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1.
Journal of the American College of Cardiology (JACC) ; 79(9):2110-2110, 2022.
Article in English | Academic Search Complete | ID: covidwho-1751340
3.
Eur Heart J Cardiovasc Pharmacother ; 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1702320

ABSTRACT

Coronavirus disease 2019 (COVID-19) is characterized by striking dysregulation of the immune system, with evidence of hyperinflammation, an impaired induction of interferons, and delayed adaptive immune responses. In addition to dysfunctional immune responses, thrombosis is a hallmark of severe COVID-19. Because traditional anticoagulation strategies are associated with increased bleeding, novel strategies that address both the immune and thrombotic dysfunction associated with COVID-19 would be of tremendous benefit. In this commentary, we discuss the unique properties of low dose naltrexone (LDN) which could be leveraged to reduce the immune-mediated thrombotic complications in COVID-19. Mechanistically, LDN can blunt innate immune responses and Toll-like receptor (TLR) signaling, reducing interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interferon (IFN) levels. Because of the immune-mediated thrombotic mechanisms that underlie COVID-19, we hypothesize that the immune-modulating and known pharmacologic properties of LDN could be leveraged as a novel therapeutic strategy in COVID-19.

4.
Cardiovasc Drugs Ther ; 2021 Nov 18.
Article in English | MEDLINE | ID: covidwho-1520388

ABSTRACT

PURPOSE: Vascular and immune dysfunction are hallmarks of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections and coronavirus disease 2019 (COVID-19). Although our understanding of the pathogenesis of COVID-19 has rapidly evolved, much of the focus has been on the immune mechanisms underlying COVID-19. In addition to immune dysfunction, vascular injury is also associated with COVID-19 and is a major driver of clinical deterioration in SARS-CoV-2 infections. The glycocalyx (GAC), a sugar-based shell that surrounds all mammalian cells, is an important regulator of vascular and immune responses. In sepsis, vascular dysfunction contributes to acute respiratory distress syndrome (ARDS) by altering vessel integrity, promoting thrombosis, and accelerating inflammation, all of which are also present in COVID-19. Observational studies in sepsis have found an association between levels of circulating GAC degradation products with both organ dysfunction and mortality. Although vascular dysfunction is a hallmark of COVID-19, it remains unclear whether GAC disruption occurs in COVID-19 and if GAC disruption contributes to the clinical progression of COVID-19. METHODS: In this prospective cohort study, we measured the GAC components syndecan-1 (SDC1) and hyaluronan (Hyal) along with inflammatory cytokines in 12 hospitalized COVID-19 patients and 8 healthy controls (HC). RESULTS: In agreement with other studies, we found that inflammatory cytokines are elevated in hospitalized COVID-19 patients compared with HC [median (IQR), all units picograms per milliliter: IL-6 4.65 (3.32-9.16) vs 0.69 (0.55-0.89), p < 0.001; TNFα 4.49 (1.87-8.03) vs 0.04 (0.04-0.84), p < 0.001]. Additionally, we found that the GAC components SDC1 and Hyal are also elevated in COVID-19 patients [median (IQR), all units picograms per milliliter: SDC1: 247.37 (101.43-458.26) vs 84.8 (52.88-123.59), p = 0.036; Hyal: 26.41 (16.4-35.1) vs 3.01 (1.66-4.61), p < 0.001]. CONCLUSION: We propose that GAC markers offer insights into the pathobiology of COVID-19, potentially guide therapeutic approaches, and could aid in early risk stratification that is particularly beneficial in phasic diseases such as COVID-19.

5.
Cardiovasc Drugs Ther ; 2021 Sep 15.
Article in English | MEDLINE | ID: covidwho-1408612

ABSTRACT

PURPOSE: COVID-19 is characterized by dysfunctional immune responses and metabolic derangements, which in some, lead to multi-organ failure and death. Statins are foundational lipid-lowering therapeutics for cardiovascular disease and also possess beneficial immune-modulating properties. Because of these immune-modulating properties, some have suggested their use in COVID-19. We sought to investigate the association between statin use and mortality in patients hospitalized with COVID-19. METHODS: Five thousand three hundred seventy-five COVID-19 patients admitted to Mount Sinai Health System hospitals in New York between February 27, 2020, and December 3, 2020, were included in this analysis. Statin use was classified as either non-user, low-to-moderate-intensity user, or high-intensity user. Multivariate Cox proportional hazards models were used to evaluate in-hospital mortality rate. Considered covariates were age, sex, race, and comorbidities. RESULTS: Compared to non-statin users, both low-to-moderate-intensity (adjusted hazard ratio; aHR 0.62, 95% confidential intervals; CI 0.51-0.76) and high-intensity statin users (aHR 0.53, 95% CI 0.43-0.65) had a reduced risk of death. Subgroup analysis of 723 coronary artery disease patients showed decreased mortality among high-intensity statin users compared to non-users (aHR 0.51, 95% CI 0.36-0.71). CONCLUSIONS: Statin use in patients hospitalized with COVID-19 was associated with a reduced in-hospital mortality. The protective effect of statin was greater in those with coronary artery disease. These data support continued use of statin therapy in hospitalized patients with COVID-19. Clinical trials are needed to prospectively determine if statin use is effective in lowering the mortality in COVID-19 and other viral infections.

6.
N Engl J Med ; 385(9): 790-802, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1343498

ABSTRACT

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Heparin/administration & dosage , Thrombosis/prevention & control , Adult , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , COVID-19/mortality , Female , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hospital Mortality , Humans , Male , Middle Aged , Survival Analysis
7.
J Am Coll Cardiol ; 76(17): 1999-2010, 2020 Oct 27.
Article in English | MEDLINE | ID: covidwho-872169

ABSTRACT

The emergence of a new coronavirus disease (coronavirus disease 2019 [COVID-19]) has raised global concerns regarding the health and safety of a vulnerable population. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incites a profound inflammatory response leading to tissue injury and organ failure. COVID-19 is characterized by the bidirectional relationship between inflammation and thrombosis. The clinical syndrome is propelled by inflammation producing acute lung injury, large-vessel thrombosis, and in situ microthrombi that may contribute to organ failure. Myocardial injury is common, but true myocarditis is rare. Elderly patients, those with established cardiovascular disease, and mechanically ventilated patients face the highest mortality risk. Therapies for COVID-19 are evolving. The antiviral drug remdesivir, dexamethasone, transfusion of convalescent plasma, and use of antithrombotic therapy are promising. Most require additional prospective studies. Although most patients recover, those who survive severe illness may experience persistent physical and psychological disabilities.


Subject(s)
Coronavirus Infections/epidemiology , Host-Pathogen Interactions , Pneumonia, Viral/epidemiology , Animals , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/therapy , Coronavirus Infections/virology , Humans , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , Risk Factors , SARS-CoV-2
8.
J Am Coll Cardiol ; 76(17): 2024-2035, 2020 Oct 27.
Article in English | MEDLINE | ID: covidwho-872167

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic exposes unexpected cardiovascular vulnerabilities and the need to improve cardiometabolic health. Four cardiometabolic drivers-abnormal adiposity, dysglycemia, dyslipidemia, and hypertension-are examined in the context of COVID-19. Specific recommendations are provided for lifestyle change, despite social distancing restrictions, and pharmacotherapy, particularly for those with diabetes. Inpatient recommendations emphasize diligent and exclusive use of insulin to avert hyperglycemia in the face of hypercytokinemia and potential islet cell injury. Continuation of statins is advised, but initiating statin therapy to treat COVID-19 is as yet unsubstantiated by the evidence. The central role of the renin-angiotensin system is discussed. Research, knowledge, and practice gaps are analyzed with the intent to motivate prompt action. An emerging model of COVID-related cardiometabolic syndrome encompassing events before, during the acute phase, and subsequently in the chronic phase is presented to guide preventive measures and improve overall cardiometabolic health so future viral pandemics confer less threat.


Subject(s)
Coronavirus Infections/complications , Metabolic Syndrome/virology , Pneumonia, Viral/complications , COVID-19 , Humans , Metabolic Syndrome/prevention & control , Pandemics
9.
Clin Trials ; 17(5): 491-500, 2020 10.
Article in English | MEDLINE | ID: covidwho-724657

ABSTRACT

BACKGROUND: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Heparin/administration & dosage , Pneumonia, Viral/drug therapy , Thrombosis/prevention & control , Adolescent , Adult , Anticoagulants/administration & dosage , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Dose-Response Relationship, Drug , Female , Humans , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Thrombosis/etiology , Treatment Outcome , Young Adult
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