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Pharmacology: Pharmacodynamics: Mechanism of action: Brilinta contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP-mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke.
Ticagrelor also increases local endogenous adenosine levels by inhibiting the equilibrative nucleoside transporter-1 (ENT-1).
Ticagrelor has been documented to augment the following adenosine-induced effects in healthy subjects and in patients with ACS: vasodilation (measured by coronary blood flow increases in healthy volunteers and ACS patients; headache), inhibition of platelet function (in human whole blood in vitro) and dyspnoea. However, a link between the observed increases in adenosine and clinical outcomes (e.g. morbidity-mortality) has not been clearly elucidated.
Pharmacodynamic effects: Onset of action: In patients with stable coronary artery disease (CAD) on ASA, ticagrelor demonstrates a rapid onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 89% by 2-4 hours post dose, and maintained between 2-8 hours. 90% of patients had final extent IPA >70% by 2 hours post dose.
Offset of action: If a CABG procedure is planned, ticagrelor bleeding risk is increased compared to clopidogrel when discontinued within less than 96 hours prior to procedure.
90 mg: Switching data: Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to ticagrelor without any interruption of antiplatelet effect (see "Dosage & Administration").
Clinical efficacy and safety: 60 mg: The clinical evidence for the efficacy and safety of ticagrelor is derived from the PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of ticagrelor combined with ASA to ASA therapy alone and the THEMIS [effect of Ticagrelor on Health outcomes in diabEtes Mellitus patients Intervention Study] study, a comparison of ticagrelor in combination with ASA to ASA alone in patients with CAD and type 2 DM.
PEGASUS study (History of Myocardial Infarction): The PEGASUS TIMI-54 study was a 21,162 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multicentre study to assess the prevention of atherothrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice daily) combined with low dose ASA (75-150 mg), compared to ASA therapy alone in patients with history of MI and additional risk factors for atherothrombosis.
Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to 3 years prior to randomisation), and had at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes mellitus requiring medication, a second prior MI, evidence of multivessel CAD, or chronic non-end-stage renal dysfunction.
Patients were ineligible if there was planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; if they had a bleeding disorder or a history of an ischaemic stroke or intracranial bleeding, a central nervous system tumour, or an intracranial vascular abnormality; if they had had gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days.
Clinical efficacy: (See Figure 1 and Table 1.)
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Click on icon to see table/diagram/imageBoth 60 mg twice daily and 90 mg twice daily regimens of ticagrelor in combination with ASA were superior to ASA alone in the prevention of atherothrombotic events (composite endpoint: CV death, MI and stroke), with a consistent treatment effect over the entire study period, yielding a 16% RRR and 1.27% ARR for ticagrelor 60 mg and a 15% RRR and 1.19% ARR for ticagrelor 90 mg.
Although the efficacy profiles of 90 mg and 60 mg were similar, there is evidence that the lower dose has a better tolerability and safety profile in relation to risk of the bleeding and dyspnoea. Therefore only Brilinta 60 mg twice daily co-administered with ASA is recommended for the prevention atherothrombotic events (CV death, MI and stroke) in patients with a history of MI and a high risk of developing an atherothrombotic event.
Relative to ASA alone, ticagrelor 60 mg twice daily significantly reduced the primary composite endpoint of CV death, MI and stroke. Each of the components contributed to the reduction in the primary composite endpoint (CV death 17% RRR, MI 16% RRR, and stroke 25% RRR).
The RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) was similar. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment.
There was no evidence of benefit (no reduction in the primary composite endpoint of CV death, MI and stroke, but an increase in major bleeding) when ticagrelor 60 mg twice daily was introduced in clinically stable patients >2 years from the MI, or more than one year after stopping previous ADP receptor inhibitor treatment (see also "Dosage & Administration").
Clinical safety: The rate of discontinuations with ticagrelor 60 mg due to bleeding and dyspnoea was higher in patients >75 years (42%) than in younger patients (range: 23-31%), with a difference versus placebo higher than 10% (42% vs. 29%) in patients >75 years.
Paediatric population: In a randomised, double-blind, parallel-group Phase III study (HESTIA 3), 193 paediatric patients (ages 2 to less than 18 years) with sickle cell disease were randomised to receive either placebo or ticagrelor at doses of 15 mg to 45 mg twice daily depending on body weight. Ticagrelor resulted in a median platelet inhibition of 35% at pre-dose and 56% at 2 hours post-dose at steady state. Compared to placebo, there was no treatment benefit of ticagrelor on the rate of vaso-occlusive crises.
The European Medicines Agency has waived the obligation to submit the results of studies with Brilinta in all subsets of the paediatric population in acute coronary syndromes (ACS) and history of myocardial infarction (MI) (see "Dosage & Administration" for information on paediatric use).
THEMIS study (Patients with Coronary Artery Disease (CAD) and Type 2 Diabetes Mellitus (DM) with History of Percutaneous Coronary Intervention (PCI)): Study Design: The THEMIS study was a 19,220 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multi-centre study to assess the prevention of atherothrombotic events with ticagrelor combined with low dose ASA (75-150 mg) compared to ASA therapy alone in patients with CAD and type 2 DM. The median ticagrelor treatment duration was 33.2 months.
Patients were eligible to participate if they were aged 50 years or over, had CAD defined as history of PCI (58% of study population) or CABG (29%) or no history of coronary revascularisation, but angiographic evidence of ≥50% lumen stenosis of at least 1 coronary artery (20%) and type 2 DM treated with glucose-lowering medication for at least 6 months prior to study start.
Patients were ineligible to participate if they had a history of MI or stroke; if there was planned use of ADP receptor antagonists, ASA treatment >150 mg od, dipyridamole, or cilostazol; if there was planned coronary, cerebrovascular, or peripheral arterial revascularization or anticipated use of CYP3A4 substrates with narrow therapeutic indices or strong CYP3A4 inhibitors; if they were at known increased risk for bleeding (e.g., need for chronic oral anticoagulants, known bleeding diathesis, coagulation disorder, recent major surgery, history of previous intracerebral bleed or GI bleeding within the past 6 months etc.) or bradycardic events unless treated with a pacemaker; if they had uncontrolled hypertension or renal failure requiring dialysis, or if they had any contraindications to receive ticagrelor treatment.
THEMIS study was conducted for a duration up to 57 months with mean (median) duration of exposure to ticagrelor of 29.2 months (33.2 months). With respect to duration of exposure to the study drug, 7322 (76.6%) patients were exposed to ticagrelor for 12 months, 6421 (67.2%) for 24 months and 4107 (43%) for 36 months. At 48 months, 1175 (12.3%) patients were exposed to ticagrelor. Patients were followed to study termination, irrespective of whether study drug had been discontinued.
Study Results: In the total THEMIS study population, ticagrelor twice daily in combination with ASA, compared to ASA alone, resulted in the prevention of atherothrombotic events (composite endpoint: CV death, MI and stroke), with a hazard ratio (HR) of 0.90 (95% CI: 0.81, 0.99, p=0.0378), corresponding to a relative risk reduction (RRR) of 10% and an absolute risk reduction (ARR) of 0.73% (number needed to treat [NNT] of 138 after 36 months of treatment). The effect was driven by the individual components MI (HR 0.84, 95% CI: 0.71, 0.98) and stroke (HR 0.82, 95% CI: 0.67, 0.99), with no difference in CV deaths (HR 1.02, 95% CI: 0.88, 1.18). Of the secondary endpoints not assessed as part of the primary composite endpoint, ticagrelor reduced the number of ischaemic stroke events (HR 0.80, 95% CI: 0.64, 0.99) with no difference in all-cause death (HR 0.98, 95% CI: 0.87, 1.10). The benefit-risk profile of ticagrelor in the total THEMIS study population was not considered favourable to support use of ticagrelor and therefore, an indication was not granted for the total study population (see "Indications/Uses" and "Precautions").
In THEMIS patients with a history of PCI, which was a pre-specified subgroup corresponding to 58% of the total study population, treatment with ticagrelor in combination with ASA, compared to ASA alone, resulted in the prevention of atherothrombotic events (composite endpoint: CV death, MI and stroke) (see Table 2). Ticagrelor treatment yielded a 15% RRR, a 1.19% ARR (number needed to treat [NNT] of 84 after 36 months of treatment) and a more favourable benefit-risk profile than the total THEMIS study population. Again, the treatment benefit was driven by the MI and stroke components of the composite endpoint.
The baseline characteristics in the subgroup of patients with a history of PCI were comparable in both treatment arms. (See Table 2.)
Click on icon to see table/diagram/imageTreatment with ticagrelor should be continued in patients with CAD, type 2 DM and history of PCI for as long as the patient remains at high risk of an atherothrombotic event and low risk of bleeding, for a duration up to three years. Efficacy and safety data are insufficient to establish whether the benefits of ticagrelor still outweigh the risks after three years of extended treatment (see "Dosage & Administration"). (See Figure 2.)
Click on icon to see table/diagram/imageThe treatment effect of BRILINTA across patient subgroups, based on patient characteristics including weight, gender, medical history, and geographic region, in THEMIS patients with a history of PCI is shown in Figure 3. (See Figure 3.)
Click on icon to see table/diagram/image90 mg: PLATO study (Acute Coronary Syndromes): The PLATO study included 18,624 patients who presented within 24 hours of onset of symptoms of unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI), and were initially managed medically, or with percutaneous coronary intervention (PCI), or with CABG.
Clinical efficacy: On a background of daily ASA, ticagrelor 90 mg twice daily showed superiority to 75 mg daily clopidogrel in preventing the composite endpoint of CV death, MI or stroke, with the difference driven by CV death and MI. Patients received a 300 mg loading dose of clopidogrel (600 mg possible if having PCI) or 180 mg of ticagrelor.
The result appeared early (absolute risk reduction [ARR] 0.6% and Relative Risk Reduction [RRR] of 12% at 30 days), with a constant treatment effect over the entire 12-month period, yielding ARR 1.9% per year with RRR of 16%. This suggests it is appropriate to treat patients with ticagrelor for up to 12 months (see "Dosage & Administration"). Treating 54 ACS patients with ticagrelor instead of clopidogrel will prevent 1 atherothrombotic event; treating 91 will prevent 1 CV death (see Figure 4 and Table 3).
The treatment effect of ticagrelor over clopidogrel appears consistent across many subgroups, including weight; sex; medical history of diabetes mellitus, transient ischaemic attack or non-haemorrhagic stroke, or revascularisation; concomitant therapies including heparins, GpIIb/IIIa inhibitors and proton pump inhibitors (see "Interactions"); final index event diagnosis (STEMI, NSTEMI or UA); and treatment pathway intended at randomisation (invasive or medical).
A weakly significant treatment interaction was observed with region whereby the hazard ratio (HR) for the primary endpoint favours ticagrelor in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-value=0.045). Exploratory analyses suggest a possible association with ASA dose such that reduced efficacy was observed with ticagrelor with increasing ASA doses. Chronic daily ASA doses to accompany ticagrelor should be 75-150 mg (see "Dosage & Administration" and "Precautions"). (See Figure 4.)
Click on icon to see table/diagram/imageTicagrelor reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population (Table 3). Thus, Brilinta 90 mg twice daily together with low dose ASA can be used in patients with ACS (unstable angina, non-ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). (See Table 3.)
Click on icon to see table/diagram/imagePLATO genetic substudy: CYP2C19 and ABCB1 genotyping of 10,285 patients in PLATO provided associations of genotype groups with PLATO outcomes. The superiority of ticagrelor over clopidogrel in reducing major CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype. Similar to the overall PLATO study, total PLATO Major bleeding did not differ between ticagrelor and clopidogrel, regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was increased with ticagrelor compared clopidogrel in patients with one or more CYP2C19 loss of function alleles, but similar to clopidogrel in patients with no loss of function allele.
Combined efficacy and safety composite: A combined efficacy and safety composite (CV death, MI, stroke, or PLATO-defined 'Total Major' bleeding) indicates that the benefit in efficacy of ticagrelor compared to clopidogrel is not offset by the major bleeding events (ARR 1.4%, RRR 8%, HR 0.92; p=0.0257) over 12 months after ACS.
Clinical safety: Holter substudy: To study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO, investigators performed Holter monitoring in a subset of nearly 3000 patients, of whom approximately 2000 had recordings both in the acute phase of their ACS and after one month. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More patients had ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6%, respectively, after 1 month (see "Precautions"). The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with history of CHF (9.2% versus 5.4% in patients without CHF history; for clopidogrel patients, 4.0% in those with versus 3.6% in those without CHF history). This imbalance did not occur at one month: 2.0% versus 2.1% for ticagrelor patients with and without CHF history, respectively; and 3.8% versus 1.4% with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients.
THALES study (Acute Ischemic Stroke or Transient Ischemic Attack (TIA)): The THALES study (NCT03354429) was a 11016-patient, randomized, double-blind, parallel-group study of Brilinta 90 mg twice daily versus placebo in patients with acute ischemic stroke or transient ischemic attack (TIA). The primary endpoint was the first occurrence of the composite of stroke and death up to 30 days. Ischemic stroke was assessed as one of the secondary endpoints.
Patients were eligible to participate if they were ≥40 years old, with non-cardioembolic acute ischemic stroke (NIHSS score ≤5) or high-risk TIA (defined as ABCD2 score ≥6 or ipsilateral atherosclerotic stenosis ≥50% in the internal carotid or an intracranial artery). Patients who received thrombolysis or thrombectomy within 24 hours prior to randomization were not eligible.
Patients were randomized within 24 hours of onset of an acute ischemic stroke or TIA to receive 30 days of either Brilinta (90 mg twice daily, with an initial loading dose of 180 mg) or placebo, on a background of aspirin initially 300-325 mg then 75-100 mg daily. The median treatment duration was 31 days.
Brilinta was superior to placebo in reducing the rate of the primary endpoint (composite of stroke and death), corresponding to a relative risk reduction (RRR) of 17% and an absolute risk reduction (ARR) of 1.1% (Table 4). The effect was driven primarily by a significant reduction in the stroke component of the primary endpoint (19% RRR, 1.1% ARR). (See Table 4.)
Click on icon to see table/diagram/imageThe Kaplan-Meier curve (Figure 5) shows the time to first occurrence of the primary composite endpoint of stroke and death. (See Figure 5.)
Click on icon to see table/diagram/imageBrilinta's treatment effect on stroke and on death accrued over the first 10 days and was sustained at 30 days. Although not studied, this suggests that shorter treatment could result in similar benefit and reduced bleeding risk.
The treatment effect of Brilinta was generally consistent across pre-defined subgroups (Figure 6). (See Figure 6.)
Click on icon to see table/diagram/imageAt Day 30, there was an absolute reduction of 1.2% (95% CI: -2.1%, -0.3%) in the incidence of non-hemorrhagic stroke and death (excluding fatal bleed) favoring ticagrelor (294 events: 5.3%) over placebo (359 events: 6.5%) in the intention-to-treat population. In the same population, there was an absolute increase of 0.4% (95% CI: 0.2%, 0.6%) in the incidence of GUSTO severe bleeding unfavorable to ticagrelor arm (28 events: 0.5%) compared to the placebo arm (7 events: 0.1%).
Pharmacokinetics: Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg.
Absorption: Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. Following an oral ticagrelor 90 mg single dose under fasted conditions in healthy subjects, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The metabolite parent ratios are 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to that in the ACS population. Based on a population pharmacokinetic analysis of the PEGASUS study the median ticagrelor Cmax was 391 ng/ml and AUC was 3801 ng*h/ml at steady state for ticagrelor 60 mg. For ticagrelor 90 mg Cmax was 627 ng/ml and AUC was 6255 ng*h/ml at steady state.
The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-fat meal resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax but had no effect on ticagrelor Cmax or the AUC of the active metabolite. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food. Ticagrelor as well as the active metabolite are P-gp substrates.
Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets with regards to AUC and Cmax for ticagrelor and the active metabolite. Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours).
Distribution: The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%).
Biotransformation: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition.
The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor.
Elimination: The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion. The mean t½ was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite.
Special populations: Elderly: Higher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite were observed in elderly (≥75 years) ACS patients compared to younger patients by the population pharmacokinetic analysis. These differences are not considered clinically significant (see "Dosage & Administration").
Paediatric population: Ticagrelor has not been evaluated in a paediatric population (see section "Dosage & Administration" and "Pharmacodynamics" as previously mentioned).
Gender: Higher exposures to ticagrelor and the active metabolite were observed in women compared to men. These differences are not considered clinically significant.
Renal impairment: Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 ml/min) compared to subjects with normal renal function.
In patients with end stage renal disease on haemodialysis AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis (49% and 61%, respectively) showing that ticagrelor is not dialysable. Exposure of the active metabolite increased to a lesser extent (AUC 13-14% and Cmax 17-36%). The inhibition of platelet aggregation (IPA) effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to subjects with normal renal function (see "Dosage & Administration").
Hepatic impairment: Cmax and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however, the IPA effect of ticagrelor was similar between the two groups. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment. In patients that had moderate or severe elevation in one or more liver function tests at baseline, ticagrelor plasma concentrations were on average similar or slightly higher as compared to those without baseline elevations. No dose adjustment is recommended in patients with moderate hepatic impairment (see "Dosage & Administration" and "Precautions").
60 mg: No dose adjustment is needed for patients with mild hepatic impairment.
Ethnicity: Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as Black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients. In clinical pharmacology studies, the exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians.
Toxicology: Preclinical Safety Data: Preclinical data for ticagrelor and its major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxic potential.
Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels (see "Adverse Reactions").
In female rats, ticagrelor at high dose showed an increased incidence of uterine tumors (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine tumors is likely hormonal imbalance which can lead to tumors in rats. The mechanism for the hepatic adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity findings are considered unlikely to be relevant for humans.
In rats, minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In rabbits a slight delay in hepatic maturity and skeletal development was seen in foetuses from dams at high dose without showing maternal toxicity (safety margin of 4.5).
Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and female rats. Pharmacokinetic studies performed with radio-labeled ticagrelor have shown that the parent compound and its metabolites are excreted in the milk of rats (see "Use in Pregnancy & Lactation").
