Ticagrelor (Monograph)

Brand name: Brilinta
Drug 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

Medically reviewed by Drugs.com on Sep 24, 2024. Written by ASHP.

Warning

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

Avoid use of aspirin maintenance dosages >100 mg daily in patients with acute coronary syndrome (ACS).¹ ¹⁵ ¹⁶ ³⁶ (See Reduced Response with Higher Aspirin Dosages in Patients with ACS under Cautions.)

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

Uses for Ticagrelor

Acute Coronary Syndrome or History of MI

Used in conjunction with aspirin to reduce the risk of cardiovascular death, MI, and stroke in patients with ACS.¹ ² ⁴ ⁵ ⁸ ⁹ ³² ³³ ³⁵ ³⁶ ⁶⁰ ⁹⁹¹ ⁹⁹² ⁹⁹⁴ ¹⁰⁰⁵

Dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is considered the current standard of care in patients with ACS.³³ ⁹⁹¹ ⁹⁹² ⁹⁹⁴ ¹⁰⁰⁵

ACC/AHA has issued guidelines for treatment options and duration of DAPT.⁹⁹¹ ⁹⁹² ⁹⁹⁴ ¹⁰⁰⁵ Aspirin should almost always be continued indefinitely; decisions about specific P2Y12 inhibitor and duration of therapy should be based on risks of bleeding versus benefits of ischemic reduction, clinical judgment, and patient preference.¹⁰⁰⁵

ACC/AHA generally recommends a shorter duration of DAPT for patients at reduced ischemic, but high bleeding, risk and a longer duration for patients at high ischemic, but reduced bleeding, risk.¹⁰⁰⁵

In ACS patients managed medically (without revascularization or reperfusion therapy) or with PCI and stent implantation (bare-metal or drug-eluting), P2Y12 inhibitor therapy should be given for at least 12 months; in patients who have tolerated DAPT without bleeding complications and do not have a high risk of bleeding, continuation of such therapy for longer than 12 months may be reasonable.¹⁰⁰⁵

With regard to the specific P2Y12 inhibitor, evidence supports use of clopidogrel or ticagrelor in medically-managed ACS patients; clopidogrel, prasugrel, or ticagrelor may be used in ACS patients treated with PCI.⁹⁹¹ ⁹⁹² ⁹⁹⁴ ¹⁰⁰⁵

In patients undergoing CABG, P2Y12 inhibitor therapy should be resumed after surgery to complete 12 months of therapy.¹⁰⁰⁵

Unlike clopidogrel, genetic polymorphism of the CYP2C19 isoenzyme does not appear to affect the pharmacodynamic or clinical response to ticagrelor.¹ The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend ticagrelor as an alternative antiplatelet agent to clopidogrel in patients who are poor or intermediate metabolizers of CYP2C19.¹⁰⁰⁰

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

Also used to reduce the risk of cardiovascular death, MI, and stroke in patients with a history of MI; in the principal study establishing efficacy for this indication, patients had a history of MI 1–3 years prior to study entry.³¹ ⁶⁰

AHA/ACC states that in patients with stable ischemic heart disease (SIHD) being treated with DAPT for previous (1–3 years prior) MI, continuation of such therapy may be reasonable if tolerated without any bleeding complications.¹⁰⁰⁵

Coronary Artery Disease but No Prior Stroke or MI

Used to reduce the risk of an initial MI or stroke in patients with established CAD who are at high risk for these thrombotic cardiovascular events.¹ ⁶²

Use in conjunction with aspirin therapy.¹

There is evidence supporting use of ticagrelor in reducing risk of a first MI and stroke in patients with CAD and type 2 diabetes mellitus, although treatment effect is small.³² ⁶² Reduction in ischemic events is accompanied by increased risk of bleeding.¹ ⁶²

Acute Ischemic Stroke or Transient Ischemic Attack

Used to reduce the risk of stroke in patients with acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] ≤5) or high-risk TIA.¹ ⁶³

Use in conjunction with aspirin therapy.¹

Not studied in patients with more severe stroke or cardioembolic stroke; those undergoing thrombectomy or thrombolysis; and those in whom treatment was administered >24 hours after symptom onset.⁶³

Ticagrelor Dosage and Administration

Administration

Administer orally without regard to meals.¹ ⁴⁸

For patients unable to swallow tablets whole, may crush and mix with water.¹ Also can administer crushed tablet in water mixture via a nasogastric tube (CH8 or greater).¹

If a dose is missed, take next dose at the regularly scheduled time.¹

Dosage

Adults

Acute Coronary Syndrome or History of MI

Oral

180-mg loading dose followed by maintenance dosage of 90 mg twice daily during the first year.¹ ³⁵ ³⁶ After first year, maintenance dosage of 60 mg twice daily recommended.¹

Adjunctive aspirin therapy: Administer maintenance dosage of 75–100 mg daily.¹ (See Reduced Response with Higher Aspirin Dosages in Patients with ACS 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 Recommendations for duration of dual antiplatelet therapy can be found in ACC/AHA guidelines.¹⁰⁰⁵ (See Acute Coronary Syndrome or History of MI under Uses.)

Coronary Artery Disease but No Prior Stroke or MI

Oral

60 mg twice daily.¹

Adjunctive aspirin therapy: Administer maintenance dosage of 75–100 mg daily.¹

Acute Ischemic Stroke or Transient Ischemic Attack

Oral

180-mg loading dose followed by maintenance dosage of 90 mg twice daily for up to 30 days.¹

Adjunctive aspirin therapy: After initial loading dose (300–325 mg), administer maintenance dosage of 75–100 mg daily.¹

Transitioning from Clopidogrel to Ticagrelor Therapy

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

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 (See Hepatic Impairment under Cautions.)

Geriatric Patients

Dosage adjustment based on age not required.¹

Cautions for Ticagrelor

Contraindications

History of intracranial hemorrhage.¹
Active pathologic bleeding (e.g., peptic ulcer, intracranial hemorrhage).¹
Hypersensitivity to the drug or any components.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

Bleeding was reported more frequently with ticagrelor compared with placebo in other preapproval studies.¹ ⁶⁰ ⁶² ⁶³

In general, risk factors for bleeding include advanced age, history of bleeding disorders, female gender, renal dysfunction, performance of PCI, and concurrent use of other drugs that affect hemostasis (e.g., anticoagulants, thrombolytic agents, high dosages of aspirin, long-term use of NSAIAs).⁶⁵

Contraindicated 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

If possible, manage bleeding without discontinuing ticagrelor; premature discontinuance may increase risk of subsequent cardiovascular events.¹ (See Discontinuance of Therapy in Patients with Coronary Artery Disease under Cautions.)

Reduced Response with Higher Aspirin Dosages in Patients with ACS

In the PLATO study, a reduced response to ticagrelor was observed when used with aspirin maintenance dosages >100 mg daily in patients with ACS.¹ ¹⁵ ¹⁶ Avoid aspirin dosages >100 mg daily.¹ (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 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 related to ticagrelor occurs, no specific treatment required; may continue therapy without interruption if possible.¹ If dyspnea is intolerable and results in discontinuance of ticagrelor, consider another antiplatelet agent.¹

Discontinuance of Therapy in Patients with Coronary Artery Disease

In general, avoid premature discontinuance of antiplatelet therapy (e.g., P2Y12-receptor antagonists, aspirin) in patients with CAD because of subsequent increased risk of ischemic complications.¹ ⁴⁵ ⁵¹ ⁵² ⁵³ ⁵⁴ ⁵⁵ ⁵⁶ ⁵⁷ Stent thrombosis, MI, and/or death observed in patients with coronary stents who prematurely discontinued antiplatelet therapy.⁴⁵ ⁵⁰ ⁵¹ ⁵² ⁵³ ⁵⁴ ⁵⁵ ⁵⁶ ⁵⁷

If temporary discontinuance of ticagrelor required (e.g., prior to significant surgery or for bleeding), reinstitute therapy as soon as possible.¹ ⁴⁵ Interrupt therapy for 5 days prior to surgical procedures with a major bleeding risk if possible; resume therapy when hemostasis is achieved.¹

Bradyarrhythmias

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 clinical studies,¹ some clinicians recommend caution when used in such patients.²¹

Laboratory Test Interference

May cause false negative results in platelet function tests for heparin-induced thrombocytopenia (e.g., heparin-induced platelet aggregation [HIPA] assay).¹ However, not expected to affect PF4 antibody testing for heparin-induced thrombocytopenia.¹

Specific Populations

Pregnancy

No drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes identified.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Breast-feeding not recommended during ticagrelor therapy.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹ ²

Geriatric Use

No overall differences in efficacy or safety between geriatric and younger patients.¹

Ticagrelor pharmacokinetics not substantially affected by age.¹ ²⁷

Hepatic Impairment

Possible increased exposure and risk of bleeding.¹ (See Absorption: Special Populations under Pharmacokinetics.)

Avoid use 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 not substantially altered in patients with renal impairment.¹ ²⁴ ³¹ (See Renal Impairment under Dosage and Administration.)

Not studied in patients with end-stage renal disease (ESRD) on dialysis; however, clinically important differences not expected in such patients receiving intermittent hemodialysis.¹

Ticagrelor is not dialyzable.¹

Common Adverse Effects

Bleeding, dyspnea.¹

Drug Interactions

Metabolized principally by CYP isoenzyme 3A4.¹ 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
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
Clarithromycin	Substantially increased exposure to ticagrelor due to potent CYP3A inhibition¹	Avoid concomitant use¹
Cyclosporine	Possible increased exposure to ticagrelor¹
Desmopressin	Pharmacokinetics of ticagrelor not affected¹	No dosage adjustment necessary¹
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
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
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
Opiate agonists (e.g., morphine)	May delay and reduce absorption of ticagrelor and its active metabolite¹ Ticagrelor exposure was decreased and time to peak plasma concentration was delayed when coadministered with IV fentanyl or IV morphine; platelet aggregation was higher up to 3 hours post-loading dose in ACS patients who received these drugs concomitantly¹	Consider use of a parenteral antiplatelet agent in ACS patients who require treatment with morphine or other opiate agonist¹
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
Thrombolytics	Possible increased risk of bleeding¹
Tolbutamide	Pharmacokinetics of tolbutamide not substantially altered¹	Dosage adjustment not necessary¹

Ticagrelor 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 observed.¹ ²⁹

Individuals with severe (Cl_cr <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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).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
Pharmacogenomics: 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 reading the FDA-approved patient labeling (medication guide).¹
Importance of patients informing clinicians (e.g., physicians, dentists) about ticagrelor therapy before any surgery or dental procedure is performed.¹ ⁴⁵
Importance of informing patients not to take aspirin dosages exceeding 100 mg daily; advise patients 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 shortness of breath.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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ticagrelor
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	60 mg	Brilinta	AstraZeneca
		90 mg*	Brilinta	AstraZeneca
			Ticagrelor Tablets

References

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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. https://pubmed.ncbi.nlm.nih.gov/21545948

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