Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment1

Incidence of dyspnea in the PLATO trial1-3

Incidence of dyspnea in the PLATO trial1-3

 

Overall rate of dyspnea

Mild dyspnea

Moderate dyspnea

Severe dyspnea

Discontinuation due to dyspnea

BRILINTA 90 mg BID + aspirin (N=9235)

Overall rate of dyspnea13.8%

Mild dyspnea9.6%

Moderate dyspnea4.5%

Severe dyspnea0.4%

Discontinuation due to dyspnea0.9%

Clopidogrel + aspirin (N=9186)

Overall rate of dyspnea7.8%

Mild dyspnea5.5%

Moderate dyspnea2.4%

Severe dyspnea0.2%

Discontinuation due to dyspnea0.1%

Patients may be counted in more than 1 event category. Patients with multiple events in the same category being tabulated are counted only once within that category.2

Dyspnea was prospectively evaluated in the PLATO trial. At enrollment, PLATO investigators were asked to record whether there was a history of dyspnea and/or current dyspnea and record occurrences of dyspnea as adverse events (AEs) or serious adverse events (SAEs) throughout the trial.3

 

  • Approximately two-thirds of dyspnea adverse events resolved during treatment4

    •  

  • If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent1

    •  

  • In the PLATO trial, onset of dyspnea was more likely to occur within 7 days of initiation in the BRILINTA group (vs the clopidogrel group) and median time to onset of dyspnea in the BRILINTA group was 23 days (vs 43 days for the clopidogrel group)3

    •  

  • In a substudy of 199 patients from the PLATO trial who underwent pulmonary function testing irrespective of whether they reported dyspnea1:

       

    • No indication of an adverse effect on pulmonary function after 1 month or after at least 6 months of chronic treatment

      •  

Incidence of dyspnea in the PEGASUS trial1,5

 

Overall rate of dyspnea

Discontinuation due to dyspnea

BRILINTA 60 mg BID + aspirin (N=6958)

Overall rate of dyspnea14.2%

Discontinuation due to dyspnea4.3%

Aspirin alone (N=6996)

Overall rate of dyspnea5.5%

Discontinuation due to dyspnea0.7%

Incidence of dyspnea in the THEMIS trial1,6

 

Overall rate of dyspnea

Discontinuation due to dyspnea

BRILINTA 60 mg BID + aspirin (N=9562)

Overall rate of dyspnea21.4%

Discontinuation due to dyspnea6.9%

Aspirin alone (N=9531)

Overall rate of dyspnea7.3%

Discontinuation due to dyspnea0.8%

Discontinuation due to dyspnea in the THALES trial1,7

 

Discontinuation due to dyspnea

BRILINTA 90 mg BID + aspirin (N=5523)

Discontinuation due to dyspnea1.0%

Aspirin alone (N=5493)

Discontinuation due to dyspnea0.2%

Hypothesized mechanism for dyspnea

  • The mechanism of dyspnea reported by patients taking BRILINTA is not known, and further studies are necessary3

       

    • Adenosine receptors are found in the lungs, where adenosine has been shown to stimulate sensory nerve fibers that can produce dyspnea8
    • One hypothesis is that ticagrelor may increase endogenous levels of adenosine by interfering with adenosine uptake and degradation. There may be other possible mechanisms involved9,10

Nonhemorrhagic adverse reactions

In PLATO: Percentage of patients reporting nonhemorrhagic adverse reactions (at least 4%) in either group and more frequently on BRILINTA 90 mg1

 

Dyspnea

Dizziness

Nausea

BRILINTA 90 mg BID + aspirin (N=9235)

Dyspnea13.8%

Dizziness4.5%

Nausea4.3%

Clopidogrel + aspirin (N=9186)

Dyspnea7.8%

Dizziness3.9%

Nausea3.8%

In PEGASUS: Nonhemorrhagic adverse reactions reported in >3.0% of patients in the BRILINTA 60 mg treatment group1

 

Dyspnea

Dizziness

Diarrhea

BRILINTA 60 mg BID + aspirin (N=6958)

Dyspnea14.2%

Dizziness4.5%

Diarrhea3.3%

Aspirin (N=6996)

Dyspnea5.5%

Dizziness4.1%

Diarrhea2.5%

Bradycardia

  • In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6%, respectively, after 1 month1
  • PLATO, PEGASUS, THEMIS, and THALES excluded patients at increased risk of bradycardic events (eg, patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardia-related syncope and not protected with a pacemaker)1
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PLATO STUDY DESIGN

PLATO was a randomized, international, double-blind, controlled comparative study in patients with ACS hospitalized with or without ST-segment elevation, with an onset of symptoms within 24 hours (N=18,624). The study compared BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) to clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of thrombotic CV events (CV death, MI, or stroke). Study period was 12 months, with median duration of therapy of 277 days. BRILINTA and clopidogrel were studied with aspirin and other standard therapies.1,11

PEGASUS STUDY DESIGN

PEGASUS-TIMI 54 compared BRILINTA (90 mg twice daily or 60 mg twice daily) vs placebo, each given with low-dose aspirin (75 to 150 mg), for the prevention of thrombotic CV events (CV death, MI, or stroke) in 21,162 patients ≥50 years of age with a history of MI (1 to 3 years prior to randomization). Patients also had at least 1 risk factor for thrombotic CV events (age ≥65 years, diabetes mellitus requiring medication, at least 1 other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min). Only the 60-mg dose strength is approved for use in patients with a history of MI 1 year after an ACS event. Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months.1,5

THEMIS STUDY DESIGN

THEMIS was a randomized, double-blind, placebo-controlled trial of ticagrelor vs placebo in 19,220 patients, on top of low-dose (75 to 150 mg) aspirin for the prevention of thrombotic CV events (CV death, MI, stroke). Patients ≥50 years with type 2 diabetes receiving an anti-hyperglycemic medication for at least 6 months, and with stable CAD (ie, history of PCI, CABG, or angiographic stenosis ≥50% in at least 1 coronary artery) were enrolled. Patients with known prior MI or stroke were excluded. Patients were treated for a median of 33 months and up to 58 months.1,6

THALES STUDY DESIGN

THALES was a randomized, international, double-blind, placebo-controlled, multicenter study to investigate dual antiplatelet therapy with BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) and aspirin vs placebo and aspirin in the prevention of stroke or death in patients with acute ischemic stroke or transient ischemic attack (N=11,016). The primary end point was the first occurrence of the composite of stroke or death at 30 days. In both arms, patients received a loading dose of aspirin 300-325 mg followed by aspirin 75-100 mg once daily. Patients were ≥40 years of age, had mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5), or high-risk TIA (ABCD2 score ≥6 or symptomatic intracranial or extracranial arterial stenosis [≥50% narrowing in the diameter of the lumen of an artery that could account for the TIA]). Patients were randomized within 24 hours and treated for a median of 31 days.1,7

ABCD2=Age, Blood pressure, Clinical features, Duration of TIA, and Diabetes mellitus; ACS=acute coronary syndrome; BID=twice daily; CABG=coronary artery bypass graft; CV=cardiovascular; MI=myocardial infarction; NIHSS=National Institutes of Health Stroke Scale; NSTEMI=non-ST-elevation MI; PCI=percutaneous coronary intervention; PEGASUS=Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin; PLATO=PLATelet inhibition and patient Outcomes; RRR=relative risk reduction; STEMI=ST-elevation MI; THALES=Acute STroke or Transient IscHemic Attack Treated with TicAgreLor and Aspirin for PrEvention of Stroke and Death; THEMIS=Effect of Ticagrelor on Health Outcomes in DiabEtes Mellitus Patients Intervention Study; TIA=transient ischemic attack; TIMI=Thrombolysis in Myocardial Infarction; UA=unstable angina.

References
  1. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024.
  2. Data on File, REF-5098. AstraZeneca Pharmaceuticals LP.
  3. 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;32(23):2945-2953.
  4. US Food and Drug Administration; Center for Drug Evaluation and Research; Division of Cardiovascular and Renal Products. Complete Response Review Addendum. Reviewed June 8, 2011. Accessed April 25, 2024.  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433orig1s000medr.pdf
  5. Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800 and Supplementary Appendix.
  6. Steg PG, Bhatt DL, Simon T, et al; THEMIS Steering Committee and Investigators. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med. 2019;381(14):1309-1320.
  7. Johnston SC, Amarenco P, Denison H, et al; THALES Investigators. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med. 2020;383(3):207-217 and Supplementary Appendix.
  8. Belchikov YG, Koenig SJ, Dipasquale EM. Potential role of endogenous adenosine in ticagrelor-induced dyspnea. Pharmacotherapy. 2013;33(8):882-887.
  9. van Giezen JJ, Sidaway J, Glaves P, et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17(2):164-172.
  10. Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259-274.
  11. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057 and Supplementary Appendix.
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IMPORTANT SAFETY INFORMATION FOR BRILINTA® (ticagrelor) 60-MG AND 90-MG TABLETS

WARNING: BLEEDING RISK

  • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding
  • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
  • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery
  • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

CONTRAINDICATIONS

  • BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

  • Dyspnea was reported more frequently with BRILINTA than in patients treated with control agents. Dyspnea from BRILINTA is often self-limiting
  • In patients being treated for coronary artery disease, discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
  • Ticagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the post-marketing setting. Clinical trials excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias
  • Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients
  • Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge
  • In patients with Heparin Induced Thrombocytopenia (HIT): False-negative results for HIT-related platelet functional tests, including the heparin-induced platelet aggregation (HIPA) assay, have been reported with BRILINTA. BRILINTA is not expected to impact PF4 antibody testing for HIT

ADVERSE REACTIONS

  • The most common adverse reactions (>5%) associated with the use of BRILINTA included bleeding and dyspnea

DRUG INTERACTIONS

  • Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
  • As with other oral P2Y12 inhibitors, co-administration of opioid agonists delays and reduces the absorption of ticagrelor. Consider the use of a parenteral anti-platelet in ACS patients requiring co-administration
  • Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
  • Rosuvastatin plasma concentrations may increase because rosuvastatin is a breast cancer resistance protein (BCRP) substrate. Monitor for statin-related adverse effects
  • Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

SPECIAL POPULATIONS

  • Lactation: Breastfeeding is not recommended

INDICATIONS

BRILINTA is indicated to reduce the risk of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for the treatment of ACS.

BRILINTA is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of ticagrelor was established in a population with type 2 diabetes.

BRILINTA is indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale Score ≤5) or high-risk transient ischemic attack (TIA).

DOSING

In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. However, in patients who have undergone PCI, consider single antiplatelet therapy with BRILINTA based on the evolving risk for thrombotic versus bleeding events.

In patients with CAD but no prior stroke or MI, administer 60 mg twice daily. Generally, use BRILINTA with a daily maintenance dose of aspirin of 75 mg to 100 mg.

In patients with acute ischemic stroke or high-risk TIA, initiate treatment with a 180-mg loading dose of BRILINTA and then continue with 90 mg twice daily for up to 30 days. Use BRILINTA with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of aspirin of 75 mg to 100 mg.

Please read full Prescribing Information, including Boxed WARNING, and Medication Guide.

You may report side effects related to AstraZeneca products.

 

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