Bleeding in the THALES trial

In patients with acute ischemic stroke (NIHSS ≤5) or high-risk TIA, Primary safety end point: GUSTO* severe bleeding event1,2

 

GUSTO severe bleeding

GUSTO severe bleeding

BRILINTA 90 mg + aspirin (N=5523) K-M%, n

K-M% n (0.5%) 280.5% 28

Placebo + aspirin (N=5493) K-M%, n

K-M% n(0.1%) 7 0.1% 7

AT 30 DAYS

AT 30 DAYSHR: 3.99 95% CI: 1.74-9.14 ARI: 0.4% NNH 2632

THALES EFFICACY
THALES STUDY DESIGN
  • Intracranial bleeding and fatal bleeding seen in THALES for BRILINTA + aspirin vs aspirin alone, respectively2:

       

    • ICH: 21 vs 6

      •  

    • Fatal bleeding: 11 vs 2

    •  

* GUSTO severe bleeding: Any one of the following: fatal bleeding, intracranial bleeding (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages <10 mm evident only on gradient-echo magnetic resonance imaging), bleeding that caused hemodynamic compromise requiring intervention (eg, systolic blood pressure <90 mm Hg that required blood or fluid replacement, or vasopressor/inotropic support, or surgical intervention).2

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IPSILATERAL ATHEROSCLEROTIC STENOSIS SUBGROUP

In patients with acute ischemic stroke (NIHSS ≤5) or high-risk TIA, Bleeding outcomes in patients with and without ipsilateral stenosis3

Patients with ipsilateral stenosis ≥30% 

 

 

GUSTO severe bleeding

Fatal bleeding

ICH

Hemorrhagic stroke

BRILINTA 90 mg + Aspirin (N=1136)

Aspirin (N=1215)

No. of patients (%)

GUSTO severe bleeding4 (0.4%)

Fatal bleeding1 (0.1%)

ICH4 (0.4%)

Hemorrhagic stroke0 (0.0%)

Aspirin (N=1215)

No. of patients (%)

GUSTO severe bleeding3 (0.2%)

Fatal bleeding1 (0.1%)

ICH3 (0.2%)

Hemorrhagic stroke0 (0.0%)

Patients without ipsilateral stenosis ≥30%

 

 

GUSTO severe bleeding

Fatal bleeding

ICH

Hemorrhagic stroke

BRILINTA 90 mg + Aspirin (N=4387)

Aspirin (N=4278)

No. of patients (%)

GUSTO severe bleeding24 (0.5%)

Fatal bleeding10 (0.2%)

ICH16 (0.4%)

Hemorrhagic stroke10 (0.2%)

Aspirin (N=4278)

No. of patients (%)

GUSTO severe bleeding4 (0.1%)

Fatal bleeding1 (0.0%)

ICH3 (0.1%)

Hemorrhagic stroke2 (0.0%)

NNH for patients without ipsilateral atherosclerosis is 2503*

 

* GUSTO severe bleeding: Any one of the following: fatal bleeding, intracranial bleeding (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages <10 mm evident only on gradient-echo magnetic resonance imaging), bleeding that caused hemodynamic compromise requiring intervention (eg, systolic blood pressure <90 mm Hg that required blood or fluid replacement, or vasopressor/inotropic support, or surgical intervention).2

FROM THE PRESPECIFIED IPSILATERAL ATHEROSCLEROSIS SUBGROUP ANALYSIS

Every 34 Patients with Ipsilateral Atherosclerosis
For every 34 patients with ipsilateral atherosclerosis (≥30%) treated with BRILINTA 90 mg plus aspirin instead of aspirin, 1 additional event of stroke or death was prevented...
Every 951 Patients with Ipsilateral Atherosclerosis
...and for every 951 patients with ipsilateral atherosclerosis (≥30%), 1 additional GUSTO severe bleeding event occurred.3,4†

*NNH was calculated using 1/ARI of BRILINTA + aspirin compared to aspirin alone (0.4%).3

†Calculation of NNH is based off of 1/ARI (1/[0.352%-0.247%]).3

 

THALES 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.2

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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.1,2

ABCD2=Age, Blood pressure, Clinical features, Duration of TIA, and Diabetes mellitus; ARI=absolute risk increase; CI=confidence interval; CV=cardiovascular; GUSTO=Global Use of Strategies to Open Occluded Coronary Arteries; HR=hazard ratio; ICH=intracranial hemorrhage; K-M=Kaplan-Meier; NIHSS=National Institutes of Health Stroke Scale; NNH=number needed to harm; NNT=number needed to treat; THALES=Acute STroke or Transient IscHemic Attack Treated with TicAgreLor and Aspirin for PrEvention of Stroke and Death; TIA=transient ischemic attack.

References
  1. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024.
  2. 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.
  3. Amarenco P, Denison H, Evans SR, et al. Ticagrelor added to aspirin in acute nonsevere ischemic stroke or transient ischemic attack of atherosclerotic origin. Stroke. 2020;51(12):3504-3513.
  4. Data on File, REF-51076, AstraZeneca Pharmaceuticals LP.
THE THALES STUDY1

11,016 patients were randomized within 24 hours and treated for 30 days1

OBJECTIVE

THALES compared dual antiplatelet therapy (DAPT) with BRILINTA 90 mg and aspirin vs placebo and aspirin in patients with acute ischemic stroke or high-risk TIA for the primary efficacy end point of the composite of stroke or death and the primary safety end point of first GUSTO severe bleeding.

STUDY DESIGN

Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial conducted across 28 countries and 414 sites

Primary efficacy composite end point: Stroke (ischemic and hemorrhagic) or all-cause death

Key secondary efficacy end point: Ischemic stroke

Primary safety end point: GUSTO severe bleeding

 

Key inclusion criteria

  • Patients ≥40 years of age, randomized within 24 hours after onset of symptoms, with:
  • Mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5 and persistent signs or symptoms at the time of randomization or acute ischemic brain lesion determined by CT scan or MRI)

OR

  • High-risk TIA (ABCD2 score ≥6 or with large-vessel disease [ie, ipsilateral ≥50% stenosis of extra- or intracranial artery])

Key exclusion criteria

  • Thrombolysis or mechanical thrombectomy within 24 hours before randomization
  • Planned use of anticoagulation
  • Planned use of antiplatelet therapy other than aspirin
  • History of atrial fibrillation/flutter or ventricular aneurysm
  • Suspicion of a cardioembolic cause of TIA or stroke
  • History of ICH or GI bleeding within the past 6 months or major surgery within 30 days

*Loading doses were given to patients as soon as possible after randomization on day 1.

ABCD2=Age, Blood pressure, Clinical features, Duration of TIA, and Diabetes mellitus; BID=twice daily; CT=computed tomography; GI=gastrointestinal; GUSTO=Global Use of Strategies to Open Occluded Coronary Arteries; ICH=intracranial hemorrhage; LD=loading dose; MRI=magnetic resonance imaging; NIHSS=National Institutes of Health Stroke Scale; QD=once daily; THALES=Acute STroke or Transient IscHemic Attack Treated with TicAgreLor and Aspirin for PrEvention of Stroke and Death; TIA=transient ischemic attack.

Reference: 1. 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, Supplementary Appendix, and Protocol.

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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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