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Brilinta

Pronunciation

Generic Name: Ticagrelor
Class: Platelet-aggregation Inhibitors
Chemical Name: (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) - 1,2 - cyclopentanediol
Molecular Formula: C23H28F2N6O4S
CAS Number: 274693-27-5

Warning(s)

  • Bleeding
  • Potential risk of bleeding; may be serious, sometimes fatal.1 2 13 41 42 (See Bleeding under Cautions.)

  • Avoid use in patients with active pathologic bleeding or history of intracranial hemorrhage.1 Do not initiate in patients undergoing urgent CABG.1

  • Whenever possible, discontinue at least 5 days prior to any surgery.1

  • Suspect bleeding in any patient receiving ticagrelor who is hypotensive and has recently undergone an invasive (e.g., PCI, coronary angiography) or surgical (e.g., CABG) procedure.1

  • If bleeding occurs, attempt to manage without discontinuing ticagrelor; increased risk of subsequent cardiovascular events possible with premature discontinuance.1 45 50 (See Discontinuance of Therapy under Cautions.)

  • Reduced Efficacy with Higher Aspirin Dosages
  • Aspirin maintenance dosages >100 mg daily appear to reduce efficacy of ticagrelor and should be avoided.1 15 16 36 (See Reduced Efficacy with Higher Aspirin Dosages under Cautions.)

  • After initial loading dose of aspirin, use ticagrelor in conjunction with aspirin maintenance dosage of 75–100 mg daily.1

Introduction

Platelet-activation and -aggregation inhibitor; nonthienopyridine, reversible, P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist.1 13 16 18 33 41 42 991 992 994 1010

Uses for Brilinta

Acute Coronary Syndrome

Used to reduce the risk of thrombotic cardiovascular events (e.g., cardiovascular death, MI) in patients with an acute coronary syndrome (ACS; unstable angina, non-ST-segment-elevation MI [NSTEMI], ST-segment elevation MI [STEMI]); includes those managed medically or with an invasive strategy (e.g., PCI with or without coronary artery stent placement, CABG).1 2 4 5 8 9 33 34 35 36 992 994 1010

Use in conjunction with aspirin therapy.1 15 16 36 (See Reduced Efficacy with Higher Aspirin Dosages under Cautions.)

Dual-drug antiplatelet therapy with a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is considered part of the current standard of care in patients with ACS.33 34 991 992 993 994 1010 The American College of Cardiology Foundation (ACCF), AHA, and other experts recommend antiplatelet therapy with a P2Y12-receptor antagonist in conjunction with aspirin for treatment and secondary prevention of ACS.33 34 992 993 994 1010 Regarding the choice of P2Y12-receptor antagonist, ticagrelor or clopidogrel generally is recommended in patients treated medically without stent placement; ticagrelor, clopidogrel, or prasugrel is recommended in patients undergoing PCI with stent placement (bare-metal or drug-eluting). 992 993 994 1010

Experts generally recommend that treatment with a P2Y12-receptor antagonist be continued for up to 12 months in patients managed medically and for at least 12 months in those undergoing PCI with stent placement (bare-metal or drug-eluting); aspirin should be continued indefinitely.992 993 994 1010

Precise role of ticagrelor relative to other P2Y12-receptor antagonists remains to be established.13 41 42 ACCP suggests ticagrelor over clopidogrel in patients with ACS regardless of whether PCI is performed.1010 The European Society of Cardiology (ESC) generally recommends ticagrelor or prasugrel over clopidogrel in patients with NSTEMI ACS.33 41 Other clinicians state that because of its reversibility and faster offset of action ticagrelor may be preferred over irreversible P2Y12-receptor antagonists in patients undergoing an early invasive strategy.8 17 28 30 41 43 Ticagrelor also may be a reasonable alternative in patients who are nonresponsive to clopidogrel.18 26 36 41 42

When selecting an appropriate antiplatelet regimen, consider individual patient (e.g., ischemic and bleeding risk) and drug-related (e.g., adverse effects, drug interaction potential) factors.13 14 41 43 49

Brilinta Dosage and Administration

General

  • Temporarily discontinue therapy at least 5 days prior to surgery (e.g., CABG); reinitiate as soon as possible after procedure.1 70

Administration

Administer orally without regard to meals.1 48

Use caution in prescribing and dispensing due to similarities in spelling and pronunciation of Brilinta (ticagrelor) and Brintellix (former trade name for vortioxetine; changed to Trintellix in May 2016).59 1011 1012 (See Prescribing and Dispensing Precautions under Cautions.)

If a dose is missed, take next dose at the regularly scheduled time; do not double the dose without approval of prescribing clinician.1

Dosage

Adults

Acute Coronary Syndrome
Oral

180-mg loading dose followed by maintenance dosage of 90 mg twice daily.1 35 36

Adjunctive aspirin therapy: After initial loading dose of aspirin (usually 325 mg), administer maintenance dosage of 75–100 mg daily.1 (See Reduced Efficacy with Higher Aspirin Dosages under Cautions.)

Manufacturer makes no specific recommendation regarding duration of maintenance therapy; however, ticagrelor was administered for up to 12 months in the pivotal efficacy study (PLATO).1 2 13 Long-term antiplatelet therapy generally recommended in patients with coronary artery stents;45 994 AHA, ACCF, and other experts recommend continuation of dual-drug antiplatelet therapy (e.g., ticagrelor and aspirin) for at least 12 months following placement of a coronary artery stent (bare-metal or drug-eluting).992 994 1010

Switching Therapy from Clopidogrel to Ticagrelor
Oral

May transition patients directly from clopidogrel to ticagrelor therapy without interruption in antiplatelet effects.1 26 In clinical trials, patients who switched from clopidogrel to ticagrelor received an initial loading dose of ticagrelor regardless of whether a previous loading dose of clopidogrel had been given.2 26 58 Manufacturer states that patients who have already received a clopidogrel loading dose may subsequently receive the recommended regimen of ticagrelor (initial loading dose of 180 mg, followed by 90 mg twice daily).1 26 58

Special Populations

Renal Impairment

No dosage adjustment required in patients with renal impairment.1 31

Hepatic Impairment

No dosage adjustment required in patients with mild hepatic impairment (Child-Pugh class A).1 29

Not adequately studied in patients with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Geriatric Patients

Dosage adjustment based on age not required.1

Other Special Populations

Dosage adjustment based on body weight, gender, ethnicity, or smoking status not required.1

Cautions for Brilinta

Contraindications

  • History of intracranial hemorrhage.1

  • Active pathologic bleeding (e.g., peptic ulcer, intracranial hemorrhage).1

  • Severe hepatic impairment.1

Warnings/Precautions

Warnings

Bleeding

Risk of bleeding, including serious, sometimes fatal bleeding.1 2 13 41 42 50 (See Boxed Warning.)

Overall risk of major and minor bleeding somewhat greater with ticagrelor than with clopidogrel in the PLATO trial.1 4 9 42 Increased risk principally involved non-CABG-related major bleeding, including fatal intracranial hemorrhage.1 2 4 6 8 9 13 41 994 Rates of major CABG-related bleeding were similar between ticagrelor and clopidogrel.1 2 4 5 16

In general, risk factors for bleeding include advanced age, history of bleeding disorders, performance of percutaneous invasive procedures, and concurrent use of drugs that affect hemostasis (e.g., anticoagulants, thrombolytic agents, high dosages of aspirin, long-term use of NSAIAs).1

Do not use in patients who are actively bleeding or who have a history of intracranial hemorrhage.1 Also not recommended in patients likely to undergo urgent CABG.1 Temporarily discontinue drug at least 5 days prior to surgery (e.g., CABG) whenever possible.1 70

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or any other invasive procedure, even if no overt manifestations of bleeding are present.1

If possible, manage bleeding without discontinuing ticagrelor; premature discontinuance may increase risk of subsequent cardiovascular events.1 50 (See Discontinuance of Therapy under Cautions.)

Reduced Efficacy with Higher Aspirin Dosages

In the PLATO study, a reduced response to ticagrelor was observed in North America compared with other regions; such geographic variation was associated with use of maintenance dosages of aspirin >100 mg daily in the US.1 15 16 Avoid aspirin dosages >100 mg daily.1 50 (See Boxed Warning.)

Other Warnings and Precautions

Dyspnea

Risk of dyspnea,1 2 4 8 13 16 20 22 24 26 30 36 generally mild to moderate and self-limiting.1 2 20 22 Adverse effects on cardiac or pulmonary function not observed.1 16 22 Mechanism of dyspnea unknown, but thought to be related to an adenosine-mediated response.13 16 20 22

If any new, prolonged, or worsening dyspnea occurs, evaluate patient to rule out any underlying associated conditions.1 If dyspnea appears related to ticagrelor, no specific treatment required; may continue drug without interruption.1

Discontinuance of Therapy

In general, avoid premature discontinuance of antiplatelet therapy (e.g., P2Y12-receptor antagonists, aspirin) because of subsequent increased risk of ischemic complications.1 45 50 51 52 53 54 55 56 57 58 1004 Premature discontinuance of antiplatelet therapy in patients with intracoronary stents has been associated with an increased risk of stent thrombosis, MI, and/or death.45 50 51 52 53 54 55 56 57 1004

If temporary discontinuance of ticagrelor required (e.g., prior to elective surgery or for bleeding), reinstitute therapy as soon as possible.1 45 50

Advise patients to never discontinue such therapy without first consulting their prescribing clinician, even if instructed to do so by another clinician (e.g., dentist).1 50 58 (See Advice to Patients.)

Cardiovascular Effects

Ventricular pauses ≥3 seconds, usually occurring during first week of therapy, reported.1 2 16 21 30 36 Mostly asymptomatic and not associated with any clinically important effects (e.g., syncope, need for pacemaker insertion).1 2 21

Because patients with baseline increased risk of bradycardia (e.g., those with sick sinus syndrome, second- or third-degree AV block, or syncope due to bradycardia without a pacemaker) were excluded from PLATO study,1 3 some clinicians recommend caution when used in such patients.21

Prescribing and Dispensing Precautions

Ensure accuracy of prescription; similarity in spelling and pronunciation of Brilinta (ticagrelor) and Brintellix (former trade name of vortioxetine, an antidepressant; trade name changed to Trintellix in May 2016) may result in medication errors.59 1011 1012

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1 2 58

Geriatric Use

No overall differences in efficacy or safety, including risk of bleeding, between geriatric and younger patients; however, increased sensitivity of some older individuals cannot be ruled out.1

Ticagrelor pharmacokinetics not substantially affected by age.1 27

Hepatic Impairment

Not adequately studied in patients with moderate or severe hepatic impairment; possible increased exposure and risk of bleeding.1 (See Absorption: Special Populations under Pharmacokinetics.)

Contraindicated in patients with severe hepatic impairment.1 Carefully consider use in those with moderate hepatic impairment after weighing risks versus benefits.1

May be used in patients with mild hepatic impairment without dosage adjustment.1 29

Renal Impairment

Pharmacokinetics and clinical efficacy of ticagrelor not substantially altered in patients with renal impairment.1 24 31

Dosage adjustment not necessary in patients with renal impairment.1 Data lacking on use in patients undergoing dialysis; ticagrelor not expected to be dialyzable.1 24

Common Adverse Effects

Bleeding, dyspnea, headache, cough, dizziness, nausea, atrial fibrillation, hypertension, noncardiac chest pain, diarrhea, back pain, hypotension, fatigue, chest pain.1

Interactions for Brilinta

Metabolized principally by CYP isoenzyme 3A4, and to a lesser extent by CYP3A5.1 Weak inhibitor of CYP3A4/5 and potential activator of CYP3A5.1 Does not inhibit CYP 1A2, 2C19, or 2E1.1

P-glycoprotein substrate and inhibitor.1

Drugs Affecting Hemostasis

Possible increased risk of bleeding.1 (See Bleeding under Cautions and see Specific Drugs under Interactions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Potential pharmacokinetic interaction (substantially increased exposure to ticagrelor); possible increased risk of bleeding.1 36 Avoid concomitant use.1

Moderate CYP3A inhibitors: Possible increased ticagrelor exposure; dosage adjustment not necessary.1

Potent CYP3A inducers: Potential pharmacokinetic interaction (substantially decreased plasma ticagrelor concentrations); possible reduced efficacy.1 36 Avoid concomitant use.1

CYP3A substrates: Potential pharmacokinetic interaction (increased plasma concentrations of substrate drug).1 36

Drugs Affecting or Affected by P-glycoprotein Transport

P-glycoprotein substrates: Potential pharmacokinetic interaction (increased plasma concentrations of substrate drug).1 36

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

May be administered concomitantly1

Angiotensin II receptor blockers

May be administered concomitantly1

Anticoagulants

Possible increased risk of bleeding1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Substantially reduced plasma ticagrelor concentrations due to CYP3A induction1

Avoid concomitant use1

Antifungals, azole (itraconazole, ketoconazole, voriconazole)

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Aspirin

Possible reduced efficacy of ticagrelor when used with aspirin dosages >100 mg daily1 15 16

Increased risk of bleeding possible with high dosages of aspirin1

Pharmacokinetics of ticagrelor not altered1

Limit concomitant aspirin maintenance dosage to 75–100 mg daily1

Atazanavir

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

β-Adrenergic blockers

May be administered concomitantly1

Clarithromycin

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Desmopressin

Pharmacokinetics of ticagrelor not affected1

No dosage adjustment necessary1

Dexamethasone

Substantially reduced plasma ticagrelor concentrations due to potent CYP3A induction1

Avoid concomitant use1

Digoxin

Pharmacokinetics of digoxin not substantially altered1

No dosage adjustment necessary; monitor serum digoxin concentrations prior to and following any change in ticagrelor therapy1

Diltiazem

Possible decreased exposure to ticagrelor due to moderate CYP3A inhibition1

No dosage adjustment necessary1

Enoxaparin

Pharmacokinetics of ticagrelor not affected1

Possible increased risk of bleeding1

No dosage adjustment necessary1

GP IIb/IIIa-receptor antagonists

May be administered concomitantly1

Heparin

Pharmacokinetics of ticagrelor not affected1

Possible increased risk of bleeding1

No dosage adjustment necessary1

HMG-CoA reductase inhibitors (statins)

Lovastatin, simvastatin: Possible increased serum concentrations of the statin1

Atorvastatin: Pharmacokinetics of atorvastatin not substantially altered1

Lovastatin, simvastatin: Do not exceed dosage of 40 mg daily1

Atorvastatin: No dosage adjustment necessary1

Hormonal contraceptives (ethinyl estradiol/levonorgestrel)

Increased peak plasma concentrations of and systemic exposure to ethinyl estradiol; pharmacokinetics of levonorgestrel not altered 1 46

Ticagrelor not expected to affect contraceptive efficacy42 46

No dosage adjustment necessary1

Indinavir

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Nefazodone

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Nelfinavir

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

NSAIAs

Possible increased risk of bleeding with chronic NSAIA use1

Proton-pump inhibitors

Platelet response to ticagrelor not affected7

May be used concomitantly1 7

Rifampin

Substantially decreased peak plasma concentrations of and systemic exposure to ticagrelor due to potent CYP3A induction1

Avoid concomitant use1

Ritonavir

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Saquinavir

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Telithromycin

Substantially increased exposure to ticagrelor due to potent CYP3A inhibition1

Avoid concomitant use1

Thrombolytics

Possible increased risk of bleeding1

Tolbutamide

Pharmacokinetics of tolbutamide not substantially altered1

Dosage adjustment not necessary1

Brilinta Pharmacokinetics

Absorption

Bioavailability

Rapidly but incompletely absorbed after oral administration;13 25 27 28 29 mean absolute oral bioavailability about 36%.1

Plasma concentrations of ticagrelor and its major metabolite increase in a dose-dependent manner; peak concentrations achieved within approximately 1.5 and 2.5 hours, respectively.1 18 25 27 28 29

Onset

Maximum inhibition of platelet aggregation observed approximately 2 hours after a dose.1 19 25 26 27 28

Additional inhibition of platelet aggregation (absolute increase of 26.4%) observed in patients who transition from clopidogrel to ticagrelor therapy.1 26

Duration

Maximum inhibition of platelet aggregation maintained for ≥8 hours after a dose.1 Following discontinuance, platelet activity returns to baseline after 5 days.1 19

Food

High-fat meal increased systemic exposure to ticagrelor by 21% and decreased peak plasma concentrations of the active metabolite by 22%; no effect on plasma concentrations of ticagrelor or systemic exposure to active metabolite.1 48

Special Populations

Individuals with mild (Child-Pugh class A) hepatic impairment had slightly higher systemic exposure to ticagrelor than those with normal hepatic function; however, no clinically important effects of such increased exposure observed.1 29

Individuals with severe (Clcr <30 mL/minute) renal impairment had slightly higher systemic exposure to ticagrelor than those with normal renal function; however, no effect on platelet inhibition or tolerability.31

Distribution

Plasma Protein Binding

>99% for both ticagrelor and active metabolite.1

Elimination

Metabolism

Metabolized principally by CYP3A4 to active metabolite.1 13 27

Elimination Route

Primarily eliminated in feces; <1% of a dose is recovered in urine (as parent drug and active metabolite).1 13

Half-life

Ticagrelor: Approximately 7 hours.1 25 28

Active metabolite: Approximately 9 hours.1 25 28

Special Populations

Population mean clearance of ticagrelor increased by approximately 22% in habitual smokers versus nonsmokers.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Store in original container and protect from moisture.1

Actions

  • Nonthienopyridine P2Y12 platelet ADP-receptor antagonist; unlike thienopyridines (e.g., clopidogrel, prasugrel), ticagrelor binds reversibly to P2Y12 receptor and does not require hepatic transformation to exerts its pharmacologic effect.1 2 3 7 13 16 18 25 27 41 42

  • Prevents signal transduction of the cyclic adenosine monophosphate (cAMP) pathway, resulting in reduced exposure of fibrinogen binding sites to the platelet glycoprotein (GP IIb/IIIa) complex and subsequent inhibition of platelet activation and aggregation.1 13

  • Inhibits reuptake of adenosine into erythrocytes.10 11 12 13 14 16

  • Compared with clopidogrel, ticagrelor produces more rapid and effective inhibition of platelet aggregation and has a faster offset of action.1 2 7 18 19 26 27 28 30 36 However, relationship between inhibition of platelet aggregation and clinical outcomes of either drug not known.1

  • Genetic polymorphism of the CYP2C19 isoenzyme does not appear to affect pharmacodynamic or clinical response to ticagrelor.1 23 41 47

Advice to Patients

  • Importance of patients taking ticagrelor exactly as prescribed and not discontinuing therapy without first consulting the prescribing clinician.1 Importance of reviewing with clinician how to resume therapy in the event of a missed dose.1 (See Administration under Dosage and Administration.) Importance of patients reading the medication guide prior to initiation of therapy and each time prescription is refilled.1

  • Importance of advising patients to check their prescription carefully to ensure that they have received the correct drug; prescribing and dispensing errors have been reported due to similarities in the spelling and pronunciation of Brilinta (the trade name for ticagrelor) and Brintellix (the former trade name for vortioxetine, an antidepressant; trade name changed to Trintellix in May 2016).59 1011 1012 (See Prescribing and Dispensing Precautions under Cautions.)

  • Importance of patients informing clinicians (e.g., physicians, dentists) about ticagrelor therapy before any surgery or dental procedure is performed.1 45 Clinicians performing any invasive procedure should consult with the prescribing clinician before discontinuing ticagrelor.1 45

  • Importance of informing patients not to take aspirin dosages exceeding 100 mg daily; advise patient to not take any other aspirin-containing drugs.1

  • Importance of informing patients that they will bruise and/or bleed more easily and that a longer than usual time will be required to stop bleeding when taking ticagrelor.1 Importance of patients informing clinicians about any unexpected, prolonged, or excessive bleeding, or blood in urine or stool.1

  • Importance of informing patients that ticagrelor can cause dyspnea; advise patient to contact their clinician if they experience any unexpected dyspnea.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly drugs that affect bleeding risk (e.g., heparin, warfarin).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ticagrelor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

90 mg

Brilinta

AstraZeneca

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: April 15, 2013
Last reviewed: November 02, 2016
Date modified: November 09, 2016

References

1. AstraZeneca. Brilinta, (ticagrelor) tablets prescribing information. Wilmington, DE; 2011 July.

2. Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361:1045-57. [PubMed 19717846]

3. James S, Akerblom A, Cannon CP et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009; 157:599-605. [PubMed 19332184]

4. Steg PG, James S, Harrington RA 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; 122:2131-41. [PubMed 21060072]

5. Held C, Asenblad N, Bassand JP 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; 57:672-84. [PubMed 21194870]

6. Becker RC, Bassand JP, Budaj A et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011; 32:2933-44. [PubMed 22090660]

7. Storey RF, Angiolillo DJ, Patil SB et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol. 2010; 56:1456-62. [PubMed 20832963]

8. Cannon CP, Harrington RA, James S et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010; 375:283-93. [PubMed 20079528]

9. James SK, Roe MT, Cannon CP et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ. 2011; 342:d3527. [PubMed 21685437]

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17. Schömig A. Ticagrelor--is there need for a new player in the antiplatelet-therapy field?. N Engl J Med. 2009; 361:1108-11. [PubMed 19717845]

18. Storey RF, Husted S, Harrington RA et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007; 50:1852-6. [PubMed 17980251]

19. Gurbel PA, Bliden KP, Butler K 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. [PubMed 19923168]

20. Storey RF, Becker RC, Harrington RA et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011; 32:2945-53. [PubMed 21804104]

21. Scirica BM, Cannon CP, Emanuelsson H et al. 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: results of the continuous electrocardiographic assessment substudy. J Am Coll Cardiol. 2011; 57:1908-16. [PubMed 21545948]

22. Storey RF, Bliden KP, Patil SB et al. 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. J Am Coll Cardiol. 2010; 56:185-93. [PubMed 20620737]

23. Wallentin L, James S, Storey RF et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010; 376:1320-8. [PubMed 20801498]

24. 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; 122:1056-67. [PubMed 20805430]

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27. Husted S, Emanuelsson H, Heptinstall S et al. 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. [PubMed 16476694]

28. 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. [PubMed 20642549]

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30. Cannon CP, Husted S, Harrington RA 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-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007; 50:1844-51. [PubMed 17980250]

31. Butler K, Teng R. Pharmacokinetics, Pharmacodynamics, and Safety of Ticagrelor in Volunteers With Severe Renal Impairment. J Clin Pharmacol. 2011; :.

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