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Table of Contents   
REVIEW ARTICLE  
Year : 2013  |  Volume : 6  |  Issue : 1  |  Page : 14-19
Ticagrelor: A new antiplatelet drug for acute coronary syndromes


Department of Clinical Pharmacy, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India

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Date of Web Publication18-Jul-2013
 

   Abstract 

Coronary heart disease and acute coronary syndrome (ACS) are a significant cause of morbidity and mortality all over the world. Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS), usually with aspirin and a thienopyridine. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice, and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Clopidogrel, the most commonly used thienopyridine, is limited by a high degree of interpatient variability and inconsistent inhibition of platelets. Ticagrelor, a new, oral, direct-acting P2Y12 receptor antagonist, produces a more profound and consistent antiplatelet effect than clopidogrel. The U.S. Food and Drug Administration approved Ticagrelor on July 20, 2011. Furthermore, ticagrelor has at least one active metabolite, which has pharmacokinetics that are very similar to the parent compound. Therefore, ticagrelor has a more rapid onset and more pronounced platelet inhibition than other antiplatelet agents. The safety and efficacy of ticagrelor compared with clopidogrel, in an ACS patient, has been recently evaluated by the PLATelet inhibition and patient Outcomes (PLATO) trial. Clinical studies of patients with both ST-elevation and non-ST-elevation ACS have shown that ticagrelor, when compared with clopidogrel, reduces the rates of vascular death and myocardial infarction. The clinical data currently available indicate that ticagrelor is a promising option for the treatment of patients with ACS and may be of particular use in those at high risk for ischemic events or in those unresponsive to clopidogrel.

Keywords: Acute coronary syndrome, adenosine diphosphate receptor, platelet aggregation, ticagrelor

How to cite this article:
Patel TV, Shah JS, Patel CN. Ticagrelor: A new antiplatelet drug for acute coronary syndromes. Ann Trop Med Public Health 2013;6:14-9

How to cite this URL:
Patel TV, Shah JS, Patel CN. Ticagrelor: A new antiplatelet drug for acute coronary syndromes. Ann Trop Med Public Health [serial online] 2013 [cited 2018 Dec 15];6:14-9. Available from: http://www.atmph.org/text.asp?2013/6/1/14/115169

   Introduction Top


The term acute coronary syndrome (ACS) is used to refer to a group of clinical symptoms associated with acute myocardial ischemia. [1] It encompasses unstable angina, non-ST segment elevation myocardial infarction, and ST segment elevation myocardial infarction. [2] ACS is usually the result of an acute or subacute primary reduction of the myocardial oxygen supply, provoked by the disruption of an atherosclerotic plaque, associated with inflammation, thrombosis, vasoconstriction, and microembolization. [1],[3]

Each year, in the United States, approximately 1.36 million hospitalizations are required for ACS (listed either as a primary or a secondary discharge diagnosis), of which 0.81 million are for myocardial infarction (MI) and the remainder are for unstable angina (UA). Roughly two-thirds of the patients with MI have Non-ST elevation myocardial infarction (NSTEMI); the rest have ST Elevation Myocardial Infarction (STEMI). [4],[5]

A number of factors are directly responsible for the development and progression of endothelial dysfunction and atherosclerosis, including hypertension, age, male gender, tobacco use, diabetes, obesity, elevated plasma homocysteine concentrations, and dyslipidemias. [6],[7]

A patient with ACS is generally treated with, (1) anti-ischemic and analgesic therapy (nitrates, morphine sulfate, beta-adrenergic blockers, calcium channel blockers, inhibitors of the renin-angiotensin-aldosterone system, intra-aortic balloon counter pulsation, analgesic therapy), (2) antiplatelet therapy (aspirin, ticlopidine, clopidogrel), (3) anticoagulants (unfractionated heparin, low molecular-weight heparin, long-term anticoagulant-like warfarin), and (4) platelet GP IIb / IIIa receptor antagonists. [8]


   Ticagrelor Top


The combination of aspirin and thienopyridine (clopidogrel or prasugrel) currently used, provides irreversible platelet inhibition, with recovery of platelet function after five to seven days, by the production of new platelets. Ticagrelor, the first reversibly binding, direct-acting oral P2Y12 receptor antagonist leads to greater and more consistent P2Y12 inhibition than clopidogrel, with a more rapid onset and offset of P2Y12 inhibition than clopidogrel. [9],[10],[11],[12],[13] The US Food and Drug Administration (FDA) has approved ticagrelor, a new oral antiplatelet agent, on July 20, 2011, for the prevention of thrombotic events, in patients with acute coronary syndromes. [14],[15]


   Chemistry and Pharmacology Top


Ticagrelor [(1S,2S,3R,5S)-3-[7-{ [(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino} -5-(propylthio)-3H- [1, 2, 3]-triazolo [4,5 d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol], is a cyclopentyl-triazolo- pyrimidine (CPTP), a new chemical class of antiplatelet agents that differs from both thienopyridines and adenosine triphosphate (ATP) analogs [Figure 1]. [16],[17] Adenine di-Phosphate (ADP) is an important physiological agonist that can independently stimulate platelet aggregation, as well as, amplify the effects of other platelet agonists. [18] ADP contributes to platelet aggregation by the activation of at least 2 G-protein-coupled receptors, P2Y1, and P2Y12. The agonism of the P2Y1 receptor leads to a rapid platelet shape change and reversible aggregation. The simultaneous activation of P2Y12 allows for a slow, yet progressive, platelet aggregation. Concomitant activation of both receptors is crucial to elicit a normal platelet response. [18],[19] However, P2Y12 also mediates thrombus growth and stability and has a more selective tissue distribution than P2Y1, making it an optimal target for therapeutic intervention. [19],[20] Ticagrelor is not a thienopyridine, but rather a cyclopentyltriazolo-pyrimidine, a new chemical drug class that allows it to be mechanistically different from the existing antiplatelet agents [Figure 1]. Ticagrelor binds and reversibly antagonizes ADP at the P2Y12 platelet receptor. [20] Furthermore, ticagrelor displays noncompetitive binding with ADP, indicating that the antagonism may be due to an independent ligand-binding site on the P2Y12 receptor. [21] As ticagrelor does not directly inhibit ADP, its proposed activity stems from a conformational change in the receptor, rendering it inactive and unable to signal platelet activation [Figure 2]. Ticagrelor, upon dissociation from the receptor, leaves the receptor intact, revealing that its ability to inhibit platelets is a dose-dependent and reversible process. [20],[21]
Figure 1: Chemical structures of the P2Y12 receptor antagonists (a) Thienopyridine, clopidogrel (b) Thienopyridine, prasugrel (c) Cyclopentyl-triazolo-pyrimidine, ticagrelor

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Figure 2: Adenosine diphosphate (ADP) binds to the P2Y12 receptor and stimulates platelet activation, which ultimately leads to a conformational shape change of the platelet, thrombin generation, and platelet aggregation. Clopidogrel and prasugrel directly and irreversibly block ADP through the antagonism of the P2Y12 receptor for the life of the platelet. Ticagrelor binds at a separate P2Y12 sub-receptor that non-competitively blocks ADP activation, through inactivating the receptor. Ticagrelor has reversible binding and leaves the receptor intact. Antiplatelet agents working at P2Y12 can be used simultaneously with aspirin, due to separate and complementary mechanisms of action, thromboxane A2 (TxA2), glycoprotein (GP), cyclooxygenase (COX), thromboxane A2 receptor (TP)[22]

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   Mechanism of Action Top


Ticagrelor (AZD6140) is the first drug of a new chemical class called cyclopentyltriazolopyrimidine, which is administered orally and has a reversible P2Y 12 receptor inhibitory effect. [23] Ticagrelor, a cyclopentyltriazolopyrimidine, is rapidly absorbed in the intestine [Figure 3]. The absorbed drug does not require further biotransformation for activation. It directly binds reversibly and directly to the ADP P2Y12 receptors on the platelets, which change the conformation of these receptors. Such binding inhibits platelet activation and eventual aggregation. [24]
Figure 3: Mechanism of action of Ticagrelor, the absorbed drug does not require further biotransformation for activation. It directly binds reversibly and directly to the ADP P2Y12 receptors on the platelets, which change the conformation of these receptors. Such binding inhibits platelet activation and eventual aggregation[24]

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Ticagrelor exerts its action via binding to the P2Y12 receptor in a manner distinct from ADP, resulting in a reversible conformational change of the receptor [Figure 4]. The ligand inhibition of the ADP receptor and subsequent signaling affect the downstream processes. These include the conversion of cyclic monophosphate from ATP, dephosphorylation of the phosphorylated vasodilator-stimulated phosphoprotein (VASP), and activation of phosphoinositide 3-kinase. The inhibition of these processes results in reduced exposure of the fibrinogen-binding sites to the GP IIb / IIIa receptor, and thereby, impairment of platelet aggregation. [26] Interestingly, ticagrelor inhibits platelet aggregation, despite increasing the concentrations of ADP, demonstrating that this receptor inhibition is noncompetitive. Therefore, even in the setting of increased ADP concentrations, there would be no reduction in the level of platelet inhibition. Likewise, the effects of ticagrelor on platelet function correlate with the plasma drug concentrations. [26],[21] In addition, ticagrelor's effects on nonplatelet-bound ADP receptors may also produce off-target effects on the vascular smooth muscle via the inhibition of vasoconstriction. Coronary blood flow, through the inhibition of adenosine uptake by erythrocytes, may also be affected. [27],[28],[29] These pleiotropic effects together with ticagrelor's unique reversible inhibition of the P2Y12 receptor may result in both unique advantages and disadvantages. [24]
Figure 4: (a and b) ADP binds to the P2Y12 receptor, resulting in conformational change and G-protein activation, (c) Binding of the clopidogrel active metabolite to the P2Y12 receptor is irreversible, rendering the receptor nonfunctional for the life of the platelet, (d) Ticagrelor binds reversibly to P2Y12 at a site distinct from the ADP binding site and inhibits ADP signaling and receptor conformational change by 'locking' the receptor in an inactive state; the receptor is functional after dissociation of the ticagrelor molecule. ADP can still bind at its binding site, and the degree of receptor inhibition (and inhibition of ADP-induced signaling) is dependant on the concentration of ticagrelor[25]

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   Pharmacokinetics Top


Ticagrelor is an oral medication that demonstrates rapid absorption, at doses from 100 to 400 mg, without requiring metabolic activation. Hepatic cytochrome P450 3A generates an equally potent active metabolite, with plasma concentrations equaling one-third of the parent compound. [30],[22]

Ticagrelor undergoes rapid absorption with peak plasma concentrations (C max ) attained at a median time (tmax) of approximately 1.5 hours after oral administration. [31] The formation of the major circulating active metabolite AR-C124910XX is rapid and is present at approximately 40% of the parent concentrations. It is metabolized by CYP3A to an equipotent active metabolite (AR-C124910XX) that is present at approximately one-third of the concentration of ticagrelor. [32] The formation of this active metabolite is rapid, and peak concentrations are reached in a median t max of approximately 2.5 hours. [25] The mean terminal half-life (t 1/2 ) of ticagrelor is 7.2 hours and 8.5 hours for the active metabolite. [31] This supports the twice-daily dosing, to maintain a steady-state plasma concentration. Ticagrelor and AR-C124910XX are further metabolized into inactive metabolites and a glucuronide derivative, which are eliminated in the urine. [25] Elimination of ticagrelor is mainly via hepatic metabolism, and the primary route of elimination of the active metabolite is likely through biliary excretion. Neither depends on renal elimination, with < 1% recovery in the urine, for the parent and active metabolite. [31]


   Pharmacodynamics Top


The pharmacodynamic response to P2Y12 inhibitors can be measured by several different methods. Traditionally, one of the most accepted methods has been light transmittance aggregometry. Preclinical studies of ticagrelor used whole blood impedance aggregometry. In clinical trials, optical aggregometry was adopted as the optimal technique for measuring the inhibition of platelet aggregation (IPA). [33] In single-dose studies ranging from 100 to 400 mg, the IPA was dose- and time-dependent and was nearly complete at two hours, with a mean IPA of 88-95%, with 20 μM of ADP. The IPA gradually declined around 12-hours postdose, as the plasma concentrations declined, confirming that the IPA was reversible. [11] Despite this, the IPA 24-hours postdose is still at least equivalent to, and in some cases higher than, clopidogrel 75 mg. [11] With multiple-dose studies, the final extent of IPA with a 100 mg twice-daily dosing of ticagrelor is 90% at a steady state. In patients with ACS, receiving low-dose aspirin, a slightly lower dose of ticagrelor, 90 mg twice daily, produces the final extent of IPA that is 80% at four weeks. Although the IPA is dose-related, doses higher than 90-100 mg twice daily result in only minimal increases in IPA. This suggests that higher doses may not result in any greater efficacy, but may expose the patient to greater safety and / or tolerability concerns. [25] Although interpatient variability in IPA response exists with ticagrelor, it is less than that of clopidogrel when a higher initial dose (i.e., loading dose) and twice-daily administration are utilized. A recently completed trial in which clopidogrel nonresponders and responders were switched to ticagrelor, revealed that ticagrelor overcame the nonresponsiveness to clopidogrel. In fact, the resulting antiplatelet effect in the nonresponders was found to be the same as in the responders. Furthermore, 98% of the patients had platelet reactivity below the levels associated with ischemic risk, while on ticagrelor (vs. 44-76% of those on clopidogrel). [25] Another unique property of ticagrelor was its reversible inhibition of the P2Y12 receptor that led to a more rapid offset of IPA, after discontinuation, when compared with clopidogrel.


   Adverse Effects Top


On the basis of clinical trials, the most common adverse event consistently reported with ticagrelor has been dyspnea. Dyspnea has been reported in up to 25% of the patients taking ticagrelor, with a 6% absolute excess, when compared with clopidogrel. [10],[34],[35] The frequency of this side effect increases in a dose-dependent manner, with the mechanism being unknown. It is thought that dyspnea may be the result of ticagrelor having an off-target effect on the adenosine reuptake. Bleeding complications have been noted in a small group of patients taking ticagrelor, although the risk of minor, major, and fatal bleeds has not been seen to differ significantly from clopidogrel. [10],[34],[35] Ticagrelor has been reported to have a higher incidence of ventricular pauses in the first week of treatment as well as slightly increased levels of creatinine and uric acid. [34] Other adverse events reported with frequency greater than clopidogrel were headache, nausea, dyspepsia, insomnia, dizziness, syncope, and hypotension. [35]


   Clinical Trials Top


[Table 1] summarizes the various clinical trials carried out on ticagrelor. [20],[36],[37]
Table 1: Summary of clinical trials on ticagrelor


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   References Top

1.National Institute for Health and Clinical Excellence Final scope for the appraisal of ticagrelor for the treatment of acute coronary syndromes, By National Institute for Health and Clinical Excellence, UK. Available from: http://www.nice.org.uk/nicemedia/live/12169/50774/50774.pdf, [Issue Date: 2012 Sep].  Back to cited text no. 1
    
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10.Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation 2009;120:2577-85.  Back to cited text no. 10
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11.Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: A double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038-47.  Back to cited text no. 11
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12.L′Allier PL, Ducrocq G, Pranno N, Noble S, Ibrahim R, Grégoire JC, et al. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: Results from the PREPAIR randomized study. J Am Coll Cardiol 2008;51:1066-72.  Back to cited text no. 12
    
13.Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, et al. A randomized comparison of high clopidogrel loading doses in patients with non- ST-segment elevation acute coronary syndromes: The ALBION trial. J Am Coll Cardiol 2006;48:931-8.  Back to cited text no. 13
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14.Available from: http: www.fda.gov [Last accessed on 2011 Nov 30].  Back to cited text no. 14
    
15.Available from: http://www.drugs.com/brilinta.html. [Last accessed on 2011 Nov 30].  Back to cited text no. 15
    
16.Van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists.Semin Thromb Hemost 2005;31:195-204.  Back to cited text no. 16
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17.Springthorpe B, Bailey A, Barton P, Birkinshaw TN, Bonnert RV, Brown RC, et al. From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 2007;17:6013-8.  Back to cited text no. 17
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18.Cattaneo M. P2Y12 receptor antagonists: A rapidly expanding group of antiplatelet agents. Eur Heart J 2006;27:1010-2.  Back to cited text no. 18
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19.Marczewski MM, Postula M, Dariusz K. Novel antiplatelet agents in the prevention of cardiovascular complications-focus on ticagrelor. Vasc Health Risk Manag 2010;6:419-29.  Back to cited text no. 19
    
20.Husted S, van Giezen JJ. Ticagrelor: The first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 2009;27:259-74.  Back to cited text no. 20
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21.Van Giezen J J, Nilsson L, Berntsson P, Wissing BM, Giordanetto F, Tomlinson W, et al. Ticagrelor binds to human P2Y12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009;7:1556-65.  Back to cited text no. 21
    
22.Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010;38:1514-21.  Back to cited text no. 22
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23.Capodanno D, Dharmashankar K, Angiolillo DJ. University of Florida College of Medicine, Jacksonville, FL 32209, USA. dominick.angiolillo@jax.ufl.edu. Expert Rev Cardiovasc Ther 2010;8:151-8.  Back to cited text no. 23
    
24.Bhatt DL.Ticagrelor in ACS-what does PLATO teach us, nature reviews. Cardiology 2009;6-737-8.  Back to cited text no. 24
    
25.Birkeland K, Parra D, Rosenstein R. Antiplatelet therapy in acute coronary syndromes: Focus on Ticagrelor. J Blood Med 2010;1:197-219.  Back to cited text no. 25
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26.Anderson SD, Shah NK, Yim J, Epstein BJ. Efficacy and safety of ticagrelor: A reversible P2Y12 receptor antagonist. Ann Pharmacother 2010;44:524-37.  Back to cited text no. 26
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27.Wihlborg AK, Wang L, Braun OO, Eyjolfsson A, Gustafsson R, Gudbjartsson T, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004;24:1810-5.  Back to cited text no. 27
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28.Hogberg C, Svensson H, Gustaffson R, Eyjolfsson A, Erlinge D. The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol 2010:142;187-92.  Back to cited text no. 28
    
29.Bjorkman JA, Kirk I, van Giezen JJ. AZD6140 inhibits adenosine uptake into erythrocytes and enhances coronary blood flow after local ischemia or intracoronary adenosine infusion. Circulation 2007;116:28.  Back to cited text no. 29
    
30.Husted S, van Giezen JJ. Ticagrelor: The first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 2009;27:259-74.  Back to cited text no. 30
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31.Zeneca A. Advisory committee briefing document, Drug Substance Ticagrelor. UK: Astara Zenaca Pharmaceutical Company; 2010.  Back to cited text no. 31
    
32.James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: Asubstudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010;31:3006-16.  Back to cited text no. 32
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33.Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 2010;66:487-96.  Back to cited text no. 33
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34.Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.  Back to cited text no. 34
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35.Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-elevation acute coronary syndrome. J Am Coll Cardiol 2007;50:1844-51.  Back to cited text no. 35
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36.AbergelE, Nikolsky E. Ticagrelor: An investigational oral antiplatelettreatment for reduction of major adverse cardiac events in patients with acute coronary syndrome. Vasc Health Risk Manag 2010;6:963-77.  Back to cited text no. 36
    
37.Nawarskas JJ, Clark SM. Ticagrelora novel reversible oral antiplatelet agent. Cardiol Rev 2011;19:95-100.  Back to cited text no. 37
[PUBMED]    

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Correspondence Address:
Tirtha V Patel
Shri Sarvajanik Pharmacy College, Near Arvind Baug, Mehsana, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.115169

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