Ticagrelor

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Ticagrelor
Ticagrelor.svg
Ticagrelor ball-and-stick animation.gif
Clinical data
Trade names Brilinta, Brilique, formerly Possia
Other namesAZD-6140
AHFS/Drugs.com Monograph
MedlinePlus a611050
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  • US:C (Risk not ruled out)
    Routes of
    administration
    by mouth
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    Legal status
    Pharmacokinetic data
    Bioavailability 36%
    Protein binding >99.7%
    Metabolism Hepatic (CYP3A4)
    Elimination half-life 7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)
    Excretion Biliary
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.114.746 OOjs UI icon edit-ltr-progressive.svg
    Chemical and physical data
    Formula C23H28F2N6O4S
    Molar mass 522.57 g·mol−1
    3D model (JSmol)
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    Ticagrelor (trade name Brilinta, Brilique, and formerly Possia) is a pharmaceutical drug used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor. [1] The drug is produced by AstraZeneca.

    Contents

    It was approved for use in the European Union by the European Medicines Agency on 3 December 2010 [2] [3] and by the US Food and Drug Administration on 20 July 2011. [4]

    Medical uses

    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] The PLATO trial has evidence to suggest that the use of ticagrelor as a pre-treatment in patients with non-ST elevation acute coronary syndrome (non-ST ACS) is superior than using clopidogrel in decreasing ischemic events and the total mortality independent of patients undergoing percutaneous coronary intervention. [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 [7] or history of myocardial infarction.[ citation needed ]

    According to ESC 2017 guidelines, Dual Antiplatelet Therapy (DAPT) with Ticagrelor in combination with Acetylsalicylic acid (Aspirin) is the preferred treatment in patients with acute coronary syndrome with or without ST segment elevation, irrespective of the initial treatment strategy – invasive or non-invasive (IB level of evidence) [8] however if there is a plan for PCI, administration of thrombolysis or the presence of some other patient factors (e.g. high bleeding risk) other antiplatelet agents are recommended. [9] [10] [11] The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy provides similar recommendations, although with a lower level of evidence (IIaB). [12] 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 not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction or death in people with acute ischemic stroke or transient ischemic attack. [13] When associated with ipsilateral atherosclerotic stenosis, however, ticagrelor was found to be superior to aspirin. [14] Further studies are required to assess the role of ticagrelor in acute cerebrovascular disease.

    A study compared ticagrelor and clopidogrel in patients with acute coronary syndrome (PLATO Trial) showed that patients treated with ticagrelor had a lower risk of infection-related deaths. [15] 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. [16]

    Contraindications

    Contraindications to ticagrelor are active bleeding, increased risk of bradycardia, concomitant therapy of ticagrelor and strong cytochrome P-450 3A (CYP3A4) inhibitors and moderate or severe hepatic impairment due to the risk of increased exposure to ticagrelor. [9] [17]

    Adverse effects

    The common adverse effects are increased risk of bleeding (which may be severe) [18] and shortness of breath (dyspnoea). [19] Dyspnoea is usually mild to moderate in intensity, occurs in the first month of treatment, is often self-limiting, and the need for discontinuation is rare. [19] [20] It does not impact on efficacy or safety outcomes in people with acute coronary syndrome (ACS) [19] and has no association with any adverse changes in heart and lung function. [20]

    Ventricular pauses ≥3 seconds may occur in ACS patients the first week of treatment, but are likely to be mostly asymptomatic and transient, without causing increased clinical bradycardic adverse events. [21] Caution is recommended when using ticagrelor in patients with advanced sinoatrial node disease. [22] Allergic skin reactions such as rash and itching have been observed in less than 1% of patients. [5]

    Interactions

    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. Ticagrelor is a weak CYP3A4 inhibitor [23] and is known to increase the concentrations of CYP3A4 metabolised medications, however this interaction is unlikely to be clinically significant for atorvastatin and simvastatin [24] [23] [25] at recommended doses. CYP3A4 inducers, 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 [26] ) are not significantly influenced by P-gp inhibitors. [5]

    It is currently recommended to use low-dose aspirin (75–100 mg per day) with ticagrelor as dual antiplatelet therapy (DAPT). [9] [27] [28] [29] [30] [31] The combination of ticagrelor with aspirin doses greater than 100 mg per day may be less effective. [32]

    Pharmacology

    Mechanism of action

    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. [33] 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). [34] [35] [36]

    Pharmacokinetics

    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. [26] 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 self-identified as 'black' and those with severe renal impairment. These differences are not considered clinically relevant. 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] [37]

    Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel. [38] 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] [39]

    Chemistry

    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 as a nucleoside analogue Ticagrelor.svg
    Ticagrelor as a nucleoside analogue
    The nucleoside adenosine for comparison Adenosin.svg
    The nucleoside adenosine for comparison

    With clopidogrel

    The PLATO trial [40] 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). [41]

    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 hazard ratio 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. [42] 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. [43]

    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. [40] It's especially of crucial importance for Asian individuals, as they are well-known to be prone to bleeding events. [44] 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. [45] [46] 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. [47] [48] 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. [49] 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.

    With prasugrel

    In 2019, the results of the ISAR-REACT 5 trial was published, comparing ticagrelor and prasugrel in patients with acute coronary syndrome. [50]

    Research

    A study published in JAMA showed antibacterial activity in conventional anti-platelet doses against antibiotic-resistant gram-positive bacteria, which needs further randomized trials for use as antibiotic. [51]

    Related Research Articles

    Aspirin medication used to reduce pain, fever, and inflammation

    Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin given shortly after a heart attack decreases the risk of death. Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. It may also decrease the risk of certain types of cancer, particularly colorectal cancer. For pain or fever, effects typically begin within 30 minutes. Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and works similarly to other NSAIDs but also suppresses the normal functioning of platelets.

    Coronary artery disease Disease characterized by plaque building up in the arteries of the heart

    Coronary artery disease (CAD), also known as coronary heart disease (CHD), ischemic heart disease (IHD), or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, myocardial infarction, and sudden cardiac death. A common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. Usually symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.

    An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

    Anticoagulant class of drugs

    Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

    Clopidogrel medication that is used to reduce the risk of heart disease and stroke in those at high risk.

    Clopidogrel, sold under the trade name Plavix among others, is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent. It is taken by mouth. Onset of effects is about two hours and lasts for five days.

    Ticlopidine chemical compound

    Ticlopidine is an antiplatelet drug in the thienopyridine family which is an adenosine diphosphate (ADP) receptor inhibitor. Research initially showed that it was useful for preventing strokes and coronary stent occlusions. However, because of its rare but serious side effects of neutropenia and thrombotic thrombocytopenic purpura it was primarily used in patients in whom aspirin was not tolerated, or in whom dual antiplatelet therapy was desirable. With the advent of newer and safer antiplatelet drugs such as clopidogrel and ticagrelor, its use remained limited.

    Prasugrel drug that acts as a platelet inhibitor and is used to prevent formation of blood clots.

    Prasugrel (trade name Effient in the US, Australia and India, and Efient in the EU) is a drug used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company.

    Acute coronary syndrome group of symptoms attributed to obstruction of the coronary arteries

    Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is chest pain, often radiating to the left shoulder or angle of the jaw, crushing, central and associated with nausea and sweating. Many people with acute coronary syndromes present with symptoms other than chest pain, particularly, women, older patients, and patients with diabetes mellitus.

    Unstable angina (UA), also called crescendo angina, is a type of angina pectoris that is irregular. It is also classified as a type of acute coronary syndrome (ACS).

    P2Y12 protein-coding gene in the species Homo sapiens

    P2Y12 is a chemoreceptor for adenosine diphosphate (ADP) that belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors. This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.

    Bivalirudin specific and reversible direct thrombin inhibitor

    Bivalirudin is a direct thrombin inhibitor (DTI).

    The history of invasive and interventional cardiology is complex, with multiple groups working independently on similar technologies. Invasive and interventional cardiology is currently closely associated with cardiologists, though the development and most of its early research and procedures were performed by diagnostic and interventional radiologists.

    Vorapaxar chemical compound

    Vorapaxar is a thrombin receptor antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co.

    Thienopyridine

    Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity.

    Myocardial infarction Interruption of blood supply to a part of the heart

    A myocardial infarction (MI), also known as a heart attack, occurs when blood flow decreases or stops to a part of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck or jaw. Often it occurs in the center or left side of the chest and lasts for more than a few minutes. The discomfort may occasionally feel like heartburn. Other symptoms may include shortness of breath, nausea, feeling faint, a cold sweat or feeling tired. About 30% of people have atypical symptoms. Women more often present without chest pain and instead have neck pain, arm pain or feel tired. Among those over 75 years old, about 5% have had an MI with little or no history of symptoms. An MI may cause heart failure, an irregular heartbeat, cardiogenic shock or cardiac arrest.

    Cangrelor chemical compound

    Cangrelor (trade name Kengreal in the US and Kengrexal in Europe) is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.

    Adenosine diphosphate (ADP) receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome (ACS) or in preventive treatment for patients who are in risk of thromboembolism, myocardial infarction or a stroke. These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. The P2Y12 receptor is a surface bound protein found on blood platelets. They belong to G protein-coupled purinergic receptors (GPCR) and are chemoreceptors for ADP.

    Reperfusion therapy is a medical treatment to restore blood flow, either through or around, blocked arteries, typically after a heart attack. Reperfusion therapy includes drugs and surgery. The drugs are thrombolytics and fibrinolytics used in a process called thrombolysis. Surgeries performed may be minimally-invasive endovascular procedures such as a percutaneous coronary intervention (PCI), followed by a coronary angioplasty. The angioplasty uses the insertion of a balloon to open up the artery, with the possible additional use of one or more stents. Other surgeries performed are the more invasive bypass surgeries that graft arteries around blockages.

    Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the afflicted area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.

    Regrelor

    Regrelor is an experimental antiplatelet drug that was under investigation by Merck Sharp and Dohme in human clinical trials. Although it was initially found to be well tolerated in healthy subjects, safety concerns led to cessation of clinical trials.

    References

    1. Jacobson KA, Boeynaems JM (July 2010). "P2Y nucleotide receptors: promise of therapeutic applications". Drug Discovery Today. 15 (13–14): 570–8. doi:10.1016/j.drudis.2010.05.011. PMC   2920619 . PMID   20594935.
    2. 1 2 "Assessment Report for Brilique" (PDF). European Medicines Agency. January 2011.
    3. European Public Assessment Report Possia
    4. "FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes". FDA. 20 July 2011. Archived from the original on 12 January 2017.
    5. 1 2 3 4 5 Haberfeld, H, ed. (2010). Austria-Codex (in German) (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
    6. Lindholm, D.; Varenhorst, C.; Cannon, C. P.; Harrington, R. A.; Himmelmann, A.; Maya, J.; Husted, S.; Steg, P. G.; Cornel, J. H.; Storey, R. F.; Stevens, S. R. (2014-08-01). "Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial". European Heart Journal. 35 (31): 2083–2093. doi:10.1093/eurheartj/ehu160. ISSN   0195-668X. PMC   4132637 . PMID   24727884.
    7. Ticagrelor Monograph . Accessed 2020-05-08.
    8. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. (January 2018). "2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)". European Heart Journal. 39 (3): 213–260. doi: 10.1093/eurheartj/ehx419 . PMID   28886622.
    9. 1 2 3 Wallentin, Lars; Becker, Richard C.; Budaj, Andrzej; Cannon, Christopher P.; Emanuelsson, Håkan; Held, Claes; Horrow, Jay; Husted, Steen; James, Stefan; Katus, Hugo; Mahaffey, Kenneth W. (2009-09-10). "Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes". New England Journal of Medicine. 361 (11): 1045–1057. doi:10.1056/NEJMoa0904327. hdl: 2437/95141 . ISSN   0028-4793. PMID   19717846.
    10. Wiviott, Stephen D.; Braunwald, Eugene; McCabe, Carolyn H.; Montalescot, Gilles; Ruzyllo, Witold; Gottlieb, Shmuel; Neumann, Franz-Joseph; Ardissino, Diego; De Servi, Stefano; Murphy, Sabina A.; Riesmeyer, Jeffrey (2007-11-15). "Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes". New England Journal of Medicine. 357 (20): 2001–2015. doi:10.1056/NEJMoa0706482. ISSN   0028-4793. PMID   17982182.
    11. Schüpke, Stefanie; Neumann, Franz-Josef; Menichelli, Maurizio; Mayer, Katharina; Bernlochner, Isabell; Wöhrle, Jochen; Richardt, Gert; Liebetrau, Christoph; Witzenbichler, Bernhard; Antoniucci, David; Akin, Ibrahim (2019-10-17). "Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes". New England Journal of Medicine. 381 (16): 1524–1534. doi: 10.1056/NEJMoa1908973 . ISSN   0028-4793. PMID   31475799.
    12. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. (September 2016). "2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Journal of the American College of Cardiology. 68 (10): 1082–115. doi: 10.1016/j.jacc.2016.03.513 . PMID   27036918.
    13. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, et al. (July 2016). "Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack". The New England Journal of Medicine. 375 (1): 35–43. doi: 10.1056/NEJMoa1603060 . PMID   27160892.
    14. Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, et al. (April 2017). "Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial". The Lancet. Neurology. 16 (4): 301–310. doi:10.1016/S1474-4422(17)30038-8. PMID   28238711. S2CID   22260221.
    15. Storey RF, James SK, Siegbahn A, Varenhorst C, Held C, Ycas J, et al. (November 2014). "Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study". Platelets. 25 (7): 517–25. doi:10.3109/09537104.2013.842965. PMC   4220996 . PMID   24127651.
    16. Sexton TR, Zhang G, Macaulay TE, Callahan LA, Charnigo R, Vsevolozhskaya OA, et al. (August 2018). "Ticagrelor Reduces Thromboin flammatory Markers in Patients with Pneumonia". JACC. Basic to Translational Science. 3 (4): 435–449. doi:10.1016/j.jacbts.2018.05.005. PMC   6115703 . PMID   30175268.
    17. Davis, Estella; Knezevich, Jon; Teply, Robyn (April 2013). "Advances in antiplatelet technologies to improve cardiovascular disease morbidity and mortality: a review of ticagrelor". Clinical Pharmacology: Advances and Applications. 5: 67–83. doi: 10.2147/cpaa.s41859 . ISSN   1179-1438. PMC   3640601 . PMID   23650452.
    18. Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Cornel JH, et al. (December 2011). "Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial". European Heart Journal. 32 (23): 2933–44. doi: 10.1093/eurheartj/ehr422 . PMID   22090660.
    19. 1 2 3 Storey RF, Becker RC, Harrington RA, Husted S, James SK, Cools F, et al. (December 2011). "Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes". European Heart Journal. 32 (23): 2945–53. doi: 10.1093/eurheartj/ehr231 . PMID   21804104.
    20. 1 2 Storey RF, Bliden KP, Patil SB, Karunakaran A, Ecob R, Butler K, et al. (July 2010). "Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study". Journal of the American College of Cardiology. 56 (3): 185–93. doi: 10.1016/j.jacc.2010.01.062 . PMID   20620737.
    21. Scirica, Benjamin M.; Cannon, Christopher P.; Emanuelsson, Håkan; Michelson, Eric L.; Harrington, Robert A.; Husted, Steen; James, Stefan; Katus, Hugo; Pais, Prem; Raev, Dimitar; Spinar, Jindrich (May 2011). "The Incidence of Bradyarrhythmias and Clinical Bradyarrhythmic Events in Patients With Acute Coronary Syndromes Treated With Ticagrelor or Clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) Trial". Journal of the American College of Cardiology. 57 (19): 1908–1916. doi: 10.1016/j.jacc.2010.11.056 . ISSN   0735-1097. PMID   21545948.
    22. 6 [ dead link ]
    23. 1 2 Danielak D, Karaźniewicz-Łada M, Główka F (July 2018). "Assessment of the Risk of Rhabdomyolysis and Myopathy During Concomitant Treatment with Ticagrelor and Statins". Drugs. 78 (11): 1105–1112. doi:10.1007/s40265-018-0947-x. PMC   6061431 . PMID   30003466.
    24. Teng R, Mitchell PD, Butler KA (March 2013). "Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers". European Journal of Clinical Pharmacology. 69 (3): 477–87. doi:10.1007/s00228-012-1369-4. PMID   22922682. S2CID   17914035.
    25. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. (September 2009). "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". The New England Journal of Medicine. 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. hdl: 2437/95141 . PMID   19717846.
    26. 1 2 Teng R, Oliver S, Hayes MA, Butler K (September 2010). "Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects". Drug Metabolism and Disposition. 38 (9): 1514–21. doi:10.1124/dmd.110.032250. PMID   20551239. S2CID   22084793.
    27. Chew DP, Scott IA, Cullen L, French JK, Briffa TG, Tideman PA, et al. (September 2016). "National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Management of Acute Coronary Syndromes 2016". Heart, Lung & Circulation. 25 (9): 895–951. doi: 10.1016/j.hlc.2016.06.789 . PMID   27476580.
    28. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. (January 2016). "2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC)". European Heart Journal. 37 (3): 267–315. doi: 10.1093/eurheartj/ehv320 . PMID   26320110.
    29. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. (December 2014). "2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology. 64 (24): e139–e228. doi: 10.1016/j.jacc.2014.09.017 . PMID   25260718.
    30. "Brilinta (ticagrelor) Prescribing Information" (PDF). AstraZeneca. 2019.
    31. "Australia Product Information Brilinta (ticagrelor)". AstraZeneca. 2019.
    32. Mahaffey KW, Wojdyla DM, Carroll K, Becker RC, Storey RF, Angiolillo DJ, et al. (August 2011). "Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial". Circulation. 124 (5): 544–54. doi: 10.1161/CIRCULATIONAHA.111.047498 . PMID   21709065.
    33. Birkeland K, Parra D, Rosenstein R (2010). "Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor". Journal of Blood Medicine. 1: 197–219. doi:10.2147/JBM.S9650. PMC   3262315 . PMID   22282698.
    34. Spreitzer H (February 4, 2008). "Neue Wirkstoffe - AZD6140". Österreichische Apothekerzeitung (in German) (3/2008): 135.
    35. Owen RT, Serradell N, Bolos J (2007). "AZD6140". Drugs of the Future. 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
    36. [ unreliable medical source? ]Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, Gurbel PA (December 2010). "First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies". Circulation. Cardiovascular Genetics. 3 (6): 556–66. doi: 10.1161/CIRCGENETICS.110.958561 . PMID   21079055.
    37. "Brilique: EPAR – Product Information" (PDF). European Medicines Agency. 2019-10-16.
    38. Miller R (24 February 2010). "Is there too much excitement for ticagrelor?". TheHeart.org.
    39. Spreitzer H (17 January 2011). "Neue Wirkstoffe - Elinogrel". Österreichische Apothekerzeitung (in German) (2/2011): 10.
    40. 1 2 [ unreliable medical source? ]Cannon CP, Harrington RA, James S, Ardissino D, Becker RC, Emanuelsson H, et al. (January 2010). "Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study". Lancet. 375 (9711): 283–93. doi:10.1016/S0140-6736(09)62191-7. PMID   20079528. S2CID   22469812.
    41. [ unreliable medical source? ]Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. (September 2009). "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". The New England Journal of Medicine. 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. hdl: 2437/95141 . PMID   19717846.
    42. Lombo B, Díez JG (2011). "Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes". Core Evidence. 6: 31–42. doi:10.2147/CE.S9510. PMC   3065559 . PMID   21468241.
    43. Serebruany VL, Atar D (September 2012). "Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials--common patterns in TRITON, RECORD, and PLATO?". Thrombosis and Haemostasis. 108 (3): 412–4. doi:10.1160/TH12-04-0251. PMID   22836596.
    44. Mak KH, Bhatt DL, Shao M, Hankey GJ, Easton JD, Fox KA, Topol EJ (April 2009). "Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study". American Heart Journal. 157 (4): 658–65. doi:10.1016/j.ahj.2008.08.031. PMID   19332192.
    45. Misumida N, Aoi S, Kim SM, Ziada KM, Abdel-Latif A (September 2018). "Ticagrelor versus clopidogrel in East Asian patients with acute coronary syndrome: Systematic review and meta-analysis". Cardiovascular Revascularization Medicine. 19 (6): 689–694. doi:10.1016/j.carrev.2018.01.009. PMID   29452843.
    46. Wu B, Lin H, Tobe RG, Zhang L, He B (March 2018). "Ticagrelor versus clopidogrel in East-Asian patients with acute coronary syndromes: a meta-analysis of randomized trials". Journal of Comparative Effectiveness Research. 7 (3): 281–291. doi:10.2217/cer-2017-0074. PMID   29094604.
    47. Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T (2015). "Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome -- randomized, double-blind, phase III PHILO study". Circulation Journal. 79 (11): 2452–60. doi: 10.1253/circj.CJ-15-0112 . PMID   26376600.
    48. Kang HJ, Clare RM, Gao R, Held C, Himmelmann A, James SK, et al. (June 2015). "Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial". American Heart Journal. 169 (6): 899–905.e1. doi: 10.1016/j.ahj.2015.03.015 . PMID   26027629.
    49. Galimzhanov AM, Azizov BS (2019). "Ticagrelor for Asian patients with acute coronary syndrome in real-world practice: A systematic review and meta-analysis of observational studies". Indian Heart Journal. 71 (1): 15–24. doi: 10.1016/j.ihj.2019.01.003 . PMC   6477146 . PMID   31000178.
    50. Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, et al. (October 2019). "Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes". The New England Journal of Medicine. 381 (16): 1524–1534. doi: 10.1056/NEJMoa1908973 . PMID   31475799.
    51. Lancellotti P, Musumeci L, Jacques N, Servais L, Goffin E, Pirotte B, Oury C (June 2019). "Antibacterial Activity of Ticagrelor in Conventional Antiplatelet Dosages Against Antibiotic-Resistant Gram-Positive Bacteria". JAMA Cardiology. 4 (6): 596–599. doi:10.1001/jamacardio.2019.1189. PMC   6506905 . PMID   31066863.