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 There is also evidence that using clopidogrel during treatment with lopinavir-ritonavir may result in an insufficient antiplatelet effect, although this has not been observed with prasugrel, which makes it the idealmedication. 32 In thepresenceof contraindications for prasugrel (e.g., previous stroke, advanced age, low body mass index, and increased risk of bleeding), clopidogrel is indicated, and platelet activity should be evaluated. 30,32 Remdesivir, an antiretroviral under investigation for use with COVID-19, was used during the Ebola epidemic. Despite its promise, in a randomized, double-blind, multicenter study, it did not result in better mortality outcomes than placebo. Although there was a trend toward symptom reductions, it was not significant. 33 No cardiotoxicity or other important drug interactions have been reported for this drug. 30,32 3.2. Hydroxychloroquine and Chloroquine Hydroxychloroquine and chloroquine are frequently used in patients with malaria and other systemic inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Apparently, they can block viral entry into cells, in addition to stimulating immunomodulation, attenuating the production of cytokines, and inhibiting autophagy and lysosomal activity in the host. They may also have antithrombotic properties, especially against antiphospholipid antibodies. 5,34,35 These drugs have been used in previous SARS and MERS epidemics, and there is evidence of their efficacy. A Chinese study of 100 patients with COVID-19 found that chloroquine was associated with radiological improvement, increased viral clearance, and decreased disease progression. Despite its promising results, the study had several limitations and can be interpreted in different ways. 5,34,35 In other observational studies, hydroxychloroquine, associated or not with azithromycin, did not result in favorable outcomes. No decrease was found in mortality or intubation time, and no difference in seroconversion was found in patients with mild to moderate disease. 36-38 Several studies are ongoing about the impact of hydroxychloroquine and/or chloroquine. Although generally well tolerated, chloroquine and hydroxychloroquine can have serious side effects, such as prolonging the QT interval and inducing hypoglycemia, retinopathy and neuropsychiatric disorders. However, no interaction with antiplatelet agents or anticoagulants has been reported. 5,34,35 3.3. Corticosteroids Methylprednisolone is another medication that can be consideredduring severe cases of COVID-19 and acute respiratory distress syndrome. Although it is known to cause water retention, hydrolytic changes and hypertension, interactionwith antiplatelets or anticoagulants has not been reported. 35 3.4. Heparins A Chinese study 39 of 449 hospitalized COVID-19 patients found that a prescription strategy of enoxaparin 40-60 mg/day or unfractionated heparin 10,000-15,000 U/day resulted in 28-day mortality benefits in two subgroups. In one of these groups, which consisted of patients with criteria for sepsis-induced coagulopathy > 4 (increased prothrombin time, decreased platelet count, and increased SOFA-Score), there was a difference of 40% vs. 64.2% (p = 0.029). The other subgroup, which consisted of patients with > 6 times the normal D-dimer concentration, there was a difference of 32.8% vs. 52.4% (p = 0.017). This demonstrates that chemical prophylaxis for VTE or full anticoagulation therapy should be considered on a case-by-case basis in all hospitalized patients with COVID-19, and a careful search should be made for thrombotic events. 26,27,31,39-41 3.5. Immunoglobulins and Anti-IL6 Antibodies Immunoglobulin use depends on two mechanisms: viral neutralization and immunomodulation.One intriguing application of viral neutralization is convalescent serum or plasma. Since this therapy has pleiotropic effects that result in suppressed inflammation, this therapy can potentially alleviate disease severity in the hyperinflammatory phase. More robust evidence is needed to confirm these findings. Likewise, it may be that COVID-19 patients with a cytokine storm can benefit from monoclonal antibodies targeting interleukin-6 receptor, since it has been successful in mitigating inflammation in transplanted patients. Although this could be reflected in the patient’s thrombotic state, there is still no concrete evidence about it. 15 Althoughanti-interleukin-6receptorantibodiesincreaseCYP3A4 expression, there are no dose-adjustment recommendations regarding patients using antiplatelet agents or anticoagulants. 5 4. Recommendations 4.1. Anticoagulants The decision to prescribe low molecular weight heparin or prophylacticunfractionatedheparin forVTEor as full anticoagulation therapy shouldbemadeona case-by-casebasis, and shouldalways be considered in hospitalized high-risk VTE patients. 5,29,39-43 Based on expert consensus and the results of a few retrospective studies, when anticoagulation is not contraindicated, anticoagulant therapy canbeconsidered for use inpatientswith severeCOVID-19 and signs of sepsis-induced coagulopathy and/or very highD-dimer levels in associationwith other biomarkers that denote severity. This strategy requires the use of strict institutional protocols that allow for surveillance and rapid intervention when complications arise. 29 It is possible that anticoagulant therapy is more beneficial when initiated in the pre-thrombotic phase than in advanced cases, when the risk of bleeding is greater. When opting for anticoagulation, it would seem reasonable to use low molecular weight heparin as the drug of choice in stable patients with normal creatinine clearance (subcutaneous dose of 1 mg/kg every 12 hours). In case of shock or creatinine clearance below50mL/min/ m², unfractionated intravenous heparin (18 IU/kg/h) is preferable, targeting an activated partial thromboplastin time between 1.5 and 1.8. However, there is no evidence to support the wide use of heparin in therapeutic doses for COVID-19. Figure 1 illustrates a suggested assessment and therapeutic strategy for this group of patients based on current evidence. 29 The European Society of Cardiology recommended full anticoagulation in all patients with signs of severity, e.g., respiratory rate>24 bpm, arterial oxygen saturation<90%, high C-reactive 296