Ticagrelor

Ticagrelor
Names
Trade namesBrilinta, Brilique, others
Other namesAZD-6140
IUPAC name
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
Clinical data
Drug classAdenosine diphosphate receptor inhibitor[1]
Main usesPrevent stroke or heart attacks in acute coronary syndrome[2][3]
Side effectsBleeding, shortness of breath[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa611050
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    Pharmacokinetics
    Bioavailability36%
    Protein binding>99.7%
    MetabolismLiver (CYP3A4)
    Elimination half-life7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)
    ExcretionBile duct
    Chemical and physical data
    FormulaC23H28F2N6O4S
    Molar mass522.57 g·mol−1
    3D model (JSmol)
    SMILES
    • CCCSC1=NC(=C2C(=N1)N(N=N2)[C@@H]3C[C@@H]([C@H]([C@H]3O)O)OCCO)N[C@@H]4C[C@H]4C5=CC(=C(C=C5)F)F
    InChI
    • InChI=1S/C23H28F2N6O4S/c1-2-7-36-23-27-21(26-15-9-12(15)11-3-4-13(24)14(25)8-11)18-22(28-23)31(30-29-18)16-10-17(35-6-5-32)20(34)19(16)33/h3-4,8,12,15-17,19-20,32-34H,2,5-7,9-10H2,1H3,(H,26,27,28)/t12-,15+,16+,17-,19-,20+/m0/s1 ☒N
    • Key:OEKWJQXRCDYSHL-FNOIDJSQSA-N ☒N

    Ticagrelor, sold under the brand name Brilinta among others, is a medication used in acute coronary syndrome to prevent stroke and heart attacks.[2][3] It is generally used with aspirin.[2] It is taken by mouth.[2]

    Common side effects include bleeding and shortness of breath.[2] Other side effects may include cough, diarrhea, and low blood pressure.[3] It is a platelet aggregation inhibitor, specifically a adenosine diphosphate receptor inhibitor, which works by blocking ADP from attaching to platelets.[2][1]

    Ticagrelor was approved for medical use in Europe 2010,[2] and in the United States in 2011.[3] In the United Kingdom 4 weeks of medication costs the NHS about £55 as of 2021.[1] In the United States this amount costs about 380 USD as of 2021.[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 suggested that the use of ticagrelor as a pre-treatment in people 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 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.

    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 percutaneous coronary intervention (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.

    Dosage

    90 mg tablet of Brilinta

    In those with acute coronary syndrome the initial dose is generally 180 mg.[2] 90 mg twice per day is than taken.[2] After a year if the medication is continued a dose of 60 mg twice per day is used.[2]

    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][15]

    Side effects

    The common side effects are increased risk of bleeding (which may be severe)[16] and shortness of breath (dyspnoea).[17] 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.[17][18] It does not impact on efficacy or safety outcomes in people with acute coronary syndrome (ACS)[17] and has no association with any adverse changes in heart and lung function.[18]

    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.[19] Caution is recommended when using ticagrelor in patients with advanced sinoatrial node disease.[20] 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[21] and is known to increase the concentrations of CYP3A4 metabolised medications; however, this interaction is unlikely to be clinically significant for atorvastatin and simvastatin[22][21][23] 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[24]) are not significantly influenced by P-gp inhibitors.[5]

    It is recommended to use low-dose aspirin (75–100 mg per day) with ticagrelor as dual antiplatelet therapy (DAPT).[9][25][26][27][28][29] The combination of ticagrelor with aspirin doses greater than 100 mg per day may be less effective.[30]

    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.[31] Moreover, the drug does not need liver 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).[32][33][34]

    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.[24] 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][35]

    Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[36] 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][37]

    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.<[38]

    Ticagrelor as a nucleoside analogue
    The nucleoside adenosine for comparison

    Society and culture

    Cost

    This medication has a cost in the U.S. of $432 (USD) for 60 tablets (90 mg)[39]

    • Ticagrelor costs (US)
      Ticagrelor costs (US)
    • Ticagrelor prescriptions (US)
      Ticagrelor prescriptions (US)

    Research

    A study published in JAMA Cardiology showed antibacterial activity in conventional antiplatelet doses against antibiotic-resistant Gram-positive bacteria, warranting further randomized trials to evaluate its value as antibiotic.[40]

    A reversal agent, bentracimab, is under investigation for use in major or bleeding.[41]

    With clopidogrel

    The PLATO trial[42] 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).[43]

    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.[44] 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.[45]

    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.[42] It's especially of crucial importance for Asian individuals, as they are well-known to be prone to bleeding events.[46] 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.[47][48] 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.[49][50] 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.[51] 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 acute coronary syndrome.[52]

    References

    1. 1 2 3 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 229. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    2. 1 2 3 4 5 6 7 8 9 10 11 "Brilique". Archived from the original on 2 May 2021. Retrieved 3 October 2021.
    3. 1 2 3 4 "Ticagrelor Monograph for Professionals". Drugs.com. Archived from the original on 17 September 2020. Retrieved 3 October 2021.
    4. ↑ "Brilinta Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 5 November 2016. Retrieved 3 October 2021.
    5. 1 2 3 4 5 Haberfeld, H, ed. (2010). Austria-Codex (in Deutsch) (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. ↑ 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.
    16. ↑ 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.
    17. 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.
    18. 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.
    19. ↑ 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.
    20. ↑ 6
    21. 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.
    22. ↑ 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.
    23. ↑ 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.
    24. 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.
    25. ↑ 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.
    26. ↑ 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.
    27. ↑ 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.
    28. ↑ "Brilinta (ticagrelor) Prescribing Information" (PDF). AstraZeneca. 2019. Archived (PDF) from the original on 2021-01-19. Retrieved 2020-05-07.
    29. ↑ "Australia Product Information Brilinta (ticagrelor)". AstraZeneca. 2019. Archived from the original on 2021-08-29. Retrieved 2020-05-07.
    30. ↑ 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.
    31. ↑ 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.
    32. ↑ Spreitzer H (February 4, 2008). "Neue Wirkstoffe - AZD6140". Österreichische Apothekerzeitung (in Deutsch) (3/2008): 135.
    33. ↑ Owen RT, Serradell N, Bolos J (2007). "AZD6140". Drugs of the Future. 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
    34. ↑ 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.
    35. ↑ "Brilique: EPAR – Product Information" (PDF). European Medicines Agency. 2019-10-16. Archived (PDF) from the original on 2018-10-07. Retrieved 2020-06-18.
    36. ↑ Miller R (24 February 2010). "Is there too much excitement for ticagrelor?". TheHeart.org. Archived from the original on 15 April 2013. Retrieved 14 March 2011.
    37. ↑ Spreitzer H (17 January 2011). "Neue Wirkstoffe - Elinogrel". Österreichische Apothekerzeitung (in Deutsch) (2/2011): 10.
    38. ↑ "Assessment Report for Brilique" (PDF). European Medicines Agency. January 2011. Archived (PDF) from the original on 2018-05-17. Retrieved 2011-02-03.
    39. ↑ "Brilinta Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 11 June 2016. Retrieved 8 April 2021.
    40. ↑ 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.
    41. ↑ "A Phase 3, Multicenter, Open-Label, Single-Arm Study of Bentracimab (PB2452) in Ticagrelor-Treated Patients With Uncontrolled Major or Life-Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure (REVERSE-IT Trial)". clinicaltrials.gov. 2021-05-11. Archived from the original on 2021-09-15. Retrieved 2021-10-03. {{cite journal}}: Cite journal requires |journal= (help)
    42. 1 2 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.
    43. ↑ 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.
    44. ↑ 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.
    45. ↑ 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.
    46. ↑ 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.
    47. ↑ 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.
    48. ↑ 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.
    49. ↑ 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.
    50. ↑ 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.
    51. ↑ 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.
    52. ↑ 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.
    External sites:
    Identifiers:
    This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.