THALES – Ticagrelor & Aspirin for Acute Ischemic Stroke or TIA

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Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.

Johnston SC, Amarenco P, Denison H, et al.; THALES Investigators.

N Engl J Med. 2020 Jul 16;383(3):207-217. [Full Text]

Visual Abstract @VisualMedApp

Presenting with a TIA or minor stroke is a predictor of major stroke in the short term, with the risk being as high as 10% 1 week after the event [1, 2] (though as low as ~2% has been observed [3]). The risk can be stratified using the ABCD² Score for TIA [4], (a score derived by the current study’s primary author) with scores of 6-7 doubling the subsequent stroke risk [3]. Rapid initiation of aspirin and statin, with adequate blood pressure control can reduce the short term stroke risk by 80% [2], but many will still go on to have a major stroke.

Clopidogrel in addition to aspirin has been shown to further reduce the risk of stroke and other major ischemic events after mild stroke or TIA (CHANCE [5], POINT [6]), though with an increased risk of bleeding [7]. Clopidogrel requires “hepatic conversion to its active form through a pathway that is inefficient in 25% of white and 60% of Asian patients”. Ticagrelor is a reversible P2Y12 inhibitor that is not dependent on metabolic activation.

The Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial assessed whether 30-days of ticagrelor and aspirin would be superior to aspirin alone in reducing the risk of subsequent stroke or death among patients after mild stroke or TIA.

Patient Population and Design

THALES recruited patients from 414 sites in 28 countries that were ≥ 40 years old after a mild-to-moderate acute non-cardioembolic cerebral ischemic event. These were defined by an NIHSS ≤ 5 or a high-risk TIA (ABCD2 ≥ 6).

They excluded those with planned thrombolysis or mechanical thrombectomy, on other anticoagulation (i.e. DOAC), a history of intracerebral hemorrhage, recent gastrointestinal bleed (within 6 mo) or major surgery (within 30 d),

Randomization occurred within 24 hours after the symptoms onset or after the time last reported normal. Once enrolled, the ticagrelor group received a loading dose of ticagrelor (180 mg) then 90 mg twice daily maintenance for 30-days. All patients received a loading dose of aspirin (325 mg) followed by daily maintenance of 75 to 100 mg.

Outcomes and Safety Measures

The primary outcome was a composite of stroke (ischemic, significant hemorrhagic, or undetermined type) or death in a time-to-first-event analysis from randomization through 30 days of follow-up.

Secondary outcomes included the first subsequent ischemic stroke and disability measured on the modified Rankin scale (0 to 1 no disability, 2 to 5 increasing disability, and 6 death).

Safety outcomes were also defined and included severe bleeding (GUSTO criteria: fatal, intracranial, or that caused hemodynamic compromise, i.e. SBP <90mmHg requiring transfusion of IVFs, vasopressors or inotropes, or surgical intervention).

Results

A total of 11,016 patients underwent randomization, with 5,523 in the ticagrelor plus aspirin group and 5,493 in the placebo plus aspirin group. The average age was ~65 years and most patients were male (~61%) and white (~54%) or Asian (~43%). There were very few TIAs (~9%) as the qualifying presentation, with most having a minor ischemia stroke (~91%). Of those with stroke, most were very mild strokes with an NIHSS ≤ 3 (~60%).

A primary-outcome of stroke or death occurred less in 5.5% of the ticagrelor–aspirin group and 6.6% of the placebo-aspirin group (HR 0.83; 95% CI 0.71-0.96; P=0.02, NNT 91), with similar results across subgroups. Subsequent ischemic stroke, a secondary outcome, also occurred less in the ticagrelor–aspirin group, 5.0% vs. 6.3% (HR 0.79; 95% CI 0.68-0.93; P=0.004).

However, in the other secondary outcome disability at 30 days (modified Rankin scale >1) there was no difference between in the ticagrelor–aspirin and aspirin groups (23.8% vs. 24.1%; OR 0.98; 95% CI 0.89-1.07; P=0.61).

Severe bleeding, the major safety outcome, occurred more frequently in the ticagrelor–aspirin group, 28 patients (0.5%), compared to 7 (0.1%) in the aspirin group (HR 3.99; 95% CI 1.74-9.14; P=0.001, NNH 264)

Discussion

The THALES trial did show that ticagrelor plus aspirin was modestly superior to aspirin alone (NNT 91) in preventing stroke or death within 30 days after a mild stroke (though patients with high risk TIA were eligible, very few were enrolled, effectively limiting generalizability to this population). There was also a concurrent slight increased risk of bleeding (NNH 264) and no difference in disability at 30 days. Do these results justify the addition of ticagrelor after a mild stroke?

Similar studies that utilized clopidogrel instead, CHANCE [5] and POINT [6], also had modest benefits with an slight increased risk of bleeding [7]. Interestingly, the benefit with the addition of clopidogrel seems to be limited to the first 21 days when those studies were pooled, with no difference between days 22-90 [7].

AHA and ASA guidelines were updated in 2021 and state that “Dual antiplatelet therapy is not recommended long term, and short term, dual antiplatelet therapy is recommended only in very specific patients, including those with early arriving minor stroke (within 24 hours, NIHSS ≤ 3) and high-risk transient ischemic attack” (ABCD2 score ≥4, different from THALES definition), a class 1 recommendation. The duration of DAPT is recommended only up to 90 days in these groups, but “may be maximized as early as the first 21 days after the event” [8]. No specific P2Y12 inhibitor is recommended by the AHA and ASA.

The results of the THALES are not unique nor do they suggest any benefit of ticagrelor over clopidogrel. But this is reassuring as the effect of short term addition of a P2Y12 inhibitor to aspirin has been consistent. And the AHA/ASA guidelines make it clear that “although most studies showed some increase in bleeding risk with DAPT, this was offset by the stroke prevention benefit if limited to short-term use” [8]; therefore, short-term DAPT should be standard immediately after minor stroke (<24 hr, NIHSS ≤ 3) and high-risk TIA (ABCD2 score ≥4).

F: Follow up30 days of trial drug, 3 visits from randomization to day 60-64.
R: RandomizationYes, fixed-randomization schedule, using balanced blocks
I: Intention to treatYes
S: Similar at baselineYes
B: BlindingYes
E: Equal treatmentYes
S: Source (funding)AstraZeneca
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