NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Clinical Review Report: Ticagrelor (Brilinta) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Aug.

1Introduction

1.1. Disease prevalence and incidence

Myocardial infarction (MI) is usually caused by blockage of a coronary artery that results in myocardial tissue death.1 The rupture or fissuring of an unstable atherosclerotic plaque is often the precipitating factor that leads to platelet activation and aggregation, and subsequent thrombus formation.9

In 2014 to 2015, there were 69,762 in-patient hospitalizations for acute MI in Canada.2 Although mortality rates have been declining, MI is associated with significant morbidity and mortality.3 Patients report having to take medication multiple times a day, frequent visits to a health care provider, taking time off work, and limitations to their activities following their MI.

1.2. Standards of therapy

Patients with MI have heightened platelet activation and aggregation and are at increased risk of recurrent ischemic events.9 Canadian and US guidelines recommend dual antiplatelet therapy, with ASA plus either clopidogrel, ticagrelor, or prasugrel, for up to the first 12 months following an acute MI.1,3,10,11 After the first year, ASA is the standard of care for the long-term secondary prevention of atherothrombotic events. Clopidogrel monotherapy is also indicated for long-term secondary prevention in patients with prior MI and may be used in place of acetylsalicylic acid (ASA) in some patients (Table 2).11,12

1.3. Drug

Ticagrelor is an oral, direct-acting, selective and reversibly binding P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y12-dependent platelet activation and aggregation.4 The new indication for ticagrelor is as follows: co-administered with low-dose (75 mg to 150 mg) acetylsalicylic acid (ASA), for the prevention of atherothrombotic events in adult patients with a history of MI (occurred at least one year ago) and a high risk of developing an atherothrombotic event. The recommended dose is 60 mg twice daily, orally. Health Canada has specified that no loading dose is required, and the 90 mg dose should not be used for this indication. Health Canada has also specified that treatment can be initiated up to two years from the spontaneous myocardial infarction, or within one year after stopping previous ADP receptor antagonist treatment, and that treatment duration is not to exceed three years of extended treatment.

Ticagrelor is also approved for the secondary prevention of atherothrombotic events (in combination with ASA) in patients with acute coronary syndromes (unstable angina, non–ST elevation MI, or ST elevation MI) who are to be managed medically and those who are to be managed with percutaneous coronary intervention (PCI) (with or without stent) and/or coronary artery bypass graft (CABG). The CADTH Canadian Drug Expert Committee (CDEC) recommended that ticagrelor not be listed at the submitted price for the following reasons:

  • The pre-specified subgroup analysis (by region), in the one large randomized controlled trial (RCT) of patients with acute coronary syndrome, did not provide evidence of the superiority of ticagrelor compared with clopidogrel in a North American patient population to support a higher price for ticagrelor.
  • Given the limitations identified with the manufacturer’s pharmacoeconomic submission, CDEC noted that the cost-effectiveness of ticagrelor could not be properly assessed.
  • The daily cost of ticagrelor ($2.96) is greater than clopidogrel ($2.58).5

Indication under review
Co-administered with low-dose ASA (75-150 mg), for the secondary prevention of atherothrombotic events in patients with a history of MI (occurred at least one year ago) and a high risk of developing an atherothrombotic event
Listing criteria requested by sponsor
Co-administered with low-dose (75-150 mg) ASA, for the prevention of atherothrombotic events in adult patients with a history of MI (occurred at least one year ago) and a high risk of developing an atherothrombotic event

Tables

Table 2Key Characteristics of Platelet Aggregation Inhibitors

TicagrelorClopidogrelPrasugrelASA
Mechanism of actionP2Y12 receptor blockerP2Y12 receptor blocker (prodrug)P2Y12 receptor blockerInhibits thromboxane A2 synthesis
IndicationaCo-administered with low-dose ASA for the secondary prevention of atherothrombotic events in patients with a history of MI (occurred at least one year ago) and a high risk of developing an atherothrombotic eventSecondary prevention of atherothrombotic events (MI, stroke, and vascular death) in patients with atherosclerosis documented by stroke, MI, or established peripheral arterial diseaseSecondary prevention following MI
Co-administered with ASA, for the secondary prevention of atherothrombotic events in patients with acute coronary syndromesIn combination with ASA, for the early and long-term secondary prevention of atherothrombotic events in patients with acute coronary syndromesCo-administered with ASA, for the early and long-term secondary prevention of atherothrombotic events in patients with ACS as follows:
–

unstable angina or NSTEMI managed with PCI

–

STEMI managed with primary or delayed PCI

Reduction of platelet aggregation and prevention of clot-related complications (non-fatal MI, non-fatal stroke, and death) in acute STEMI, NSTEMI, and unstable angina
Route of administrationOralOralOralOral
Recommended doseb60 mg twice daily75 mg daily10 mg daily80 mg to 162 mg daily
Serious side effects/safety issues

Bleeding, use with caution in patients with bradycardia

Contraindications: active bleeding, history of intracranial hemorrhage, severe hepatic impairment, hypersensitivity, taking strong CYP3A4 inhibitors

Common: bleeding, dyspnea, headache

Bleeding, TTP, acquired hemophilia

Contraindications: active bleeding, significant hepatic impairment, hypersensitivity

Common: bleeding, rash, dyspepsia, abdominal pain, and diarrhea

Bleeding (use with caution in those ≥ 75 years old or < 60 kg body weight), TTP

Contraindications: active bleeding, history of stroke or TIA, severe hepatic impairment, hypersensitivity

Common: bleeding, rash, anemia

Use caution in patients with decreased renal function, bleeding tendencies, significant anemia, hypoprothrombinemia, thrombocytopenia, vitamin K deficiency or severe hepatic disease

Contraindications: active peptic ulcer, hypersensitivity

Common: gastrointestinal toxicity

ACS = acute coronary syndrome; ASA = acetylsalicylic acid; MI = myocardial infarction; NSTEMI = non–ST segment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST segment elevation myocardial infarction; TIA = transient ischemic attack; TTP = thrombotic thrombocytopenic purpura.

a

Health Canada indication.

b

Recommended dose for long-term secondary prevention.

Source: Product monographs.4,12–14

Copyright © 2016 Canadian Agency for Drugs and Technologies in Health.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK539151
Contents