Ticagrelor (trade name Brilinta, Brilique, and Possia) is a platelet aggregation inhibitor produced by AstraZeneca. Ticagrelor is an antagonist of the P2Y12 receptor.[1] The drug was approved for use in the European Union by the European Medicines Agency on December 3, 2010.[2][3] The drug was approved by the US Food and Drug Administration on July 20, 2011.[4] Ticagrelor is used for the prevention of thrombotic events (for example stroke or heart attack) in different categories of patients. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.[5] There is no high quality evidence for the use of ticagrelor before percutaneous coronary intervention (PCI) in non-ST elevation acute coronary syndrome.[6] The FDA indication for ticagrelor is reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in people with acute coronary syndrome or history of myocardial infarction.[citation needed] According ESC 2017 guidelines, ticagrelor is the first-option treatment in patients with acute coronary syndrome with or without ST segment elevation, irrespective of treatment strategy (invasive or non-invasive) - IB level of evidence.[7] The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy provides similar recommendations, although with the lower level of evidence - IIaB.[8] Furthermore, the 2017 ESC Focused Update on Duration of Dual Antiplatelet Therapy allows physicians to administer ticagrelor to patients with stable coronary artery disease undergoing percutaneous coronary intervention after taking thrombotic and haemorrhagic risk into consideration. Ticagrelor was found to be comparable to aspirin in people with acute ischemic stroke or transient ischemic attack.[9] A study published in JAMA reveals antibacterial activity in conventional anti platelet dose against antibiotic-resistant gram-positive bacteria which needs further randomized trails for use as antibiotic.[10] Another study compared ticagrelor and clopidogrel in patients with acute coronary syndrome (PLATO Trial) revealed that patients treated with Ticagrelor had a lower risk of infection-related deaths.[11] The Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE) study showed improvement in lung function in patients hospitalized for pneumonia in patients using ticagrelor.[12] Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzyme CYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.[5] The most common side effects are shortness of breath (dyspnea, 14%)[13] and various types of bleeding, such as hematoma, nosebleed, gastrointestinal, subcutaneous or dermal bleeding. Ventricular pauses of 3 seconds occur in 5 percent of people in the first week of treatment. Ticagrelor should be administered with caution or avoided in patients with advanced sinoauricular disease.[14] Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[5] Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels of ticagrelor and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John's wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9. The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxin, ciclosporin and other P-gp substrates. Levels of ticagrelor and AR-C124910XX (the active metabolite of ticagrelor formed by O-deethylation[15]) are not significantly influenced by P-gp inhibitors.[5] In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.[16] Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity to adenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.[2] Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[15] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor's plasma concentrations. Drug and metabolite are mainly excreted via bile and feces. Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as 'coloured' and those with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.[5] Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[17] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.[5][18] Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.[19] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).[20][21][22] The PLATO trial[23] found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084) and higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, p=0.03). While the patient group on ticagrelor had more instances of fatal intracranial bleeding, there were significantly fewer cases of fatal non-intracranial bleeding, leading to an overall neutral effect on fatal or life-threatening bleeding vs. clopidogrel (p=0.70). Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, p<0.001).[24] The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.[25] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials' primary efficacy outcomes should not be significant.[26] Also, there are some disagreement regarding efficacy and safety of ticagrelor in Asian patients. As mentioned before, ticagrelor provides significant thrombotic benefits, but increases bleeding risk at the same time.[23] It's especially of crucial importance for Asian individuals, as they are well-known to be prone to bleeding events.[27] Current evidence on the risk/benefit ratio of ticagrelor in this vulnerable population is somewhat controversial. Some meta-analyses of randomized controlled trials (RCTs) suggested that ticagrelor was associated with an increase in serious haemorrhagic events, which wasn't accompanied with ischaemic advantages in Asian patients.[28][29] However, these meta-analyses were mainly based on results of two RCTs with relatively small sample size and other pitfalls in design, which prevents researchers from generalization on the whole Asian population.[30][31] On the other hand, recent meta-analysis of observational studies implied that ticagrelor provides ischaemic benefits (mainly by reducing the risk of stroke) without a significant increase in major bleeding.[32] The "real-world" settings gave strong support for this study, nevertheless, further high-quality research are of vital importance to provide definite recommendations for clinical practice.