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Ticagrelor: Oral Reversible P2Y12 Receptor Antagonist for the Management of Acute Coronary Syndromes

      Abstract

      Background

      The clinical benefits of dual antiplatelet treatment (aspirin + clopidogrel) in the management of acute coronary syndromes (ACS) are well established. However, clopidogrel is a prodrug that requires hepatic activation. Concerns regarding its delayed onset of action, variability in antiplatelet effects, and prolonged recovery of platelet function after discontinuation have prompted the development of P2Y12 receptor antagonists. Ticagrelor is the most recently developed P2Y12 receptor antagonist available in the United States. Ticagrelor is a nonthienopyridine antiplatelet agent and is the first reversible oral antagonist of the P2Y12 receptors.

      Objective

      This article reviews the pharmacology, clinical efficacy, and tolerability of ticagrelor use in management of ACS.

      Methods

      Peer-reviewed clinical trials, review articles, and relevant treatment guidelines published from 1966 to March 15, 2012, were identified from the MEDLINE and Current Content databases using the search terms ticagrelor, ACS, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. Citations from available articles were also reviewed for additional references.

      Results

      Nine pharmacokinetics/pharmacodynamics studies in humans and 1 clinical study were identified. In addition, the findings from 6 subanalyses based on the clinical study were included. Compared with clopidogrel, ticagrelor was associated with a significantly reduced composite rate of death from cardiovascular causes, myocardial infarction, or stroke (ticagrelor, 9.8%; clopidogrel, 11.7%; hazard ratio [HR] = 0.84; 95% CI, 0.77–0.92; P < 0.001). The difference in the rates of major bleeding was not significant (ticagrelor, 11.6%; clopidogrel, 11.2%). Ticagrelor was associated with a higher rate of non–coronary artery bypass graft surgery related major bleeding (4.5% vs 3.8%; P = 0.03), including fatal intracranial bleeding (0.1% vs 0.01%; P = 0.02), and fewer cases of other types of fatal bleeding (0.1% vs 0.3%; P = 0.03). Other adverse events reported with ticagrelor use included dyspnea (13.8%), headache (6.5%), and bradyarrhythmia (5.8%). The effects of ticagrelor have not been compared to those of other antiplatelet agents, including prasugrel.

      Conclusions

      Based on the findings from the present review, ticagrelor provides reversible inhibition of adenosine diphosphate–induced platelet aggregation, with a faster onset of action than clopidogrel, and is effective in the treatment of patients with ACS. More data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel.

      Key words

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      References

        • Roger V.L.
        • Go A.S.
        • Lloyd-Jones D.M.
        • et al.
        Heart Disease and Stroke Statistics—2012 Update: A Report From the American Heart Association.
        (Accessed January 4, 2012)
        • Bassand J.P.
        • Hamm C.W.
        • Ardissino D.
        • et al.
        Guidelines for the diagnosis and treatment of non-ST segment elevation acute coronary syndromes.
        Eur Heart J. 2007; 28: 1598-1660
        • Davi G.
        • Patrono C.
        Platelet activation and athero-thrombosis.
        N Engl J Med. 2007; 357: 2482-2494
      1. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        (Accessed January 5, 2012)
      2. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction (Updating the 2004 and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        (Accessed January 5, 2012)
        • Yusuf S.
        • Zhao F.
        • Mehta S.R.
        • et al.
        Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
        N Engl J Med. 2001; 345: 494-502
        • Mehta S.R.
        • Yusuf S.
        • Peters R.J.
        • et al.
        Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
        Lancet. 2001; 358: 527-533
        • Sabatine M.S.
        • Cannon C.P.
        • Gibson C.M.
        • et al.
        Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.
        N Engl J Med. 2005; 352: 1179-1189
        • Pare G.
        • Mehta S.R.
        • Yusuf S.
        • et al.
        Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.
        N Engl J Med. 2010; 363: 1704-1714
        • Plosker G.L.
        • Lyseng-Williamson K.A.
        Clopidogrel: a review of its use in the prevention of thrombosis.
        Drugs. 2007; 67: 613-646
        • Wiviott S.D.
        • Antman E.M.
        • Braunwald E.
        Prasugrel.
        Circulation. 2010; 122: 394-403
        • Mega J.L.
        • Close S.L.
        • Wiviott S.D.
        • et al.
        Cytochrome P450 genetic polymorphisms and the response to prasugrel relationship to pharmacokinetics, pharmacodynamic, and clinical outcomes.
        Circulation. 2009; 119 (2553–2544)
        • Wiviott S.D.
        • Braunwald E.
        • McCabe C.H.
        • et al.
        Prasugrel versus clopidogrel in patients with acute coronary syndrome.
        N Engl J Med. 2007; 357: 2001-2015
      3. Brilinta (ticagrelor) tablets [prescribing information].
        (Accessed January 5, 2012)
        • Capodanno D.
        • Dharmashankar K.
        • Angiolillo D.J.
        Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist.
        Expert Rev Cardiovasc Ther. 2010; 8: 151-158
        • Storey R.F.
        Pharmacology and clinical trials of reversibly binding P2Y12 inhibitors.
        Thromb Haemost. 2011; 105: S75-S81
      4. Plavix (clopidogrel bisulfate) tablets [prescribing information].
        (Accessed March 15, 2012)
      5. Effient (prasugrel) tablets [prescribing information].
        (Accessed March 15, 2012)
        • Teng R.
        • Oliver S.
        • Hayes M.A.
        • Butler K.
        Absorption, distribution, metabolism and excretion of ticagrelor in healthy subjects.
        Drug Metab Dispos. 2010; 38: 1514-1521
        • Teng R.
        • Butler K.
        Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects.
        Eur J Clin Pharmacol. 2010; 66: 487-496
        • Butler K.
        • Teng R.
        Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers.
        Br J Clin Pharmacol. 2010; 70: 65-77
        • Teng R.
        • Mitchell P.D.
        • Butler K.
        Lack of significant food effect on pharmacokinetics of ticagrelor in healthy volunteers.
        (Accessed January 5, 2012)
        • Butler K.
        • Teng R.
        Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment.
        J Clin Pharmacol. 2011; 51: 978-987
        • Butler K.
        • Teng R.
        Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment.
        (Accessed January 5, 2012)
        • Li H.
        • Butler K.
        • Yang L.
        • et al.
        Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single center study.
        Clin Drug Investig. 2012; 32: 87-97
        • Gurbel P.A.
        • Bliden K.P.
        • Butler K.
        • et al.
        Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.
        Circulation. 2010; 121: 1188-1199
        • Storey R.
        • Angiolillo D.J.
        • Patil S.B.
        • et al.
        Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (Platelet inhibitor and patient outcomes) PLATELET Substudy.
        J Am Coll Cardiol. 2010; 56: 1456-1462
        • Wallentin L.
        • Richard B.C.
        • Budaj A.
        • et al.
        Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
        N Engl J Med. 2009; 361: 1045-1057
        • Cannon C.P.
        • Harrington R.A.
        • James S.
        • et al.
        Comparison of ticagrelor with clopidogrel in patients with planned invasive strategy for acute coronary syndromes (PLATO): a randomized double-blind study.
        Lancet. 2010; 375: 283-293
        • James S.K.
        • Row M.T.
        • Cannon C.P.
        • et al.
        Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomized platelet inhibition and patient outcomes (PLATO) trial.
        BMJ. 2011; 342: d3527
        • Held C.
        • Asenblad N.
        • Bassand J.P.
        • et al.
        Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial.
        J Am Coll Cardiol. 2011; 57: 672-684
        • Steg P.G.
        • James S.
        • Harrington R.A.
        • et al.
        Ticagrelor versus clopidogrel in patients with ST elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a platelet inhibition and patient outcomes (PLATO) trial subgroup analysis.
        Circulation. 2010; 122: 2131-2141
        • James S.
        • Budaj A.
        • Aylward P.
        • et al.
        Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet inhibition and Patient Outcomes (PLATO) trial.
        Circulation. 2010; 122: 1056-1067
        • James S.
        • Angiolillo D.J.
        • Cornel J.H.
        • et al.
        Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the Platelet Inhibition and Patient Outcomes (PLATO) trial.
        Eur Heart J. 2010; 31: 3006-3016
        • Storey R.F.
        • Becker R.C.
        • Harrington R.A.
        • et al.
        Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the platelet inhibition and Platelet Outcome [PLATO] pulmonary function substudy).
        Am J Cardiol. 2011; 108: 1542-1546
        • Scirica B.M.
        • Cannon C.P.
        • Emanuelsson H.
        • et al.
        The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy.
        J Am Coll Cardiol. 2011; 57: 1908-1916
      6. AstraZeneca Sets Premium Price for Ticagrelor (Brilinta).
        (Accessed January 12, 2012)
      7. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
        (Accessed January 12, 2012)