Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death - THALES

Nov 16, 2020
Font Size
A
A
A
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
AstraZeneca
Date Presented:
11/16/2020
Date Published:
07/15/2020
Date Updated:
11/16/2020
Original Posted Date:
07/15/2020
References

Contribution To Literature:

DAPT with ticagrelor + aspirin reduced subsequent ischemic stroke at 30 days but increased all bleeding, including intracranial, compared with aspirin alone among patients with low- to medium-risk ischemic stroke that did not require thrombolytics or thrombectomy.

Description:

The goal of the trial was to assess the safety and efficacy of dual antiplatelet therapy (DAPT) with aspirin and ticagrelor compared with aspirin alone among patients with acute noncardioembolic ischemic stroke.  

Study Design

Eligible patients were randomized in a 1:1 fashion to either aspirin + ticagrelor (n = 5,523) vs. aspirin (n = 5,493) alone. Ticagrelor was given as a loading dose of 180 mg followed by 90 mg BID, and aspirin as 300-325 mg loading dose, following by 75-100 mg daily.

  • Total number of enrollees 11,016
  • Duration of follow-up: 30 days
  • Mean patient age: 65 years
  • Percentage female: 39%
  • Percentage with diabetes: 28%

Inclusion criteria:

  • ≥40 years of age
  •  Mild-to-moderate acute noncardioembolic ischemic stroke
  • National Institutes of Health Stroke Scale score of ≤5 (range, 0-42, with higher scores indicating more severe stroke)
  • High-risk transient ischemic attack (TIA) as determined according to a score of ≥6 on the ABCD2 scale (range, 0-7, with higher scores indicating higher risk of stroke) or symptomatic intracranial or extracranial arterial stenosis (≥50% narrowing in the diameter of the lumen of an artery that could account for the TIA)
  • No contraindication on imaging to antiplatelet therapy

Exclusion criteria:

  • Intravenous or intra-arterial thrombolysis or mechanical thrombectomy planned within 24 hours before randomization
  • Planned use of anticoagulation or specific antiplatelet therapy other than aspirin
  • Hypersensitivity to ticagrelor or aspirin
  • History of atrial fibrillation or ventricular aneurysm or a suspicion of a cardioembolic cause of the TIA or stroke
  • Planned carotid endarterectomy that required discontinuation of the trial medication within 3 days after randomization
  • Known bleeding diathesis or coagulation disorder
  • History of intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, or major surgery within 30 days before randomization

Other salient features/characteristics:

  • Prior ischemic stroke: 16%; prior TIA: 5%
  • Use of aspirin prior to event: 13%, clopidogrel: 1.4%

Principal Findings:

The primary outcome, death or stroke at 30 days, for aspirin + ticagrelor vs. aspirin, was 5.5% vs. 6.6% (hazard ratio 0.83, 95% confidence interval 0.71-0.96, p = 0.02).

  • Subsequent ischemic stroke: 5.1% for aspirin + ticagrelor vs. 6.3% for aspirin (p = 0.004)
  • All-cause mortality: 0.7% for aspirin + ticagrelor vs. 0.5% for aspirin

Secondary outcomes for aspirin + ticagrelor vs. aspirin:

  • Overall disability: 23.8% vs. 24.1% (p = 0.61)
  • Severe bleeding: 0.5% vs. 0.1% (p = 0.0001)
  • Intracranial hemorrhage or fatal bleeding: 0.4% vs. 0.1% (p = 0.0005)
  • Hemorrhagic stroke: 0.2% vs. <0.1%

Disability with recurrent strokes: The primary outcome event with modified Rankin Scale score (mRS) >1 for ticagrelor + aspirin vs. aspirin was 4% vs. 4.7% (HR 0.83, 95% CI 0.69-0.99, p = 0.04).

  • Recurrent stroke with mRS 0 or 1 for ticagrelor + aspirin vs. aspirin: 1.3% vs. 1.6% (p = 0.14)
  • Ordinal analysis of subsequent ischemic stroke based on 30-day mRS showed a significant shift in favor of the ticagrelor group (odds ratio 0.77; 95% CI 0.65-0.91; p = 0.002)
  • GUSTO severe bleeding with mRS >1 for ticagrelor + aspirin vs. aspirin: 0.4% vs. 0.1% (p = 0.006)

Role of ipsilateral stenosis: 21.3% had ipsilateral atherosclerotic stenosis of ≥30% in the cervicocranial vasculature. In this subgroup, the primary outcome for ticagrelor + aspirin vs. aspirin was 8.1% vs. 10.9%, p = 0.023 (p for interaction = 0.25). Severe bleeding: 0.4% vs. 0.2% (p = not significant).

Interpretation:

The results of this trial indicate that DAPT with ticagrelor + aspirin reduced subsequent ischemic stroke at 30 days but increased all bleeding, including intracranial, compared with aspirin alone among patients with low- to medium-risk ischemic stroke that did not require thrombolytics or thrombectomy. There was no difference in overall disability, but patients receiving ticagrelor + aspirin had less disability with recurrent strokes.

In the SOCRATES trial comparing ticagrelor to aspirin (both as monotherapy), efficacy and bleeding were both similar, with benefits noted in certain subsets, such as those on prior aspirin; there was also a benefit noted for  reduction in ischemic strokes with ticagrelor.

References:

Amarenco P, Denison H, Evans SR, et al., on behalf of the THALES Steering Committee and Investigators. Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin. Stroke 2020;Nov 16:[Epub ahead of print].

Presented by Dr. Pierre Amarenco at the American Heart Association Virtual Scientific Sessions, November 16, 2020.

Amarenco P, Denison H, Evans SR, et al., on behalf of the THALES Steering Committee and Investigators. Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling Stroke: A Randomized Clinical Trial. JAMA Neurol 2020;Nov 7:[Epub ahead of print].

Johnston SC, Amarenco P, Denison H, et al., on behalf of the THALES Investigators. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N Engl J Med 2020;383:207-17.

Editorial: Rothwell PM. Antiplatelet Treatment to Prevent Early Recurrent Stroke. N Engl J Med 2020;383:276-8.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Cardiac Surgery and Arrhythmias, Interventions and Vascular Medicine

Keywords: AHA20, AHA Annual Scientific Sessions, Aspirin, Brain Ischemia, Carotid Stenosis, Constriction, Pathologic, Fibrinolytic Agents, Hemorrhage, Intracranial Hemorrhages, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Secondary Prevention, Stroke, Thrombectomy, Vascular Diseases


< Back to Listings