Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial.

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19. Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

The Effectiveness of Antiplatelet Therapy and the Factors Influencing It in Patients with Acute Coronary Syndrome before and during the COVID-19 Pandemic.

Background and Objectives: Dual antiplatelet therapy (DAPT) is essential in the treatment of patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the effectiveness of antiplatelet medication in our practice and to investigate the factors that influence it. Materials and Methods: A prospective cohort observational study was conducted, in which 193 patients with ACS were enrolled. The patients were stented in the catheterization laboratory between May 2019 and October 2020, before and during the COVID-19 pandemic, and were receiving DAPT. Their platelet functions were tested using a Multiplate Analyzer. In addition to this, clinical data, demographics, laboratory tests, and cardiovascular risk factors were also analyzed. Results: 43.46% of the patients treated with aspirin were found to be resistant to it. This phenomenon was more common in men (48.17% vs. 31.48%, p = 0.036), and it was associated with being under the age of 50 (OR: 2.08; 95% CI: 1.11-3.90) and weighing over 70 kg (OR: 3.00; 95% CI: 1.21-7.40). Most of the patients treated with clopidogrel were in the optimal treatment window, while about half of the patients treated with ticagrelor had an exaggerated pharmacological response. Among the laboratory parameters, leukocytosis and platelet count were found to be determinants of platelet reactivity for both the aspirin and ticagrelor treatments. Conclusions: Many patients treated with antiplatelet agents are outside of the treatment window. The results obtained showed that low doses of gastro-resistant aspirin tablets are ineffective, and their efficacy can be influenced by various clinical and laboratory factors. Patients receiving ticagrelor have significantly reduced platelet reactivity, influenced only by certain laboratory indicators. The pandemic significantly influenced the results of the platelet aggregation tests only in patients treated with clopidogrel.

Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies.

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.

Pleiotropic Effects of Ticagrelor: Influence on CYP4F2 Gene and Protein Expression in HUVEC and HepG2, and Escherichia coli Bacterial Survival.

Background: Antiplatelet drugs, such as ticagrelor, which target platelet P2Y12 receptors, are used for prevention of ischemic heart disease. Ticagrelor is also known to have pleiotropic effects of unknown mechanisms. Ticagrelor could influence the expression of molecules involved in resolution of inflammation. This study aimed to investigate if ticagrelor could change the expression of CYP4F2 and its encoded protein concentration and, additionally, to determine ticagrelor possible antibacterial activity against gram-negative bacteria. Methods: CYP4F2 expression was determined in HUVEC and HepG2 cell lines by qPCR. CYP4F2 protein concentration was determined by ELISA. Antibiotic susceptibility testing was performed using a disc diffusion method. Results: Ticagrelor was observed to reduce the expression of CYP4F2 in HUVEC and HepG2 cell lines. It also reduced CYP4F2 protein levels in HUVEC cells. Ticagrelor had no bactericidal activity against gram-negative third generation cephalosporin resistant E. coli. Conclusion: Ticagrelor reduced CYP4F2 protein concentration in HUVEC, and CYP4F2 expression in HUVEC and HepG2 cells, but had no effect on third-generation cephalosporin-resistant E. coli strains.

Potential antiviral properties of antiplatelet agents against SARS-CoV-2 infection: an in silico perspective.

SARS-CoV-2 represents the causative agent of the current pandemic (COVID-19). The drug repurposing technique is used to search for possible drugs that can bind to SARS-CoV-2 proteins and inhibit viral replication. In this study, the FDA-approved antiplatelets are tested against the main protease and spike proteins of SARS-CoV-2 using in silico methods. Molecular docking and molecular dynamics simulation are used in the current study. The results suggest the effectiveness of vorapaxar, ticagrelor, cilostazol, cangrelor, and prasugrel in binding the main protease (Mpro) of SARS-CoV-2. At the same time, vorapaxar, ticagrelor, and cilostazol are the best binders of the spike protein. Therefore, these compounds could be successful candidates against COVID-19 that need to be tested experimentally.

Type 2 myocardial infarction and myocardial injury: eligibility for novel medical therapy to derisk clinical trials.

BACKGROUND: Patients with type 2 myocardial infarction (T2MI) and other mechanisms of nonthrombotic myocardial injury have an unmet therapeutic need. Eligibility for novel medical therapy is generally uncertain. METHODS: We predefined colchicine, eplerenone and ticagrelor as candidates for repurposing towards novel therapy for T2MI or myocardial injury. Considering eligibility for randomisation in a clinical trial, each drug was classified according to indications and contraindications for therapy and survival for at least 24 hours following admission. Eligibility criteria for prescription were evaluated against the Summary of Medical Product Characteristics. Consecutive hospital admissions were screened to identify patients with ≥1 high-sensitivity troponin-I value >99th percentile. Endotypes of myocardial injury were adjudicated according to the Fourth Universal Definition of MI. Patients' characteristics and medication were prospectively evaluated. RESULTS: During 1 March to 15 April 2020, 390 patients had a troponin I>URL. Reasons for exclusion: type 1 MI n=115, indeterminate diagnosis n=42, lack of capacity n=14, death <24 hours n=7, duplicates n=2. Therefore, 210 patients with T2MI/myocardial injury and 174 (82.8%) who survived to discharge were adjudicated for treatment eligibility. Patients who fulfilled eligibility criteria initially on admission and then at discharge were colchicine 25/210 (11.9%) and 23/174 (13.2%); eplerenone 57/210 (27.1%) and 45/174 (25.9%); ticagrelor 122/210 (58.1%) and 98/174 (56.3%). Forty-six (21.9%) and 38 (21.8%) patients were potentially eligible for all three drugs on admission and discharge, respectively. CONCLUSION: A reasonably high proportion of patients may be considered eligible for repurposing novel medical therapy in secondary prevention trials of type 2 MI/myocardial injury.