ABC | Volume 115, Nº2, August 2020

Statement Arq Bras Cardiol. 2020; 115(2):292-301 Position Statement on the Use of Antiplatelet Agents and Anticoagulants in Patients Infected with the New Coronavirus (COVID-19) – 2020 ACS diagnosis, even in the presence of electrocardiographic changes. A case series was published 21 of 18 patients in New York hospitals with COVID-19 and ST-segment elevation suggestive of acute myocardial infarction, including four with diffuse ST-segment elevation and 14 with focal ST-segment elevation. Of these patients, 50% had coronary angiography and 33% had no obstructive coronary disease. In all, 44% of the patients were diagnosed with acute myocardial infarction. Thus, even in patients with ST-segment elevation, differential diagnoses must be considered due to the heterogeneous clinical picture. However, regardless of the etiology, mortality was 72%. Therapeutic decision making and invasive stratification strategies should consider the clinical condition, the findings of complementary tests, the team’s experience, and the availability of the hemodynamics laboratory. 14,16 In two other studies, a lower incidence of ACS was found in northern California compared to the same period the previous year, while a higher incidence of out-of-hospital cardiac arrest was found in Italy. This suggests a lower demand for emergency services by the population. 22,23 In addition to all these factors, the effects of social isolation have raised enormous concern. Most people have drastically reduced physical activity. In addition, diets can become inadequate due to higher carbohydrate intake. Such lifestyle changes may contribute to thrombotic events, including stroke and ACS. 24 2.4. Thromboembolic Mechanism Patients infected with COVID-19 are likely to have an increased risk of venous thromboembolism (VTE). Although a large case series has not yet been published, there are reports of abnormal coagulation parameters in hospitalized patients with severe COVID-19. 25-27 A recent case series of 106COVID-19patientswhounderwent pulmonary arteriography found that 30% had VTE. Patients with COVID-19 and pulmonary embolism had higher levels of D-dimer than thosewithout an embolism (p<0.001), in addition to a greater need for intensive care (75% vs. 32%, p < 0.001). A D-dimer level > 2,660 µg/L showed 100% sensitivity and 67% specificity for pulmonary embolism. 28 D-dimer levels have been associated with higher mortality rates and seem to progressively increase with infection severity. The phase of the disease in which acute respiratory distress syndrome develops and the radiological patternworsens ismarked by a significant increase in D-dimer levels, which is observed in the most severe cases of myocardial injury and disseminated intravascular coagulation. The systemic inflammatory response in infected patients can result in endothelial injury with a consequent increase in thrombin production and a reduction in endogenous fibrinolysis. This prothrombotic state is called sepsis- induced coagulopathy and precedes disseminated intravascular coagulation. The various mechanisms involved in sepsis-induced coagulopathy act simultaneously, culminating in a prohemostatic state. Apparently, inflammatory cytokines are the most important mediator of this clotting disorder during sepsis. 29 A cross-interaction has been demonstrated between inflammation and coagulation, with inflammation inducing coagulation activation and coagulation accentuating inflammatory activity. Platelets play a central role in the development of coagulation abnormalities in sepsis and can be activated directly by pro-inflammatory mediators, such as platelet activating factor, as well as through thrombin. Platelet activation can also stimulate fibrin formation by an alternative mechanism. The expression of P-selectin in the platelet membrane not only induces the adhesion of platelets to leukocytes and endothelial cells but also increases the expression of tissue factor in monocytes. Under normal circumstances, coagulation activation is controlled by three important physiological anticoagulant pathways: the antithrombin system, the activatedproteinC system, and the tissue factor pathway inhibitor. In sepsis, all three pathways become dysfunctional. In the midst of this imbalance in the coagulation system, endogenous fibrinolysis is greatly reduced. 29 In a Chinese retrospective cohort study, elevated D-dimer levels (> 1 g/L) were strongly associated with hospital death. In another study comparing COVID-19 survivors and non-survivors, non-survivors had significantly higher levels of D-dimer and fibrin degradation products, and 71.4% of non-survivors met the clinical criteria for disseminated intravascular coagulation during the course of disease. In addition to disseminated intravascular coagulation, critically ill patients who have experienced prolonged immobilization are at high risk of VTE. Vascular inflammation can also contribute to a state of hypercoagulation and endothelial dysfunction in such patients. In seriously ill patients with COVID-19who clinically deteriorate, as evidenced by hypoxia or hemodynamic instability, thromboembolic disease should be considered. 25-27 3. Drug Interactions and Cardiovascular Pro- /Antithrombotic Effects So far, there is no specific treatment for COVID-19 infection, and a variety of therapeutic regimens have been used in severe cases in a hospital environment, although the efficacy and safety of many are still being investigated. Since these drugs can be used in specific situations, it is worth considering their side effects on the cardiovascular system and possible drug interactions with other therapies frequently used in cardiac patients. 3.1. Antiretrovirals Ribavirin and remdesivir block RNA polymerase, while lopinavir-ritonavir inhibits viral replication. Ribavirin-induced cardiotoxicity has not been reported. However, lopinavir-ritonavir prolongs the QT and PR intervals, especially in patients who already have long QT intervals or are using other medications that interact with the QT interval. Both ribavirin and lopinavir-ritonavir enhance the anticoagulant effect, modifying the action of warfarin (mainly ribavirin) and new anticoagulants such as apixaban and rivaroxaban (mainly lopinavir- ritonavir). 30-32 In another study, an association of dabigatran and antivirals in hospitalized COVID-19 patients resulted in increased in serumplasma levels, requiring medication withdrawal inmore than half of the patients. 31 Lopinavir-ritonavir may also influence the activity of P2Y 12 inhibitors by inhibiting CYP3A4, which reduces the serum level of active metabolites of clopidogrel and increases the activity of ticagrelor. Therefore, due to the high risk of bleeding, the concomitant use of ticagrelor and lopinavir- ritonavir is discouraged. 11 295