Ticagrelor

Ticagrelor (trade name Brilinta, Brilique, and Possia) is a platelet aggregation inhibitor produced by AstraZeneca.

Ticagrelor
Clinical data
Trade namesBrilinta, Brilique, Possia
Other namesAZD-6140
AHFS/Drugs.comMonograph
MedlinePlusa611050
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration
    by mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability36%
    Protein binding>99.7%
    MetabolismHepatic (CYP3A4)
    Elimination half-life7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)
    ExcretionBiliary
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEMBL
    ECHA InfoCard100.114.746
    Chemical and physical data
    FormulaC23H28F2N6O4S
    Molar mass522.567 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    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]

    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] 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.

    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

    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]

    Adverse effects

    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]

    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. 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]

    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
    The nucleoside adenosine for comparison

    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.[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]

    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.[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]

    Comparison with clopidogrel

    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 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.[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.

    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. "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.
    5. Haberfeld, H, ed. (2010). Austria-Codex (in German) (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
    6. Bellemain-Appaix A, Kerneis M, O'Connor SA, Silvain J, Cucherat M, Beygui F, et al. (October 2014). "Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis". BMJ. 349: g6269. doi:10.1136/bmj.g6269. PMC 4208629. PMID 25954988.
    7. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN (August 2017). "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.
    8. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O-Gara PT, Sabatine MS, Smith PK, Smith SC (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): 1082–1115. doi:10.1016/j.jacc.2016.03.513. PMID 27036918.
    9. 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.
    10. Lancellotti P, Musumeci L, Jacques N, Servais L, Goffin E, Pirotte B, Oury C (May 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.
    11. 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.
    12. Sexton TR, Zhang G, Macaulay TE, Callahan LA, Charnigo R, Vsevolozhskaya OA, et al. (August 2018). "Ticagrelor Reduces Thromboinflammatory 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.
    13. Brilinta: Highlights of prescribing information
    14. 6
    15. 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.
    16. Husten L (July 20, 2011). "AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval ?". CardioBrief. Blog at WordPress.com.
    17. Miller R (24 February 2010). "Is there too much excitement for ticagrelor?". TheHeart.org.
    18. Spreitzer H (17 January 2011). "Neue Wirkstoffe - Elinogrel". Österreichische Apothekerzeitung (in German) (2/2011): 10.
    19. 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.
    20. Spreitzer H (February 4, 2008). "Neue Wirkstoffe - AZD6140". Österreichische Apothekerzeitung (in German) (3/2008): 135.
    21. Owen RT, Serradell N, Bolos J (2007). "AZD6140". Drugs of the Future. 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
    22. 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.
    23. 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.
    24. 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.
    25. 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.
    26. 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.
    27. Mak KH, Bhatt DL, Shao M, Hankey GJ, Easton JD, Fox KA, Topol EJ (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): 658–665. doi:10.1016/j.ahj.2008.08.031. PMID 19332192.
    28. Misumida N, Aoi S, Kim SM, Ziada KM, Abdel-Latif A (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.
    29. Wu B, Lin H, Tobe RG, Zhang L, He B (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.
    30. 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): 2452–2460. doi:10.1253/circj.CJ-15-0112.
    31. Kang HJ, Clare RM, Gao R, Held C, Himmelmann A, James SK, Lim ST, Santoso A, Yu CM, Wallentin L, Becker RC (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. doi:10.1016/j.ahj.2015.03.015.
    32. 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.
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