Ticagrelor

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Ticagrelor
Ticagrelor.svg
Ticagrelor ball-and-stick animation.gif
Clinical data
Trade namesBrilinta, Brilique, others
Other namesAZD-6140
AHFS/Drugs.comMonograph
MedlinePlusa611050
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Bioavailability36%
Protein binding>99.7%
MetabolismLiver (CYP3A4)
Elimination half-life7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)
ExcretionBile duct
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.114.746 Edit this at Wikidata
Chemical and physical data
FormulaC23H28F2N6O4S
Molar mass522.57 g·mol−1
3D model (JSmol)
 ☒NcheckY (what is this?)  

Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor.[1] The drug is produced by AstraZeneca.

90 mg tablet of Brilinta

It was approved for medical use in the European Union in December 2010,[2][3] and in the United States in July 2011.[4][5]

A reversal agent, bentracimab, is under investigation for use in major or life-threatening hemorrhage.[6]

Medical uses[]

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.[medical citation needed]

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.[8] The PLATO trial concluded superiority of ticagrelor compared to clopidogrel in reducing the rate of death from vascular causes, MI, and stroke in patients presenting with acute coronary syndromes.[9] A post-hoc subgroup analysis of the PLATO trial suggested a reduction in total mortality with ticagrelor compared to clopidogrel in patients with non-ST elevation acute coronary syndrome.[10] However, this finding should only be considered exploratory as it was not a primary endpoint of the PLATO trial.[9] Subsequent studies have also been underpowered in evaluating total mortality benefits with ticagrelor.[11] Further studies are required to provide statistically significant outcomes for total mortality with ticagrelor before this can be applied convincingly to clinical practice.

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)[12] 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.[13][14][15] The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy provides similar recommendations, although with a lower level of evidence (IIaB).[16] 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.

In people with non-cardioembolic minor ischaemic stroke or high-risk TIA, ticagrelor monotherapy did not reach statistical significance in reducing the composite of stoke, myocardial infarction or death compared to aspirin despite numerical reduction.[17] Ticagrelor plus aspirin was superior to aspirin alone in reducing the composite of stroke or death at 30 days in the large THALES randomised controlled trial; however, at an increased risk of severe bleeding.[18] Although supporting the role of short-term dual antiplatelet therapy post minor ischaemic stroke or high-risk TIA, there are currently no published head-to-head comparisons of ticagrelor plus aspirin versus the current standard-of-care in this cohort of clopidogrel plus aspirin. Further studies addressing this (including the results of the currently ongoing CHANCE-2 trial) are required to clarify the role of ticagrelor in clinical practice post stroke. In trials of both ticagrelor monotherapy and ticagrelor plus aspirin versus aspirin alone for minor ischaemic stroke or high-risk TIA, the subgroup of patients with ipsilateral stenosis of intracranial or extracranial arteries had a higher absolute risk of recurrent stroke and greater magnitude of absolute benefit than the subgroup without ipsilateral stenosis.[19][20] However, these subgroup analyses were hypothesis-generating only.[19][20]

A study compared ticagrelor and clopidogrel in participants with acute coronary syndrome (PLATO Trial) showed that participants treated with ticagrelor had a lower risk of infection-related deaths.[21] The Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE) study showed improvement in lung function in participants hospitalized for pneumonia using ticagrelor.[22]

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.[13][23]

Adverse effects[]

The common adverse effects are increased risk of bleeding (which may be severe)[24] and shortness of breath (dyspnoea).[25] Dyspnoea is usually transient and mild-to-moderate in severity, with a higher risk at < 1 month, 1–6 months and >6 months of follow up compared to clopidogrel.[25][26][27][28] Discontinuation of therapy is rare, although some patients do not persist or switch therapies.[25][26][27] However, patients should be reassured to continue therapy, as ticagrelor does not impact on efficacy and safety with acute coronary syndrome (ACS).[25] Furthermore, there are no associations between dyspnoea and adverse changes in heart and lung function in patients without baseline ACS, heart failure or significant lung disease.[26]

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.[29] Caution is recommended when using ticagrelor in patients with advanced sinoatrial node disease.[30] Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[8]

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[31] and is known to increase the concentrations of CYP3A4 metabolised medications; however, this interaction is unlikely to be clinically significant for atorvastatin and simvastatin[32][31][13] 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[33]) are not significantly influenced by P-gp inhibitors.[8]

It is recommended to use low-dose aspirin (75–100 mg per day) with ticagrelor as dual antiplatelet therapy (DAPT).[13][34][35][36][37][38] The combination of ticagrelor with aspirin doses greater than 100 mg per day may be less effective.[39]

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.[40] Moreover, the drug does not need hepatic 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).[41][42][43]

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.[33] 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.[8][44]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[45] 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.[8][46]

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.[2]

Ticagrelor as a nucleoside analogue
The nucleoside adenosine for comparison

Comparison with related drugs[]

With clopidogrel[]

The PLATO trial[47] 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).[48]

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.[49] 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.[50]

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.[47] It's especially of crucial importance for Asian individuals, as they are well-known to be prone to bleeding events.[51] 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.[52][53] 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.[54][55] 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.[56] 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 patients with acute coronary syndrome.[15]

Research[]

An in vitro assay and mouse model 2019 study published in JAMA Cardiology showed antibacterial activity against antibiotic-resistant Gram-positive bacteria including Methicillin Resistant Staphylococcus Aureus (MRSA) and Vancomycin Resistant Enterococcus (VRE).[57] Importantly, this study used concentrations of ticagrelor for bactericidal activity that far exceeded those achieved by standard post Acute Coronary Syndrome (ACS) doses.[57] A retrospective cohort study found patients treated with conventional doses of ticagrelor for ACS were associated with a 64% reduced risk of gram-positive infection in the first year of ticagrelor post ACS compared with clopidogrel.[58]  A Danish observational cohort study also found a lower 1-year risk of Staphylococcus aureus bacteraemia in ticagrelor treated patients compared with clopidogrel.[59]  These findings are limited by their study design but warrant further randomised-trials in humans to assess the practicality of ticagrelor as an antibiotic.[57]

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External links[]

  • "Ticagrelor". Drug Information Portal. U.S. National Library of Medicine.
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