Several older studies have suggested that the risks of long-term dual antiplatelet therapy for the secondary prevention of ischemic stroke outweigh the potential benefits. For example, in 2004, the Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) trial found that adding aspirin to clopidogrel in high-risk patients with recent ischemic stroke or transient ischemic attack (TIA) was associated with an increased risk of life-threatening or major bleeding with no reduction in major vascular events at 18 months.¹ In 2008, the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial compared aspirin plus extended-release dipyridamole to clopidogrel and found no difference between the two groups in recurrent stroke rate.² However, more intracranial hemorrhage was observed in the aspirin-dipyridamole group. In 2012, the Secondary Prevention of Small Subcortical Strokes (SPS3) trial showed that, among patients with recent symptomatic lacunar stroke, the addition of clopidogrel to aspirin resulted in an increased risk of bleeding and death without a reduction in risk of recurrent stroke after a mean follow-up of 3.4 years.³

More recently, the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial investigated whether dual antiplatelet therapy may be beneficial in the short-term, as opposed to over the long-term, in patients with recent minor ischemic stroke or TIA.⁴ In this study, 5,170 patients were randomized to treatment with aspirin plus clopidogrel (loading dose of clopidogrel 300mg) for 21 days post-stroke or to aspirin plus placebo for 21 days post-stroke (Table 1). Treatment was initiated within 24 hours of the qualifying event. Recurrent stroke occurred in 212 (8.2%) of patients in the dual antiplatelet group, as compared with 303 (11.7%) of those in the aspirin group (hazard ratio [HR] 0.68; 95% confidence interval [CI], 0.57 to 0.81). No difference in hemorrhage rate was observed between the two groups.

The CHANCE trial was followed in 2018 by the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial which used a similar design aside from a loading dose of clopidogrel of 600mg and a duration of dual antiplatelet therapy of 90 days.⁵ In this study, 4,881 patients were enrolled, and ischemic stroke was observed in 112 (4.6%) of the dual antiplatelet group compared with 155 (6.3%) of the aspirin group (HR 0.72; 95% CI, 0.56-0.92). Unlike in CHANCE, a higher risk of major hemorrhage was observed in the dual antiplatelet arm than in the aspirin arm (0.9% compared to 0.4%; HR 2.32; 95% CI, 1.10-4.87). The benefit of DAPT was greater in the first 30 days than at days 31 to 90 (HR 0.73; 95% CI, 0.56-0.95), and the risk of major hemorrhage was lower in the first 7 days than from days 8 to 90 (HR 2.69; 95% CI, 1.05-6.86).

A subsequent pooled analysis of the CHANCE and POINT data found that the benefit of DAPT was largely confined to the first 21 days after stroke/TIA.⁶ In 2019, the American Heart Association/American Stroke Association (AHA/ASA) guidelines were updated to include a highest-level recommendation that "in patients presenting with minor non-cardioembolic ischemic stroke who did not receive IV alteplase, treatment with dual antiplatelet therapy (aspirin and clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset."⁷ As a result of this recommendation, short-term DAPT with aspirin and clopidogrel after a qualifying TIA or minor ischemic stroke has become standard of care.

Unlike CHANCE and POINT, The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial examined the benefit of dual antiplatelet therapy with short-term aspirin and ticagrelor for 30 days after stroke.⁸ Eligible patients were ≥40 years and had a mild-to-moderate acute non-cardioembolic ischemic stroke or high-risk TIA or symptomatic intracranial or extracranial arterial stenosis. Randomization occurred within 24 hours of symptom onset, and all patients received a loading dose of aspirin and either a loading dose of ticagrelor 180mg or a "loading dose" of placebo as soon as possible after randomization. Aspirin and ticagrelor or placebo were continued for 30 days.

A total of 11,016 patients were included in THALES. The primary endpoint of composite stroke or death occurred in 303 (5.5%) patients in the dual antiplatelet group and 362 (6.6%) in the aspirin only group (HR 0.93; 95% CI, 0.71-0.96). Severe bleeding occurred in 28 (0.5%) patients in the DAPT group and in seven patients (0.1%) in the aspirin group (HR 3.99; 95% CI, 1.74-9.14).

An exploratory analysis of the THALES trial examined the benefits of DAPT with aspirin and ticagrelor for a subgroup of patients with presumed ischemic stroke of atherosclerotic origin.⁹ In this analysis, 2,351 patients with non-cardioembolic non-severe acute ischemic stroke or high-risk TIA and ipsilateral (i.e. potentially causative) intracranial or extracranial atherosclerosis with ≥30% narrowing were randomized to either aspirin plus ticagrelor or aspirin plus placebo to continue for 30 days post-stroke. The primary endpoint was the composite of stroke or death. Patients in the ticagrelor and aspirin group had fewer primary endpoint events (92/1136, or 8.1%) than the placebo and aspirin group (132/1215, or 10.9%) (HR 0.73; 95% CI, 0.56-0.96) with a resultant number needed to treat of 34 (95% CI, 19-171). No difference in severe bleeding was observed between the two arms.

As shown in the Table 1, the magnitude of benefit of DAPT in the THALES patients with ipsilateral atherosclerotic stenosis was greater than that observed in the THALES patients without ipsilateral atherosclerotic stenosis (2.8% vs. 1.1%). This finding suggests that patients with symptomatic atherosclerotic stenosis may represent an enhanced population more likely to benefit from short-term DAPT with aspirin and ticagrelor post-stroke.

Overall, however, the best short-term antithrombotic regimen post-stroke remains unresolved. Based on the positive results of CHANCE and POINT, the stroke community has largely adopted the guideline-concordant use of dual antiplatelet therapy with aspirin and clopidogrel for 21 days post-stroke. The results of THALES suggest that there is a role for a future randomized controlled trial to compare the relative efficacy and safety of short-term aspirin plus clopidogrel versus short-term aspirin plus ticagrelor after acute ischemic stroke. Each arm should be enriched with patients with atherosclerotic stroke etiology to determine whether a subgroup effect exists.

Table 1: Comparison of three recent randomized controlled trials and one exploratory analysis of short-term dual antiplatelet therapy after ischemic stroke/TIA.

	CHANCE (2013)	POINT (2018)	THALES (2020)	THALES atherosclerotic subgroup (2020)
Subjects Enrolled	5,170	4,881	11,016	2,351
Inclusion Criteria	Stroke with NIHSS ≤3 or TIA with ABCD2 score ≥4	Stroke with NIHSS ≤3 or TIA with ABCD2 score ≥4	Stroke with NIHSS ≤5 or ABCD2 ≥6 or symptomatic intracranial or extracranial arterial stenosis	Stroke with symptomatic intracranial or extracranial arterial ≥30% stenosis
Intervention	Clopidogrel (300mg loading dose followed by 75mg daily) for 90 days plus aspirin (75mg daily) for 21 days	Clopidogrel (600mg loading dose followed by 75mg daily) for 90 days plus aspirin (50-325mg daily) for 90 days	Ticagrelor (180mg loading dose followed by 90mg BID) for 30 days plus aspirin (loading dose of 300-325mg followed by 75-100mg daily) for 30 days	Ticagrelor (180mg loading dose followed by 90mg BID) for 30 days plus aspirin (loading dose of 300-325mg followed by 75-100mg daily) for 30 days
Control	Placebo plus aspirin (75mg daily) for 90 days	Placebo plus aspirin (50-325mg daily) for 90 days	Placebo plus aspirin (loading dose of 300-325mg followed by 75-100mg daily) for 30 days	Placebo plus aspirin (loading dose of 300-325mg followed by 75-100mg daily) for 30 days
Duration of DAPT	21 days	90 days	30 days	30 days
Primary Outcome	Stroke (ischemic or hemorrhagic) during 90 days of follow-up	Composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes	Stroke or death within 30 days	Stroke or death within 30 days
Primary Outcome	8.2% in DAPT versus 11.7% in aspirin-only (p<0.001)	5% in DAPT versus 6.5% in aspirin-only (p=0.02)	5.5% in DAPT versus 6.6% in aspirin-only (p=0.02)	8.1% in DAPT versus 10.9% in aspirin-only (p=0.02)
Major Hemorrhage or Severe Bleeding	0.2% In DAPT versus 0.2% in aspirin-only (p=NS)	0.9% In DAPT versus 0.4% in aspirin-only (p=0.02)	0.5% in DAPT versus 0.1% in aspirin-only (p=0.001)	0.4% in DAPT versus 0.2% in aspirin-only
Hemorrhagic Stroke	0.3% in DAPT versus 0.3% in aspirin-only (p=NS)	0.2% in DAPT versus 0.1% in aspirin-only (p=NS)	0.2% in DAPT versus <0.1% in aspirin-only	0 versus 0

References

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2. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-51.
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6. Pan Y, Elm JJ, Li H, et al. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: a pooled analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trials. JAMA Neurol 2019;76:1466-73.
7. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019;50:e344-e418.
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Clinical Topics: Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism

Keywords: AHA Annual Scientific Sessions, AHA20, Platelet Aggregation Inhibitors, Ischemic Attack, Transient, Purinergic P2Y Receptor Antagonists, Tissue Plasminogen Activator, Brain Ischemia, Fibrinolytic Agents, Aspirin, Secondary Prevention, American Heart Association, Constriction, Pathologic, Confidence Intervals, Follow-Up Studies, Random Allocation, Standard of Care, Stroke, Lacunar, Stroke, Atherosclerosis

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