to 1.14; P=0.37). 488 of 881 patients in the hypothermia group (55%) had moderately severe impairment or worse (modified Rankin scale score 4) compared to 479 of 866 patients in the normothermia group (55%) who had moderately severe disability or worse (modified Rankin scale score 4). (relative risk with hypothermia, 1.00; 95 percent CI, 0.92 to 1.09). In the predetermined subgroups, the results were consistent. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group (24 percent vs. 17 percent, P0.001) than in the normothermia group. The incidence of additional adverse events did not differ significantly between the two groups.

CONCLUSIONS
Targeted hypothermia did not reduce the risk of death in patients in coma following out-of-hospital cardiac arrest by 6 months when compared to targeted normothermia. (TTM2 ClinicalTrials.gov number: NCT02908308. opens in new tab; funded by the Swedish Research Council and others.)

Dr. Jeffrey Weitz, M.D. -@Cardio_KULeuven #VenousThromboembolism #Cardiology #Research Abelacimab for Prevention of Venous Thromboembolism

Link to Abstract- https://www.nejm.org/doi/full/10.1056/NEJMoa2105872?query=cardiology

Abstract-

BACKGROUND
The relevance of factor XI in postoperative venous thromboembolism etiology is unknown. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in an inactive precursor state called the zymogen.

METHODS In this open-label, parallel-group study, 412 patients undergoing total knee arthroplasty were randomly assigned to one of three abelacimab (30 mg, 75 mg, or 150 mg) regimens administered postoperatively in a single intravenous dose or 40 mg of enoxaparin administered subcutaneously once daily. The major efficacy endpoint was venous thromboembolism, which was diagnosed by either obligatory venography of the operative leg or objective confirmation of symptomatic episodes. Up to 30 days following surgery, the primary safety outcome was a composite of major or clinically relevant nonmajor bleeding.

RESULTS
Venous thromboembolism occurred in 13 of 102 patients (13 percent), 5 of 99 patients (5 percent), and 4 of 98 patients (4 percent) in the 30-mg abelacimab group, compared to 22 of 101 patients (22 percent) in the enoxaparin group. The 30-mg abelacimab regimen was not inferior to enoxaparin, but the 75-mg and 150-mg abelacimab regimens were (P0.001). In the 30-mg, 75-mg, and 150-mg abelacimab groups, bleeding occurred in 2%, 2%, and none of the patients, respectively, and in the enoxaparin group, bleeding occurred in none of the patients.

CONCLUSIONS
Factor XI is critical for the development of postoperative venous thromboembolism, according to this study. After total knee arthroplasty, factor XI inhibition with a single intravenous dose of abelacimab was successful in preventing venous thromboembolism and was linked with a low risk of bleeding. (ANT-005 TKA EudraCT number, 2019-003756-37; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics; Anthos Therapeutics;