This document has been updated since its original release. [Details]

Another oral antiplatelet agent

Key points

  • Ticagrelor is an oral antiplatelet drug
    It binds to the P2Y12 adenosine disphosphate receptor to reduce platelet activation and aggregation.
  • Ticagrelor must be prescribed with aspirin
    Prescribe aspirin at a dose between 75 and 150 mg/day. At higher aspirin doses ticagrelor may not be more effective than clopidogrel.
  • Ticagrelor and aspirin reduces the incidence of vascular deaths and myocardial infarctions more than clopidogrel and aspirin
    However, there was a non-significantly greater number of strokes and intracranial bleeds among people taking ticagrelor and aspirin compared with those taking clopidogrel and aspirin.
  • Some adverse events are more common than with clopidogrel
    Discontinuations, minor bleeding requiring medical intervention, non-coronary artery bypass graft (CABG) bleeding, dyspnoea and ventricular pauses are significantly higher among people taking ticagrelor and aspirin rather than clopidogrel and aspirin.
  • Safety and efficacy after 12 months has not been studied
    The optimal duration of therapy is unknown. The median exposure to ticagrelor in the PLATO study was 276 days.
  • Ticagrelor must be taken twice daily
    Unlike clopidogrel and prasugrel, which are taken once daily.

Evidence snapshot

What is known about this drug

In acute coronary syndrome, the combination of ticagrelor and aspirin reduced the incidence of vascular deaths and myocardial infarctions more than clopidogrel and aspirin. It did not lower the risk of stroke compared with clopidogrel and aspirin.

Some adverse events appear to be more common among people taking ticagrelor and aspirin rather than clopidogrel and aspirin. Bleeding (non-CABG bleeding, minor bleeding requiring medical intervention and fatal intracranial bleeds), dyspnoea, ventricular pauses and raised serum uric acid and serum creatinine are all significantly more common among people taking ticagrelor and aspirin.

Discontinuations due to adverse effects were significantly higher among people taking ticagrelor and aspirin instead of clopidogrel and aspirin.

Areas of uncertainty

The safety and efficacy of ticagrelor and aspirin after 12 months have not been studied. There have been no head-to-head trials against prasugrel.

What does NPS say?

The combination of ticagrelor and aspirin reduces the incidence of vascular deaths and myocardial infarctions more than clopidogrel and aspirin. This must be weighed against an increased risk of adverse events. Clopidogrel and aspirin may be a better option for people at high risk of bleeding or at increased risk of dyspnoea or bradycardia.

PBS listing

Authority required (Streamlined)

Treatment of acute coronary syndrome (MI or unstable angina) in combination with aspirin.1,2

May be prescribed by nurse practitioners (shared care model)

Authorised nurse practitioners may prescribe this medicine as part of a formal care plan with a medical practitioner. See the PBS website for more information on nurse practitioner PBS prescribing.

What is it?

Ticagrelor is another oral antiplatelet drug. Like clopidogrel and prasugrel it inhibits platelet aggregation by blocking the platelet P2Y12 adenosine disphosphate receptor. But unlike prasugrel and clopidogrel, ticagrelor binds reversibly, so its inhibitory effect on platelet aggregation is more quickly reversed. The inhibitory effects of ticagrelor 3 days after discontinuation are similar to those seen 5 days after stopping clopidogrel.3,4

Clopidogrel and prasugrel are prodrugs, whereas ticagrelor does not need to be metabolised to become biologically active.

Who is it for?

Ticagrelor — in combination with aspirin — is for the treatment of acute coronary syndrome (MI or unstable angina).

It should not be used in people with a history of intracranial haemorrhage, moderate to severe hepatic impairment or in people using strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin).5

Use with caution in people with:

  • an increased risk of bleeding
  • a history of dyspnoea or bradycardia
  • asthma, chronic obstructive pulmonary disease or heart failure (see Safety issues).

Where does it fit?

Ticagrelor in combination with aspirin is an alternative to clopidogrel and aspirin or prasugrel and aspirin* in people with an acute coronary syndrome (MI or unstable angina).

ST-segment-elevation myocardial infarction (STEMI)

Current Australian guidelines recommend treatment with aspirin and clopidogrel for up to 12 months after an ST-segment-elevation MI. The newer antiplatelet therapies, ticagrelor and prasugrel, can be considered if the patient is undergoing percutaneous coronary intervention (PCI) and is at high risk of another ischaemic event (e.g. people with diabetes, stent thrombosis) although the risk of bleeding needs to be carefully assessed.6

Non-ST-segment-elevation acute coronary syndromes (NSTEACS)

Current Australian guidelines recommend people with high-risk NSTEACS and at low risk of bleeding be treated with prasugrel or ticagrelor. People with high-risk NSTEACS who are also at high risk of bleeding should be treated with clopidogrel.6


* The combination of prasugrel and aspirin is only PBS listed for treatment of an acute coronary syndrome managed by percutaneous coronary intervention.

† Includes people who have chest pain at rest or repetitive or prolonged pain in addition to changes on their electrocardiogram or elevated troponin levels.

How does it compare?

The pivotal study on ticagrelor (the PLATO study; n = 18,624) enrolled people hospitalised for an acute coronary syndrome (STEMI or NSTEACS) whose symptoms had begun within the previous 24 hours.

At 12 months, ticagrelor in combination with aspirin lowered the incidence of a composite outcome of death from vascular causes, MI or stroke compared with the combination of clopidogrel and aspirin (Table 1). Ticagrelor and aspirin reduced the incidence of vascular deaths and MI more than clopidogrel and aspirin. However, there was a non-significant increase in the number of strokes among the group taking ticagrelor rather than clopidogrel. 7

Table 1 PLATO efficacy study results at 12 months as a percentage of all randomised participants 7

Outcome

Ticagrelor and aspirin (n = 9333)

Clopidogrel and aspirin (n = 9291)

Hazard ratio (95% CI)

Difference: ticagrelor and aspirin compared with clopidogrel and aspirin

Death from vascular causes‡, MI or stroke

9.8%

11.7%

0.84
(0.77 to 0.92)

19 fewer events per 1000 people

MI

5.8%

6.9%

0.84
(0.75 to 0.95)

11 fewer events per 1000 people

Death from vascular causes*

4.0%

5.1%

0.79
(0.69 to 0.91)

11 fewer events per 1000 people

Stroke

1.5%

1.3%

1.17
(0.91 to 1.52)

Two more events per 1000 people

Death from cardiovascular causes or cerebrovascular causes and any death without another known cause


All-cause mortality was lower in the ticagrelor and aspirin arm than in the clopidogrel and aspirin arm of the PLATO study (4.5% vs. 5.9%, respectively).7 However, this can only be considered an exploratory finding.§


§ In the PLATO study, individual endpoints were organised hierarchically then tested sequentially until the first non-significant endpoint difference was observed. At this point formal statistical testing stopped and any further tests were only exploratory. The endpoint of stroke was tested before all-cause mortality. Because stroke was non-significant the all-cause mortality result is only exploratory.

Optimal duration of therapy is unknown

Although the product information recommends that ticagrelor therapy be continued for at least 12 months, its safety and efficacy after 12 months has not been studied. The median exposure to ticagrelor in the PLATO study was 276 days, and 34% (n = 3138) of participants in the ticagrelor arm took the drug for longer than 360 days. 4,7 About half of the participants in the ticagrelor arm took the drug for less than 9 months.4

Reassess the risks and benefits of treatment if considering continuing ticagrelor after 12 months.

At high aspirin doses clopidogrel may be more effective than ticagrelor

The PLATO protocol specified an aspirin dose of 75–100 mg daily. However, if a patient received a stent the dose could be increased up to 325 mg daily for 6 months or less.8,9 In a subgroup analysis ticagrelor and aspirin was not as effective as clopidogrel and aspirin in North American participants.ll Most of these participants took ≥ 300 mg aspirin throughout the study.10 Post-hoc analyses suggest that clopidogrel is superior to ticagrelor when the aspirin dose is > 150 mg daily. 4


ll Making multiple comparisons increases the likelihood of finding something by chance. As this result was one of a large number of PLATO subgroup analyses it may be a chance finding.

No head-to-head trials with prasugrel

There have been no studies directly comparing ticagrelor with prasugrel.

Ticagrelor is effective in clopidogrel non-responders

In one small trial, 41 people identified as being non-responders to clopidogrel were randomised to clopidogrel or ticagrelor for 14 days. They were then immediately switched to the other medication for another 14 days of treatment. Inhibition of platelet aggregation was significantly improved when people were taking ticagrelor rather than clopidogrel. 3

The effect of ticagrelor did not appear to be affected by the presence or absence of the CYP2C19 or ARCB1 polymorphisms.11 These polymorphisms account for some but not all of the variability in response to clopidogrel.12

There is no evidence that switching people already on long-term clopidogrel therapy to ticagrelor in the absence of a new coronary event improves outcomes. Nor is there randomised evidence that altering antiplatelet therapy based on genetic tests improves clinical outcomes.12,13


¶ Identified by platelet function testing.

Safety issues

Some adverse events are more common among people taking ticagrelor and aspirin rather than clopidogrel and aspirin. Major bleeding unrelated to a CABG, minor bleeding that required medical intervention, dyspnoea, ventricular pauses and raised serum uric acid and serum creatinine levels were all significantly more common among people taking ticagrelor and aspirin. There was a small but non-significant increase in the number of intracranial bleeds among people taking ticagrelor and aspirin. However, significantly more of these intracranial bleeds were fatal in people taking ticagrelor and aspirin. Significantly more people taking ticagrelor and aspirin discontinued treatment because of adverse events or because they were no longer willing to continue treatment. 7

The safety of ticagrelor beyond 12 months is yet to be established.

Report suspected adverse reactions to the TGA online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Increased risk of bleeding

While the overall rate of major bleeding and life-threatening or fatal bleeding (Table 2) did not differ between ticagrelor and clopidogrel in the PLATO study, more people taking ticagrelor and aspirin experienced major bleeding that was unrelated to CABG, intracranial bleeding and minor bleeding requiring medical intervention. 4,7

Table 2 Bleeding events at 12 months in the PLATO safety population as a percentage of all participants who received at least one dose of study drug4,7
Outcome Ticagrelor and aspirin (n = 9235) Clopidogrel and aspirin (n = 9186) Hazard ratio (95% CI) or p-value Difference: ticagrelor and aspirin compared with clopidogrel and aspirin

Major** or minor bleeding

16.1%

14.6%

1.11 (1.03 to 1.20)

15 more events per 1000 people

Major bleeding (primary endpoint)**

11.6%

11.2%

1.04 (0.95 to 1.13)

Four more events per 1000 people

Major bleeding unrelated to CABG

4.5%

3.8%

1.19 (1.02 to 1.38)

Seven more events per 1000 people

Minor bleeding††

4.8%

3.8%

p < 0.05

10 more events per 1000 people

Life-threatening or fatal bleeding

5.8%

5.8%

1.03 (0.90 to 1.16)

n/a

** Defined as fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolaemic shock or severe hypotension due to bleeding and requiring pressors or surgery, significantly disabling bleeding, a drop in haemoglobin levels ≥ 30 g/L, or transfusion of ≥ 2 units of red blood cells

†† Any bleeding requiring medical intervention but not meeting the criteria for major bleeding

Avoid ticagrelor in certain patients at higher risk of bleeding

People at risk of bleeding were excluded from the PLATO study. Avoid using ticagrelor in these people. They include people:

  • with active bleeding
  • with a history of bleeds (e.g. intracranial or gastrointestinal)
  • who have had major surgery in the last 30 days
  • who required treatment with anticoagulants or thrombolytics
  • with thrombocytopenia.4,5,8

Small increase in intracranial bleeding

There were 26 cases (0.3%) of intracranial bleeding in the ticagrelor group compared with 14 cases (0.2%) in the clopidogrel group (hazard ratio [HR] 1.87, 95% confidence interval [CI] 0.98 to 3.58). In 11 of the ticagrelor patients (0.1%) this bleed was fatal compared with one fatal intracranial bleed (0.01%) in the clopidogrel group (p = 0.02). 7

Do not use ticagrelor in people with a history of intracranial haemorrhage5 or in those at increased risk of intracranial haemorrhage.

There were fewer non-intracranial fatal bleeds in the ticagrelor group (0.1% vs 0.3%).7

Discontinuations were more common among people taking ticagrelor

In the PLATO study, significantly more people stopped taking ticagrelor than clopidogrel (23.4% vs 21.5%, respectively). Significantly more people stopped taking ticagrelor because of adverse events (7.4% vs 6.0%) or because they were no longer willing to continue treatment (10.1% vs 9.2%).7

Higher rates of dyspnoea

Dyspnoea, including that leading to treatment discontinuation, is more common among people taking ticagrelor rather than clopidogrel.3,7,14 At 12 months in the PLATO study, 13.8% of people taking ticagrelor experienced dyspnoea compared with 7.8% of people taking clopidogrel (HR 1.84, 95% CI 1.68 to 2.02). Significantly more people taking ticagrelor discontinued treatment because of dyspnoea although absolute numbers were small (0.9% vs 0.1%, HR 6.12, 95% CI 3.41 to 11.01). 7 Older people, people with asthma, chronic pulmonary obstructive disease or heart failure and people with a history of dyspnoea appear to be more likely to experience dyspnoea. 4 Use ticagrelor with caution in these people.

Dyspnoea is usually mild or moderate** and often begins within 7 days of starting treatment with ticagrelor.15 Most episodes of dyspnoea resolved during the PLATO study, but usually lasted for more than 20 days.16 Dyspnoea may persist for the duration of ticagrelor therapy.14 Significantly more people in the ticagrelor and aspirin group still had ongoing dyspnoea 30 days after the PLATO study was completed — and study medication had been discontinued — than in the clopidogrel and aspirin group (5.0% vs 3.1%; p < 0.0001). 15


‡‡ In the PLATO study mild dyspnoea was defined as dyspnoea that was recognised as being present but was easily tolerated. Moderate dyspnoea was defined as that which caused discomfort sufficient to cause interference with normal activities.15

Increased occurrence of ventricular pauses

Ambulatory electrocardiographic monitoring was performed in a subset of participants (n = 2908) in the PLATO study. Significantly more people taking ticagrelor experienced ventricular pauses of 3 seconds or more in the first week of treatment (5.8% vs 3.6%, respectively; p = 0.01). While there was no significant difference in the incidence of ventricular pauses at 1 month, almost one-third of people had dropped out of the substudy by this time. There was no difference in the rates of symptomatic bradycardia in the ticagrelor or the clopidogrel group. 7,17

Avoid using ticagrelor in people who are at risk of bradycardia. People at increased risk of bradycardia were excluded from the PLATO trial.8

Reason for PBS listing

In July 2011 the PBAC gave a positive recommendation for the PBS listing of ticagrelor on the basis of acceptable cost-effectiveness compared with clopidogrel in combination with aspirin. While the PBAC considered it reasonable to describe ticagrelor in combination with aspirin as superior in effectiveness compared with clopidogrel and aspirin, it stated that the claim of comparative safety may not be reasonable.2

Dosing issues

In people who are started on ticagrelor therapy, a single loading dose of 180 mg (two tablets of 90 mg) is recommended. After that, dosing is one 90 mg tablet twice daily.5

Ticagrelor must be used in combination with low-dose aspirin.1 The product information recommends aspirin 100 mg daily although this can be varied according to clinical need. 5 Australian guidelines recommend an aspirin dose of 75–150 mg daily after an acute coronary event.9 At higher aspirin doses ticagrelor may not be more effective than clopidogrel.

While the antiplatelet effects of ticagrelor are more rapidly reversible, the extent of platelet aggregation 24 hours after the last dose is similar in people taking clopidogrel or ticagrelor.3 Therefore, a single missed dose may not adversely affect patient outcomes.

Ticagrelor should not be used in people with a history of intracranial haemorrhage, moderate to severe hepatic impairment or in people using strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin).5 Do not use it in people at increased risk of intracranial haemorrhage.

It may be necessary to reduce the antiplatelet effect before surgery. Stop ticagrelor 5 days before elective surgery.5

Drug interactions

CYP3A4 inhibitors may increase the risk of bleeding in patients taking ticagrelor. Do not use ticagrelor and strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin) concomitantly. Moderate CYP3A4 inhibitors (e.g. verapamil, erythromycin, fluconazole) should be used cautiously.5

Avoid use in people taking doses of simvastatin > 40 mg/day, as this may increase the risk of myopathy and rhabdomyolysis.5

Information for patients

Advise patients and carers:

  • that ticagrelor must be taken twice daily
  • if they miss a dose, they should take their next dose (90 mg) at the usual time. They should not take a double dose
  • to take low-dose aspirin as prescribed
  • to see a doctor immediately if they have any prolonged or excessive bleeding or signs of internal bleeding, such as unexplained bruising, blood in the urine or black stools
  • that ticagrelor may cause shortness of breath and that they should see a doctor if they experience prolonged or worsening shortness of breath or if it prevents them from carrying out their usual activities
  • not to take non-prescription medicines containing aspirin or NSAIDs, as this increases the risk of bleeds; paracetamol can be used for minor ailments
  • to tell all their health professionals that they are taking ticagrelor
  • that they must not stop taking ticagrelor without speaking with their doctor.

Discuss the Brilinta Consumer Medicine Information (CMI) leaflet with the patient.

References

  1. Pharmaceutical Benefits Advisory Committee. Positive recommendations made by the PBAC – July 2011. Canberra: Australian Government Department of Health and Ageing, 2011. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-july11-positive (accessed 22 August 2011).
  2. Pharmaceutical Benefits Branch. Public Summary Document: Ticagrelor, tablet, 90 mg, Brilinta – July 2011. Canberra: Australian Government Department of Health and Ageing, 2011. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-ticagrelor-july11 (accessed 1 November 2011).
  3. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010;121:1188–99. [PubMed]
  4. Therapeutic Goods Administration. Australian Public Assessment Report for ticagrelor. Canberra: TGA, 2011 July 2011 http://www.tga.gov.au/pdf/auspar/auspar-brilinta.pdf (accessed 22 August 2011).
  5. AstraZeneca Pty Ltd. Brilinta product information 9 June 2011. Australia: 2011.
  6. Chew D, Aroney CN, Aylward P, et al. 2011 Addendum to the Guidelines for the Management of Acute Coronary Syndromes 2006. Heart Lung Circ 2011;20:487–502. http://www.heartfoundation.org.au/SiteCollectionDocuments/2011-ACS-addendum-article-in-press.pdf (accessed 2 November 2011).
  7. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. [PubMed]
  8. James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 2009;157:599–605. [PubMed]
  9. Acute Coronary Syndrome Guidelines Working Group. Guidelines for the management of acute coronary syndromes 2006. Med J Aust 2006;184:S9–29. [PubMed]
  10. Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011;124:544–54. [PubMed]
  11. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010;376:1320–8. [PubMed]
  12. Holmes DR Jr, Dehmer GJ, Kaul S, et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2010;56:321–41. [PubMed]
  13. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;57:1920–59. [PubMed]
  14. Storey RF, Bliden KP, Patil SB, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol 2010;56:185–93. [PubMed]
  15. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011. [PubMed]
  16. Center for Drug Evaluation and Research. Brilinta - Application Number 022433Orig1s000 Medical Reviews. Rockville, Maryland: Food and Drug Administration, 2011 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000MedR.pdf (accessed 12 October 2011).
  17. Scirica BM, Cannon CP, Emanuelsson H, et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy. J Am Coll Cardiol 2011;57:1908–16. [PubMed]

Revision history

Updated August 2012 following the PBS listing of ticagrelor, with revised PBS listing and Reason for PBS listing sections. Evidence since the original release date has not been reviewed. First published December 2011.