Ticagrelor

Ticagrelor

Clinical data
Routes of administration	oral
ATC code	none
Pharmacokinetic data
Bioavailability	36%
Protein binding	99%
Metabolism	hepatic (CYP3A4)
Elimination half-life	6.9 h
Excretion	mainly biliary
Identifiers
IUPAC name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
CAS Number	274693-27-5
PubChem CID	9871419
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C23H28F2N6O4S
Molar mass	522.567 g/mol
3D model (JSmol)	Interactive image
SMILES Fc2ccc(cc2F)C3CC3Nc5nc(SCCC)nc4c5nnn4C1CC(C(O)C1O)OCCO

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]. Dr. Gibson has received research grant support form Astra Zeneca the manufacturer of Ticagrelor as well as the manufacturers of competing antiplatelet agents .

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Synonyms and keywords: Brilinta

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or the FDA Medwatch site.

Overview

Ticagrelor (previously known as AZD6140) is a member of a new generation of P2Y₁₂ inhibitors. Chemically, this is a first-in-class member of the cyclo-pentyl-triazolo-pyrimidine (CPTP) family with a mean terminal half-life of approximately 7 h and a median Tmax of 2.6 h. Ticagrelor’s steady-state volume of distribution (87.5 L) indicates it does not extensively distribute into or bind to tissues.

Indications

Ticagrelor is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). Ticagelor has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Avoid maintenance doses of aspirin above 100 mg daily.

Method of action

Like thienopyridines, ticagrelor is only orally available, but in contrast with these pro-drugs, ticagrelor is direct acting, i.e. does not require metabolic activation. In addition, ticagrelor is a reversible P2Y₁₂ inhibitor with more rapid onset and off set of action compared with clopidogrel. Ticagrelor has 2 metabolites. The major ticagrelor metabolite (AR-C124910XX) has a P2Y₁₂ inhibiting activity comparable to the parent compound while a second metabolite (AR-C133913XX) is inactive. Ticagrelor is rapidly and extensively metabolized in the liver by CYP3A4. The P2Y₁₂ receptor is targeted by ticagrelor via a mechanism that is non-competitive with ADP, suggesting the existence of an independent receptor-binding site. Compared with clopidogrel, ticagrelor provides greater and more consistent platelet inhibition.

Dosing

Initiate Ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily After the initial loading dose of aspirin (usually 325 mg), use Ticagrelor with a daily maintenance dose of aspirin of 75-100 mg.

ACS patients who have received a loading dose of clopidogrel may be started on Ticagrelor.

Ticagrelor can be administered with or without food.

A patient who misses a dose of Ticagrelor should take one 90 mg tablet (their next dose) at its scheduled time.

Dosage Forms and Strengths

Ticagrelor 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.

Contraindications

History of Intracranial Hemorrhage

Ticagrelor is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population.

Active Bleeding

Ticagrelor is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Severe Hepatic Impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins.

Warnings and Precautions

General Risk of Bleeding

Drugs that inhibit platelet function including Ticagrelor increase the risk of bleeding. Ticagrelor increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased.

In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDS]).

When possible, discontinue Ticagrelor five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding.

If possible, manage bleeding without discontinuing Ticagrelor. Stopping Ticagrelor increases the risk of subsequent cardiovascular events.

Concomitant Aspirin Maintenance Dose

In PLATO, use of Ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Therefore, after the initial loading dose of aspirin (usually 325 mg), use Ticagrelor with a maintenance dose of aspirin of 75-100 mg.

Moderate Hepatic Impairment

Ticagrelor has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Dyspnea

Dyspnea was reported in 14% of patients treated with Ticagrelor and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with Ticagrelor, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to Ticagrelor, no specific treatment is required; continue Ticagrelor without interruption.

In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

Discontinuation of Ticagrelor

Avoid interruption of Ticagrelor treatment. If Ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of Ticagrelor will increase the risk of myocardial infarction, stent thrombosis, and death.

Strong Inhibitors of Cytochrome CYP3A

Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole.

Cytochrome CYP3A Potent Inducers

Avoid use with potent CYP3A inducers, such as rifampin, dexamethasone, phenytoin, rbamazepine, and phenobarbital.

FDA Panel Review of Ticagrelor on July 28th, 2010

While the administration of Ticagrelor was associated with a reduction in adverse events in the PLATO trial as a whole , there was a lack of benefit, and in fact an excess risk of adverse events in patients treated with Ticagrelor in North America. The confidence interval for the hazard in the United States did not overlap with the confidence interval for benefit in the ex-US population, and the p-value for the interaction by region was 0.045. The regional analysis was not pre-specified. There were few patients enrolled from Canada, and the hazard was apparent when the analysis was confined to those patients from the United States of America (H.R for the primary endpoint was 1.27 for US, and 1.17 for Canada). The hazard ratio observed in the United States for MI was 1.38 (95% CI 0.95-2.01), for CV death was 1.26 (95% CI 0.69-2.31) and for [[stroke] was 1.75. There were three countries with a hazard ration > 1.27 and these were the United States, Australia and Taiwan. As part of a sensitivity analysis, when the United States (an outlier in terms of hazard) was excluded as were Turkey, Hungary, and Poland (outliers in terms of benefit), the overall results of the study were similar.

Much of the panel discussion centered around the basis for the hazard associated with Ticagrelor administration observed in the United States. A key finding was that the aspirin dose in United States patients was higher than that in the rest of the world. The PLATO study recommended, but did not mandate that low-dose aspirin be used. As a result, 92% of patients were treated with low dose aspirin. It should be noted that the current ACC / AHA guidelines recommend high dose aspirin in those patients undergoing intracoronary stent placement, and this may explain in part the reason why some patients, and particularly those in the United States, were treated with high dose (325 mg dialy) aspirin. The median aspirin dose in the United States was 325 mg and the average dose was 217 mg; ex-US the median aspirin dose was 100 mg, and the average dose was 99 mg.

The interaction term regarding the impact of aspirin dose on outcomes was highly statistically significant (p=0.00006, Chi2 of 16). Even if multiple exploratory comparisons were made, this p-value would remain statistically significant. The interaction with aspirin dose was observed for the dose chosen for chronic administration and not for the loading dose chosen for acute administration. Ex-US data was used to model the relationship between the aspirin dose and clinical outcomes in the PLATO trial. The projected event rates associated with different aspirin doses based upon ex-US data successfully predicted the event rates observed in the United States. It should be noted though, that there were very few patients outside the US who received high dose aspirin that were used to create this model. Inverting the clinical outcomes in just 20 patients (i.e. stating that a patient with an event did not have an event) significantly altered the model, so much so that no hazard was observed at high doses in this sensitivity analysis. While the interaction with clinical outcomes was explained almost exclusively by aspirin dose, and not by the country the patient came from, the presenters did vary in their interpretation as to whether other factors may have explained the effect of aspirin dose: aspirin was associated with PCI performance, stent placement and glycoprotein IIb IIIa inhibitor administration. Patients in the United States were heavier, had more diabetes, had a greater incidence of prior MI, underwent PCI more often, more often had a stent placed, more often had a drug eluting stent placed rather than bare metal, underwent CABG more often, had a greater incidence of NSTEMI, less unstable angina and they were less compliant with study drug than the rest of the world. It was also speculated by the FDA that higher aspirin dose may be a surrogate for higher patient risk in general in ways that could not be easily quantified.

While aspirin dose was associated with efficacy, it was not associated with differences in the rate of bleeding. The rate of serious bleeding was similar between the two arms of the PLATO study. However, hemorrhagic stroke was doubled in Ticagrelor patients. Among patients with hemorrhagic stroke, 1/2 died while being treated with Ticagrelor while 1/6 died while treated with clopidogrel.

It should be noted that there are no randomized trials that evaluate the optimal dose of aspirin as part of chronic pharmacotherapy. Meta-analyses suggest that low-dose aspirin may be as if not more effective than full dose aspirin (325 mg daily). The CURRENT / OASIS 7 trial evaluated the relative efficacy of high and low dose aspirin over the course of the first 30 days in patients with acute coronary syndromes. High dose aspirin was not of benefit over the course of 30 days in this randomized study, but this study is not informative with respect to safety and efficacy of high vs low dose aspirin after 30 days. Panel members as well as FDA officials also commented on the fact that aspirin monotherapy has not been compared with thienopyridine monotherapy in the setting of ACS. There has been a supposition that a thienopyridine can be substituted for aspirin in the patient with aspirin intolerance, but this has not been studied.

Several theories were offered regarding the underlying pathobiology of adverse outcomes associated with higher doses of aspirin in the context of ticagrelor therapy. At low doses, aspirin inhibits thromboxane A2 and thereby inhibits platelet aggregation. At high doses, aspirin begins to inhibit prostaglandins which are vasodilators, and may therefore cause vasoconstriction. The balance between platelet inhibition and vasoconstriction may be shifted to different degrees in the presence of a thienopyridine such as clopidogrel or a thienopyridine-like agent such as Ticagrelor.

With respect to the hazard observed in patients from the United States, the FDA concluded that the mechanism seemed unlikely to be due to a difference in aspirin dose alone, that the data regarding the model of aspirin dose was not robust, that the role of chance although low could not be excluded, that there was no clear explanation, that the reversal in direction is quite odd and hard to explain, and that the region-specific analysis was not pre-specified.

There was no benefit observed associated with Ticagrelor administration among patients who were troponin negative and among those patients classified as having unstable angina at discharge. Among the 10,000 patients who were enrolled in a substudy of pharmacogenomics, 28% of patients were identified as carriers of the Cyp 2c19 allele (associated with impaired generation of the active metabolite of clopidogrel), and the benefits were similar in this carrier population as they were in non-carriers. There was no difference in angiographic outcomes between the Ticagrelor vs clopidogrel treated patients. 48% of ticagrelor patients had been previously treated with clopidogrel, and the results were more favorable in those patients pre-treated with clopidogrel. The HR was 0.82 if no clopidogrel had been administered. The FDA pointed out that there was little to no benefit at day 1, and that the benefit began to emerge by day 2-3.

The FDA briefing document indicated that Ticagrelor reduced atorvastatin metabolism (degradation) by 36%. 90% of the patients in PLATO were on a lipid lowering agent, and there was no difference between the two treatment arms and the achieved LDL. It therefore does not appear that an off target LDL-lowering effect of Ticagrelor explains the late benefits that were observed, although the impact on other lipid elements has not been closely examined.

The rate of drug discontinuation was 2% higher in the ticagrelor arm, and half of the cases of discontinuation were due to dyspnea. Most case of dyspnea lasted only 20 days, and 2/3rds resolved spontaneously.

Making a Choice Regarding Thienopyridine Therapy

"I think physicians will need to make their choice of pharmacotherapy based upon the net clinical benefit of an agent in a given patient. They will need to factor in the perceived risk of a recurrent ischemic event vs the risk of a bleeding event or stroke. Age, history of TIA / stroke, body weight, presence of a drug eluting stent, location of that stent (a high risk left main location for instance), history of bleeding, the anticipated duration of therapy (months versus a year), co-morbidities, upcoming surgery or dental work, genetics, pharmacodynamics (the level of inhibition on the agent), aspirin dose, dosing of coumadin or other oral anticoagulant in a patient with atrial fibrillation or VTE, the ability of the patient to comply with the therapy and the cost of the agent will likely be key factors they will consider.” C. Michael Gibson, M.S., M.D.

References

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