Cardiovascular
Welcome to AstraZeneca Cardiovascular
AstraZeneca has been driving cardiovascular innovation for more than 100 years. Our enduring goal is to push the boundaries of science to further reduce cardiovascular morbidity and mortality beyond current treatments, and to deliver transformative cardiovascular medicines to the people who need them.
Our core mission is to save the lives of patients by jointly addressing their cardio-renal-metabolic risks. Science is uncovering commonalities between cardiovascular (CV), renal and metabolic diseases (CVRM), explaining why reducing CV risk is so complex. With this knowledge, we are daring to do things differently by shifting focus from treating patients with a single disease, to addressing overlapping disease areas and risk factors.
Our focus is making sure every decision and development is rooted in our ambition to follow the science. We seek to produce medicines that not only provide superior efficacy compared to current treatments in their core indications, but that also help address associated complications.
Our scientific goal is to slow the progression of CV-related disease, and ultimately, modify or even halt the natural course of the disease itself and regenerate organs.
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BRILIQUE® (ticagrelor)
BRILIQUE (ticagrelor) is the P2Y12 inhibitor licensed in combination with aspirin to protect patients with prior MI and a high risk* of atherothrombotic events against subsequent CV events in both the acute and long-term treatment settings†1
*High risk is defined as ≥1 additional atherothrombotic risk factor (age ≥65 years, >1 prior MI, multivessel coronary artery disease, diabetes requiring medication, chronic non-end-stage renal dysfunction)1
†BRILIQUE (ticagrelor) 90mg twice daily in combination with acetylsalicylic acid (ASA) is indicated for patients with Acute Coronary Syndromes (ACS) for up to 12 months. BRILIQUE (ticagrelor) 90mg twice daily is not indicated for use in patients beyond 12 months. There are limited data on the efficacy and safety of BRILIQUE (ticagrelor) 60mg beyond 3 years of extended treatment
Approved Brilique SPC, section 4.1, 4.2, 5.1, 19.09.2019
Safety information
The most frequently reported adverse events for Brilique are bleeding, dyspnea and hyperuricaemia. Brilique is not to be used for patients with an active pathological bleeding, previous intracranial bleeding, severe hepatic impairment or co-administration of ticagrelor with strong CYP3A4 inhibitors. The use of Brilique in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events
Approved Brilique SPC, section 4.3, 4.8, 19.09.2019
Post-MI patients remain at high and persistent CV-risk
Helicon
108 315 patients admitted to hospital with a primary MI. 18,3% patients had recurrent stroke, MI or CV death within 1 year of index MI. 20% patients who remained event-free for 1 year had recurrent stroke, MI or CV death within the next 3 years.
Jernberg T et al. Eur Heart J. 2015;36:1163-1170.
Prospect
697 patients with ACS that underwent treatment with PCI. 20,4% patients had recurrent major adverse cardiovascular events within 3 years. Events were almost equally attributable to culprit lesions and non-culprit lesions (12.6% vs. 11.6% patients, respectively)
Stone GW et al. New Eng J Med 2011;364:226-235.
Preclude
99 546 first-occurrence MI related to a non-culprit lesion was twice as high than compared to a culprit lesion (Kaplan-Meier rates 0.080 vs. 0.027, respectively).
Varenhorst C et al. J Am Heart Assoc. 2018;7:e007174. DOI: 10.1161/JAHA.117.007174.
Indication and dosing
Brilique, co‑administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with
- acute coronary syndromes (ACS) or
- a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event
Patients taking Brilique should also take a daily low maintenance dose of ASA 75‑150 mg, unless specifically contraindicated.
Acute coronary syndromes
Brilique treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Treatment with Brilique 90 mg twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated.
History of myocardial infarction
Brilique 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event. Treatment may be started without interruption as continuation therapy after the initial one‑year treatment with Brilique 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of Brilique beyond 3 years of extended treatment.
Approved Brilique SPC, section 4.2, 19.09.2019
Brilique mechanism of action
Brilique 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. 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 dyspnea.
Approved Brilique SPC, section 5.1, 19.09.2019
Clinical efficacy
ACS – Brilique vs clopidogrel clinical data
PLATO was a multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. Study period was 12 months, with a median duration of therapy of 277 days.
PLATO demonstrated a reduction in subsequent CV events (composite of CV death, MI or stroke) in patients with ACS taking Brilique 90 mg* compared with clopidogrel* at 12 months: 9.8% vs 11.7%, respectively (16% RRR, 1.9% ARR).This efficacy benefit was seen early and accrues over the full 12 months.1
In the PLATO trial, Brilique 90 mg* CV death at 12 months was significantly a 21% RRR (1.1% ARR) lower in ACS patients treated with Brilique 90 mg* compared with clopidogrel.*
*in combination with ASA 75-150 mg
Wallentin L et al. N Engl J Med 2009;361:1045-57.
High risk post MI patients
PEGASUS-TIMI 54 study
PEGASUS-TIMI 54 was a randomized, double-blind, placebo-controlled, multinational clinical trial. 21 162 patients with a history of a spontaneous MI and one additional risk factor randomized to receive Brilique* 90 mg orally twice daily, Brilique* 60 mg orally twice daily, or low dose ASA. Additional risk factors were age ≥65 years, diabetes, second prior MI, multivessel coronary arthery disease or chronic non-end stage renal dysfunction.
*in combination with ASA 75-150 mg
Bonaca MP et al. Am Heart J 2014;167:437–444.
PEGASUS-TIMI 54 time from withdrawal analysis
In a pre-specified analysis from PEGAUS-TIMI 54 was conducted to investigate the hypothesis that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy.
The greatest benefit with Brilique* 60 mg was seen in patients who had discontinued P2Y12 inhibition within 30 days HR 0.75 (95% CI 0.61–0.92, p=0.0064) and the curves diverge over time. No benefit was seen in patients who had discontinued P2Y12 inhibition > 1 year ago.
*in combination with ASA 75-150 mg
Bonaca MP et al. Eur Heart J 2015. doi:10.1093/eurheartj/ehv531
Safety profile
Bleedings
PLATO-study demonstrated no increase in overall major bleeding or fatal bleeding with Brilique* 90 mg compared with clopidogrel*. However, more combined major + Minor bleeding occurred with Brilique* 90 mg compared with clopidogrel*.
In PEGASUS-TIMI 54 study rates of TIMI major bleeding were higher with Brilique* 60 mg (2.30%) than with ASA (1.06%) (P<0.001 vs. ASA). There were no differences in intracranial hemorrhage or fatal bleeding in the groups.
*in combination with ASA 75-150 mg
Wallentin L et al. N Engl J Med 2009;361:1045-57.Bonaca MP et al. Am Heart J 2014;167:437–444.
Precautions for use
The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. If clinically indicated, ticagrelor should be used with caution in the following patient groups:
- Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coaulation disorders, active or recent gastrointestinal bleeding).
- Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non‑steroidal anti‑inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing.
- Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken. If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 7 days prior to surgery.
- ACS patients with prior ischaemic stroke can be treated with Brilique for up to 12 months. In the absence of data, treatment beyond one year is not recommended in patients with history of MI with prior ischaemic stroke.
Approved Brilique SPC, section 4.4, 19.09.2019
Dyspnoea
Dyspnoea was reported in patients treated with ticagrelor. In PLATO study, dyspnoea adverse events (AEs) was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. Dyspnoea is usually mild to moderate in intensity and often resolves without need for treatment discontinuation and most were reported as a single episode early after starting treatment. About 30% of episodes resolved within 7 days. Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with ticagrelor. Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The higher incidence of dyspnoea with Brilique is not associated with new or worsening heart or lung disease.
If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped.
Approved Brilique SPC, section 4.8, 19.09.2019
Contraindications
- Hypersensitivity to the active substance or to any of the excipients
- Active pathological bleeding
- History of intracranial haemorrhage
- Severe hepatic impairment
- Co‑administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co‑administration may lead to a substantial increase in exposure to ticagrelor
Approved Brilique SPC, section 4.3, 19.09.2019
Interaction
Potent CYP3A4 inducers
Co‑administration of ticagrelor with potent CYP3A inducers (rifampicin, phenytoin, carbamazepine and phenobarbital) may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged.
Potent P-gp and CYP3A inhibitor
Potent P‑gp inhibitors and moderate CYP3A4 inhibitors (e.g. cyclosporine, verapamil, quinidine) may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution.
Others
Clinical pharmacology interaction studies showed that co‑administration of ticagrelor with heparin, enoxaparin and ASA or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP‑induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor.
Medicinal products metabolised by CYP3A4
Co‑administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse effects of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.
Ticagrelor is a mild CYP3A4 inhibitor. Co‑administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride orergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products.
Digoxin
Appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P‑gp dependent medicinal products like digoxin concomitantly with ticagrelor.
Co‑administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa assays. However, due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of ticagrelor with medicinal products known to alter haemostasis.
Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase the risk of bleeding.
Approved Brilique SPC, section 4.5, 19.09.2019
Before prescribing, please read carefully the whole Brilique SmPC