In the THALES Trial, Past, Present, and Future Meet

Patients with minor ischemic stroke or a high-risk transient ischemic attack (TIA) face a high risk of recurrent stroke or other vascular events. The risk is particularly high in the first few weeks after the index event. Dual antiplatelet therapy (DAPT), comprising clopidogrel and aspirin, is an effective strategy for reducing recurrence. The benefits of DAPT have been confirmed in the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trials [1, 2]. More recently, results from the Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial were published in the New England Journal of Medicine [3]. Here, we briefly describe the history of antiplatelet therapy trials for ischemic stroke patients, summarize the THALES study, and explore future research directions (Fig. 1).

Fig. 1.

A brief history of DAPT clinical trials in ischemic stroke or TIA. DAPT dual antiplatelet therapy, TIA transient ischemic attack.

Exploration of DAPT

Antiplatelet drugs can effectively prevent stroke recurrence and are one of the most important discoveries in the history of ischemic stroke treatment. In 1997, the effectiveness of antiplatelet drugs was demonstrated in the Chinese Acute Stroke Trial (CAST) and The International Stroke Trial (IST) [4–6]. However, the risk of stroke recurrence remains in some of the patients who receive aspirin. Three representative phase III randomized control trials were run during the exploratory phase of DAPT from 2004 to 2012: Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH), Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS), and Secondary Prevention of Small Subcortical Strokes (SPS3) [7–9]. The combined therapeutic regimen in MATCH and SPS3 was aspirin plus Clopidogrel, while PRoFESS used aspirin plus sustained-release dipyridamole. The studies suggested that dual antiplatelet treatment not only did not reduce the risk of stroke recurrence in patients, but also increased the risk of bleeding.

In 2013, the CHANCE study, with the right patients enrolled, the right time to start intervention, and the right regimen of dual antiplatelet treatment, was published in the New England Journal of Medicine and showed exciting prospects for DAPT (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days vs placebo plus aspirin at 75 mg per day for 90 days). Clopidogrel plus aspirin reduced the risk of 90-day stroke recurrence by 32% without increasing bleeding risk. The POINT trial compared the effectiveness and safety outcomes between clopidogrel plus aspirin (clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin at 50 mg to 325 mg per day) and aspirin monotherapy at the same range of doses in acute minor stroke and high-risk TIA patients, and this showed that DAPT reduced ischemic stroke recurrence by 26% and composite vascular events by 25% in 90 days [2]. The twin studies led to updates in the clinical guidelines for cerebrovascular disease worldwide.

THALES

THALES is a global, multicenter, randomized, double-blinded, placebo-controlled, parallel-grouped, phase III clinical study with an events-driven design. It aimed to compare the effectiveness and safety of ticagrelor plus aspirin and aspirin alone for secondary prevention in non-severe, non-cardioembolic ischemic stroke or high-risk TIA. A total of 11,073 patients with mild-to-moderate non-cardiogenic ischemic stroke who were not undergoing thrombolysis or thrombectomy were enrolled within 24 h after symptom onset; in a 1:1 ratio, they received a 30-day regimen of ticagrelor plus aspirin (DAPT group) or matching placebo plus aspirin. The primary composite outcome was stroke or death within 30 days after initial stroke. The secondary outcome was ischemic stroke recurrence. The primary safety outcome was the first severe bleeding event (GUSTO-defined).

THALES showed greater benefit in the DAPT group for the primary outcome. Thirty-day stroke or death occurred in 303 (5.5%) and 362 patients (6.6%) in the DAPT and control groups (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.71–0.96; P = 0.02). The DAPT group showed a significantly reduced risk of 30-day ischemic stroke recurrence (5.0% vs 6.2%, HR 0.79; 95% CI, 0.68–0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding risk was increased in the ticagrelor–aspirin group (0.5% vs 0.1%, HR 3.99, 95% CI 1.74–9.14); intracranial hemorrhage (0.4% vs 0.1%, HR 3.33, 95% CI 1.34–8.28, P = 0.01) and premature permanent discontinuation of trial treatment owing to bleeding (2.9% vs 0.6%, HR 4.80, 95% CI 3.28–7.02, P < 0.001) were also increased. The benefit from treatment with ticagrelor–aspirin compared with aspirin alone would be expected to result in 92 needed-to-treat to prevent one primary-outcome event and 263 needed-to-harm for severe bleeding. On balance, the overall benefits outweigh the risks.

The primary outcome of the THALES study indicated that among patients with a mild-to-moderate acute non-cardioembolic ischemic stroke or TIA, the risk of stroke or death within 30 days was lower with ticagrelor–aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. The risk of severe bleeding was higher in the ticagrelor-aspirin group.

Reflection on THALES and Future Directions

CHANCE, POINT, and THALES are important studies for patients with high-risk non-disabling ischemic cerebrovascular events (HR-NICE) in the DAPT stage (Table 1). There are several differences between these studies. First, although all the studies focused on HR-NICE patients, the criteria for inclusion were different. CHANCE and THALES enrolled patients within 24 h after onset but POINT enrolled patients within 12 h. THALES enrolled mild-to-moderate ischemic stroke patients [NIHSS (NIH Stroke Scale/Score) ≤5] and the definition of high risk TIA was ABCD² ≥ 6, while CHANCE and POINT enrolled patients with minor stroke (NIHSS ≤ 3) and defined high-risk TIA as ABCD² ≥ 4. Lastly, the duration of DAPT was 21 days in CHANCE, 90 days in POINT, and 30 days in THALES.

Table 1.

Comparison of recent trials of dual antiplatelet therapy for ischemic stroke.

	CHANCE1	POINT2	THALES3
Year published	2013	2018	2020
Study design	Randomized, double blind, placebo controlled	Randomized, double blind, placebo controlled	Randomized, double blind, placebo controlled
Sample size	5170	4882	11,016
Criterion for time from onset to randomization	≤ 24 h	≤ 24 h	≤ 24 h
Criterion for enrolled NIHSS score in ischemic stroke	≤ 3	≤ 3	≤ 5
Criterion of enrolled ABCD2 Score in TIA	≥ 4	≥ 4	≥ 6
Interventions:	Clopidogrel + Aspirin	Clopidogrel + Aspirin	Ticagrelor + Aspirin
Clopidogrel	Day 1: 300 mg	Day 1: 600 mg	NA
	Days 2–90: 75 mg	Days 2–90: 75 mg
Aspirin	Day 1: 75–300 mg	Days 1–90: 50–325 mg	Day 1: 300–325 mg
	Days 2–21: 75 mg		Days 2–30: 75–100 mg
Ticagrelor	NA	NA	Days 1–30: 180 mg
Controls	Aspirin	Aspirin	Aspirin
Aspirin:	Day 1: 75–300 mg	Days 1–90: 50–325 mg	Day 1: 300–325 mg
	Days 2–21: 75 mg		Days 2–30: 75–100 mg
Duration of dual antiplatelet therapy	21 days	90 days	30 days
Time frame of primary outcomes	Day 90	Day 90	Day 30
Primary efficacy outcome (intervention vs control)	Stroke:	Stroke+MI+CV death:	Stroke+death:
	8.2% vs 11.7%	5.0% vs 6.5%	5.5% vs 6.6%
	HR: 0.68 (0.57 to 0.81), P < 0.001	HR: 0.75 (0.59 to 0.95), P = 0.02	HR: 0.83 (0.71 to 0.96), P = 0.02
Key secondary efficacy outcome	Stroke + MI + CV death:	Stroke:	Ischemic Stroke:
	8.4% vs 11.9%	4.8% vs 6.4%	5.0% vs 6.3%
	HR: 0.69 (0.58 to 0.82), P < 0.001	HR: 0.74 (0.58 to 0.94), P = 0.01	HR: 0.79 (0.68 to 0.73), P = 0.004
Primary safety outcome	Moderate to severe bleeding:	Major hemorrhage:	Severe bleeding:
	0.4% vs 0.3%	0.9% vs 0.4%	0.5% vs 0.1%
	HR: 0.84 (0.30 to 2.31), P = 0.73	HR: 2.32 (1.10 to 4.87), P = 0.02	HR: 3.99 (1.74 to 9.14), P = 0.01

MI, myocardial infarction, HR, hazard ratio, TIA, transient ischemic attack, NIHSS, National Institutes of Health Stroke Scale.

All three studies demonstrated that DAPT taken at an early stage after a stroke reduces the recurrence and death risk in HR-NICE patients. For primary efficiency outcomes, the CHANCE regimen showed the greatest benefit. Composite vascular events were reduced by 31% in CHANCE, 25% in POINT, and 17% in THALES. Ischemic stroke recurrence was reduced by 33% in CHANCE, 28% in POINT, and 21% in THALES. For safety outcomes, the risk of major bleeding significantly increased in both POINT and THALES but not in CHANCE. Time-course analysis in POINT and pooled analysis in POINT and CHANCE demonstrated that the best treatment duration of combined clopidogrel and aspirin therapy was 21 days. The THALES study considered that stroke recurrence usually occurs within 30 days after the first onset. Therefore, the duration of the dual antiplatelet therapy was 30 days. Given the increased bleeding risk associated with the longer treatment time of the dual antiplatelet therapy, time-course analysis in THALES need to be conducted.

After the publication of THALES, Prof. Peter M. Rothwell affirmed its value but pointed out that an indirect comparison of choosing ticagrelor or clopidogrel as a second antiplatelet drug to aspirin was unreliable [10]. James Grotta from Houston Medical Center (USA) noted that there is still a lack of evidence supporting the combined ticagrelor plus aspirin regimen. Yongjun Wang indicated that both regimens have shown more clinical benefits than risks but also recognized its limitations. Clopidogrel plus aspirin showed better efficiency and safety, but more than half of the Chinese stroke patients were CYP2C19 LOF carriers, which could limit the effect of clopidogrel in the Chinese population. Although ticagrelor plus aspirin could “avoid barriers of LOF”, this regimen has a higher bleeding risk. In the future, patients will likely receive rapid genetic screening for the CYP2C19 polymorphism, and LOF carriers would receive the ticagrelor plus aspirin regimen while non-carriers would receive clopidogrel plus aspirin. An ongoing direct comparison of dual antiplatelet strategies in patients with TIA or minor stroke (Clopidogrel with Aspirin in High-risk Patients with Acute Non-disabling Cerebrovascular Events II [CHANCE-2; ClinicalTrials.gov number, NCT04078737).] will provide direct evidence for making a proper choice.

By summarizing several important studies in the DAPT stage, we can conclude that (1) for HR-NICE patients, the P2Y12 antagonist is a better choice and P2Y12 monotherapy is not superior to aspirin; (2) for acute non-cardiogenic stroke (NIHSS ≤ 3) and high-risk TIA patients (ABCD² ≥ 4) who will not receive recombinant tissue plasminogen activator (rt-PA) treatment, after initiating clopidogrel plus aspirin within 24 h after onset the recommended length of time should be 21 days, which could significantly reduce ischemic stroke recurrence in the 90 days following first onset (Class I, Level A, AHA/ASA); (3) for acute non-cardiogenic stroke (NIHSS ≤ 5) and high risk TIA patients (ABCD² ≥ 6) who will not receive rt-PA treatment, after initiating ticagrelor plus aspirin within 24 h after onset, the recommended length of time should be 30 days, which could also lead to a reduction of recurrent stroke and death.