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
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; 2021.
  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. Accessed May 27, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433orig1s000medr.pdf
  5. Bonaca MP, Bhatt DL, Cohen M, et al; for the 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; for the 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; for the 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; for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057 and Supplementary Appendix.