Produção Nacional
Revisado por pares
Anticoagulant and antiarrhythmic effects of heparin in the treatment of COVID‐19 patients
2020; Elsevier BV; Volume: 18; Issue: 8 Linguagem: Inglês
10.1111/jth.14902
ISSN1538-7933
AutoresFrancisco Sandro Menezes Rodrigues, José Gustavo Padrão Tavares, Marcelo Pires de Oliveira, Rafael Guzella de Carvalho, Paolo Ruggero Errante, Murched Omar Taha, Djalma José Fagundes, Afonso Caricati‐Neto,
Tópico(s)Long-Term Effects of COVID-19
ResumoMost severe manifestations of COVID‐19 cases, such as multiple organ failure and death, have been linked to coagulation dysfunction markers, such as platelet reduction and increases in prothrombin time, fibrin degradation products, and, mainly, D‐dimer.1.Basu‐Ray I, Soos MP. Cardiac manifestations of coronavirus (COVID‐19). StatPearls. 2020.Google Scholar A recent paper by Tang et al2.Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar in this journal reported that heparin treatment reduced mortality of COVID‐19 patients with elevated D‐dimer; similar preliminary results have been reported elsewhere.3.Negri EM, Piloto BM, Morinaga LK, et al. Heparin therapy improving hypoxia in COVID‐19 patients ‐ a case series. São Paulo; 2020. https://doi.org/10.1101/2020.04.15.20067017.Google Scholar A mounting body of evidence shows that SARS‐CoV‐2 causes a "cytokine storm"1.Basu‐Ray I, Soos MP. Cardiac manifestations of coronavirus (COVID‐19). StatPearls. 2020.Google Scholar, 4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar that activates the coagulation cascade, leading to thrombosis. Similar to the findings in severe sepsis, generalized deposition of intravascular thrombi compromises the blood supply of several organs, leading to organ failure.5.Burzynski L.C. Humphry M. Pyrillou K. et al.The coagulation and immune systems are directly linked through the activation of interleukin‐1α by Thrombin.Immunity. 2019; 50: 1033-1042.e6Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Disseminated intravascular coagulation secondary to severe infection is classically associated with gram‐positive and gram‐negative bacteria, malaria, and other hemorrhagic fevers, such as hemorrhagic dengue, although SARS‐CoV and MERS‐CoV have also been shown to trigger disseminated intravascular coagulation. Similar results in COVID‐192.Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar, 3.Negri EM, Piloto BM, Morinaga LK, et al. Heparin therapy improving hypoxia in COVID‐19 patients ‐ a case series. São Paulo; 2020. https://doi.org/10.1101/2020.04.15.20067017.Google Scholar, 4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar now suggest that widespread coagulation events significantly contribute to worse outcomes and patient mortality, which might be attenuated by anticoagulant treatment. We would also like to add that, although a direct anticoagulant effect is likely crucial to the therapeutic effect of heparin, it also has antiarrhythmic properties6.Godoy C.M.G.d. Vasques Ê.R. Caricati‐Neto A. et al.Heparin oligosaccharides have antiarrhythmic effect by accelerating the sodium‐calcium exchanger.Front Cardiovasc Med. 2018; 5: 67Crossref PubMed Scopus (10) Google Scholar, 7.Fender A.C. Wakili R. Dobrev D. Straight to the heart: Pleiotropic antiarrhythmic actions of oral anticoagulants.Pharmacol Res. 2019; 145: 104257Crossref PubMed Scopus (15) Google Scholar that could show promise in the treatment of COVID‐19, in which cardiac arrhythmias are the immediate cause of several patient deaths.4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar Heparin oligosaccharides have a marked antiarrhythmic effect in an animal model of heart ischemia‐reperfusion, as well as in isolated rat atria, reducing both ventricular arrhythmias and atrioventricular block, likely by increasing Na+‐Ca2+ exchanger activity.6.Godoy C.M.G.d. Vasques Ê.R. Caricati‐Neto A. et al.Heparin oligosaccharides have antiarrhythmic effect by accelerating the sodium‐calcium exchanger.Front Cardiovasc Med. 2018; 5: 67Crossref PubMed Scopus (10) Google Scholar About 16% of COVID‐19 patients show cardiac arrhythmias and 7.2% had acute cardiac lesions.4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar Increased cardiac lesion markers, such as interleukin‐6, high‐sensitivity troponin I, and lactate dehydrogenase are correlated with poorer patient outcomes.4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar COVID‐19 increases troponin I and these higher levels correlate with more frequent complications, including malignant ventricular arrhythmias.4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar There are many reports of fulminant myocarditis with cardiogenic shock, associated with atrial and ventricular arrhythmias.1.Basu‐Ray I, Soos MP. Cardiac manifestations of coronavirus (COVID‐19). StatPearls. 2020.Google Scholar, 4.Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID‐19.J Cardiovasc Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (395) Google Scholar In a recent report on Wuhan COVID‐19 patients, 16.7% of all hospitalized patients and 44.4% of intensive care unit patients had cardiac arrhythmias.8.Chen T. Wu D. Chen H. et al.Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.BMJ. 2020; : m1091Crossref PubMed Scopus (2577) Google Scholar Besides, several drugs proposed for use in the treatment of COVID‐19, such as hydroxychloroquine (HCQ), block voltage‐gated K+ channels, which may cause drug‐induced long QT syndrome and atrioventricular blocks.9.Konstantopoulou A. Mechanisms of drug‐induced proarrhythmia in clinical practice.World J Cardiol. 2013; 5: 175Crossref PubMed Google Scholar Therefore, the concomitant use of HCQ and other antiarrhythmic medications, such as amiodarone or sotalol, may further increase the QT interval and require close electrocardiogram monitoring. Further characterization of arrhythmic load and mechanisms of death are critical to guide additional treatments and preventive strategies, including the potential role of cardioversion. Azithromycin and other macrolides have also been combined with chloroquine and derivatives in COVID‐19 patients, but these antimicrobial drugs also induce long QT.9.Konstantopoulou A. Mechanisms of drug‐induced proarrhythmia in clinical practice.World J Cardiol. 2013; 5: 175Crossref PubMed Google Scholar Combined HCQ‐azithromycin‐treated patients are at an increased risk for drug‐induced long QT syndrome and torsades des pointes. Lopinavir and ritonavir also prolong PR and QT intervals and may cause severe atrioventricular blocks and torsades de pointes.10.Stolbach A. Paziana K. Heverling H. Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.J Med Toxicol. 2015; 11: 326-341Crossref PubMed Scopus (59) Google Scholar Hypokalemia may also increase vulnerability to several tachyarrhythmias and, therefore, COVID‐19 patients will likely require close electrolyte and QT monitoring whenever treated with HCQ‐azithromycin because of the interactions of SARS‐CoV2 with the renin‐angiotensin‐aldosterone system and the likelihood of hypokalemia.1.Basu‐Ray I, Soos MP. Cardiac manifestations of coronavirus (COVID‐19). StatPearls. 2020.Google Scholar, 2.Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar The American College of Cardiology now offers an easy‐to‐use calculator to help medical professionals in determining which patients are at an increased risk for ventricular arrhythmias when treated with HCQ‐azithromycin. Other HCQ interactions in COVID‐19 risk groups may include antihypertensive drugs, such as beta antagonists and Ca2+ channel blockers, leading to severe bradycardia and cerebral hypoperfusion.9.Konstantopoulou A. Mechanisms of drug‐induced proarrhythmia in clinical practice.World J Cardiol. 2013; 5: 175Crossref PubMed Google Scholar Neither Tang et al2.Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar nor Negri et al3.Negri EM, Piloto BM, Morinaga LK, et al. Heparin therapy improving hypoxia in COVID‐19 patients ‐ a case series. São Paulo; 2020. https://doi.org/10.1101/2020.04.15.20067017.Google Scholar report any increase in bleeding with heparin treatment, though this might be a concern with other COVID‐19 drug combinations. For instance, lopinavir/ritonavir inhibit CYP3A4 and may drastically increase Xa factor inhibition when combined with apixaban or rivaroxaban.10.Stolbach A. Paziana K. Heverling H. Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.J Med Toxicol. 2015; 11: 326-341Crossref PubMed Scopus (59) Google Scholar The use of heparins in the treatment of patients with COVID‐19 is likely to be beneficial and effective because it combats the coagulopathies that lead to hypoxia and generalized organ failure, but also because it is likely to attenuate cardiac arrhythmias and sudden deaths associated both with COVID‐19 itself or with its pharmacological therapy. It remains to be seen whether other antiarrhythmic drugs also have a role to play in the treatment of COVID‐19, at least in patients at higher risk for cardiac arrhythmias. The authors report no conflicts of interest. Francisco Sandro Menezes‐Rodrigues, José Gustavo Padrão‐Tavares, Marcelo Pires‐Oliveira, Rafael Guzella de Carvalho, Paolo Ruggero Errante, Murched Omar Taha, Djalma José Fagundes, and Afonso Caricati‐Neto wrote the manuscript and approved the final version.
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