Bleeding in the THEMIS trial

In high-risk patients with CAD who had T2D and no history of MI or stroke,

  • Primary Safety End Point (TIMI Major bleeding) BRILINTA 60 mg plus aspirin (N=9562) vs aspirin alone (N=9531):
    • K-M% at 36 months, 2.2% vs 1.0%, respectively (HR 2.32; 95% CI 1.82-2.94)1
    • Events per 1000 patient years: 9 vs 4, respectively2
  • Fatal bleeding events per 1000 patient years: 1 vs 0, respectively2
THEMIS EFFICACY
THEMIS STUDY DESIGN
 

Bleeding in patients with and without a history of PCI3*

Bleeding in patients with and without a history of PCI3*

 

 

 

TIMI major bleeding

TIMI major or minor bleeding

Fatal bleeding

Intracranial hemorrhage

PATIENTS WITH A HISTORY OF PCI

BRILINTA 60 mg + aspirin (N=5536)

Aspirin (N=5564)

n (%) patients with events

TIMI major bleeding111 (2.0%)

TIMI major or minor bleeding157 (2.8%)

Fatal bleeding6 (0.1%)

Intracranial hemorrhage33 (0.6%)

PATIENTS WITH A HISTORY OF PCI

Aspirin (N=5564)

n (%) patients with events

TIMI major bleeding62 (1.1%)

TIMI major or minor bleeding80 (1.4%)

Fatal bleeding6 (0.1%)

Intracranial hemorrhage31 (0.6%)

 

 

 

TIMI major bleeding

TIMI major or minor bleeding

Fatal bleeding

Intracranial hemorrhage

PATIENTS WITHOUT A HISTORY OF PCI

BRILINTA 60 mg + aspirin (N=4026)

Aspirin (N=3967)

n (%) patients with events

TIMI major bleeding95 (2.4%)

TIMI major or minor bleeding128 (3.2%)

Fatal bleeding11 (0.3%)

Intracranial hemorrhage37 (0.9%)

PATIENTS WITHOUT A HISTORY OF PCI

Aspirin (N=3967)

n (%) patients with events

TIMI major bleeding38 (1.0%)

TIMI major or minor bleeding49 (1.2%)

Fatal bleeding4 (0.1%)

Intracranial hemorrhage15 (0.4%)

THEMIS PCI EFFICACY SUBGROUP
THEMIS STUDY DESIGN

THEMIS used the following bleeding severity categorization: TIMI major: fatal bleeding or any intracranial bleeding or clinically overt signs of hemorrhage associated with a drop in Hb of ≥5 g/dL or a fall in Hct of ≥15%. Fatal: a bleeding event that directly led to death within 7 days. TIMI minor: clinically apparent with 3-5 g/dL decrease in Hb.

 

*Safety analysis population was all randomly assigned patients who took at least 1 dose of study drug.3

 

THEMIS was not designed or powered to demonstrate the efficacy or safety of BRILINTA compared with placebo in specific subgroups. Subgroup analyses were performed to evaluate consistency of results in different cohorts. Analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.

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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.1,2

CABG=coronary artery bypass graft; CAD=coronary artery disease; CV=cardiovascular; Hb=hemoglobin; Hct=hematocrit; MI=myocardial infarction; PCI=percutaneous coronary intervention; THEMIS=Effect of Ticagrelor on Health Outcomes in DiabEtes Mellitus Patients Intervention Study; TIMI=Thrombolysis in Myocardial Infarction; T2D=type 2 diabetes.

References
  1. 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.
  2. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024.
  3. Bhatt DL, Steg PG, Mehta SR, et al; THEMIS Steering Committee and Investigators. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet. 2019;394(10204):1169-1180.
BRILINTA was studied in more than 19,000 patients with CAD + T2D in themis1,2

The THEMIS trial was a Phase 3b, randomized, double-blind, placebo-controlled trial comparing BRILINTA 60 mg twice daily versus aspirin for the prevention of CV events in patients with coronary artery disease (CAD), who also had type 2 diabetes (T2D) and no history of MI or stroke, at high risk for such events (N=19,220). All patients received low-dose aspirin 75–150 mg once daily, unless contraindicated or not tolerated.1,2

The primary efficacy end point was composite of CV death, MI, or stroke. The primary safety end point was TIMI major bleeding. Median follow-up was 33 months and up to 58 months.1

Key inclusion criteria were CAD defined as a history of PCI/CABG or ≥50% lumen stenosis confirmed by angiography, age ≥50, and T2D (glucose-lowering medication for ≥6 months).1 Patients were excluded if they had a history of previous MI or stroke or planned revascularization.2

Select baseline characteristics

Median age: 66 years

Male sex: 68.6%

More than half (58%) of patients had PCI in the past (median time since most recent PCI: 3.3 years)2

CABG=coronary artery bypass graft; CAD=coronary artery disease; CV=cardiovascular; MI=myocardial infarction; PCI=percutaneous coronary intervention; THEMIS=Effect of Ticagrelor on Health Outcomes in DiabEtes Mellitus Patients Intervention Study; TIMI=Thrombolysis in Myocardial Infarction; T2D=type 2 diabetes.

References: 1. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024. 2. 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 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.

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