Early Antithrombotic Therapy in Acute Ischemic Stroke

Abstract

Antithrombotic therapy plays a crucial role in secondary prevention following ischemic stroke from the acute phase. Numerous trials, along with a meta-analysis, contributed to establishing aspirin as the primary medication for secondary stroke prevention. According to the Cochrane Database of Systematic Review 2022, initiating antiplatelet therapy with aspirin at a dose of 160 mg to 300 mg daily within 48 hours of stroke onset reduces the risk of death or dependency at the end of follow-up. Other antiplatelet drugs, such as clopidogrel, cilostazol, prasugrel, and intravenous ozagrel sodium, are also available within the Japanese Health Care Insurance System. Two pivotal trials from the 2010s underscored the effectiveness and safety of dual antiplatelet therapy (DAPT) using aspirin and clopidogrel, administered for 21 days to 3 months following acute ischemic stroke or transient ischemic attack. However, the extension of DAPT with aspirin and clopidogrel beyond 3 months may result in substantial bleeding risks. Although prasugrel offers a rapid, potent, and consistent inhibition of platelet aggregation and can be used in place of clopidogrel, there is a lack of substantial real-world clinical data on its use in acute ischemic stroke. It is important to recognize that antiplatelet drugs might not be beneficial and could even increase the risk of hemorrhagic events in cardioembolic stroke. In cases of ischemic stroke with nonvalvular atrial fibrillation, direct oral anticoagulants are the primary choice if applicable. Warfarin continues to be the anticoagulant of choice for secondary stroke prevention in patients with mechanical valve replacements. In patients who have undergone intravenous thrombolysis, antithrombotic therapy is generally delayed for up to 24 hours, although there are no definitive guidelines for the period during and immediately after mechanical thrombectomy. This review provides an overview of the current status of antithrombotic therapy for acute ischemic stroke.

Introduction

Stroke is a leading cause of death globally and ranks as the fourth highest cause in Japan.¹⁾ Ischemic strokes account for approximately 70% of all stroke subtypes.¹⁾ Although recent advancements in reperfusion therapies, such as intravenous thrombolysis and endovascular treatments, have significantly improved functional outcomes following ischemic stroke,^2–5) the issue of secondary stroke prevention remains still a global challenge.^6,7) Major risk factors for stroke recurrence include age, hypertension, diabetes, dyslipidemia, atrial fibrillation (AF), chronic kidney disease, and a history of stroke. Traditional yet modern approaches to secondary stroke prevention involve risk managements and antithrombotic therapy. Aspirin is the most widely used antithrombotic drug due to its immediate effect and low cost. Recent studies on early interventions with antithrombotic drugs have revealed that early stroke recurrence rates are significantly higher than long-term recurrence rates.^8,9) These findings highlight the critical need for prompt and intensive management of patients following ischemic stroke or transient ischemic attack (TIA) to reduce the risk of subsequent ischemic stroke. This review aims to summarize and provide updates on antithrombotic therapy for acute ischemic stroke.

Antithrombotic Drugs

Antithrombotic drugs comprise antiplatelet drugs and anticoagulant drugs. The mechanisms of pathological thrombus formation and propagation are encapsulated by Virchow’s triad, which includes endothelial injury, blood flow stasis or alteration, and hypercoagulability. Both platelet function and the coagulation pathway play significant roles in thrombus formation. When the endothelium is compromised by vascular risk factors like hypertension, tissue collagen becomes exposed to blood, prompting platelets to adhere. These adhered platelets release substances that activate further platelet aggregation, leading to the formation of a platelet plug. Concurrently, exposure or release of tissue factor at the site of endothelial injury triggers the coagulation cascade, resulting in thrombus generation. Thrombin converts fibrinogen into fibrin, forming a mesh that traps blood cells and reinforces the platelet plug into a pathological thrombus. To mitigate this process, antiplatelet agents primarily decrease platelet aggregation in arterial circulation and inhibit thrombus formation, while anticoagulants primarily reduce coagulation in the heart and venous system. The major side effect associated with both antiplatelet and anticoagulant drugs is an increased, albeit small, risk of excessive bleeding, which can occur in the digestive tract, urinary system, central nerve system, and any other parts of body.

In Japan, the oral antiplatelet drugs for patients with non-cardioembolic stroke include aspirin, a cyclooxygenases inhibitor; clopidogrel and prasugrel, both P2Y12 receptor antagonists with a thienopyridine structure; and cilostazol, a phosphodiesterase-3 inhibitor.¹⁰⁾ In terms of oral anticoagulant medications, patients have access to direct oral anticoagulants (DOACs) such as dabigatran, a direct thrombin inhibitor; rivaroxaban, apixaban, and edoxaban, all direct factor Xa inhibitors; as well as warfarin, a vitamin K antagonist.¹⁰⁾ Intravenous unfractionated heparin is also available as an anticoagulant drug. As local drugs in Japan, intravenous ozagrel, a thromboxane A2 synthase inhibitor, is available as an antiplatelet drug, and intravenous argatroban, a direct thrombin inhibitor, is an applicable anticoagulant primarily for large artery atherosclerosis.¹⁰⁾

Early Antithrombotic Therapy in Noncardioembolic Ischemic Stroke

In 1997, main results from the Chinese Acute Stroke Trial¹¹⁾ and International Stroke Trial¹²⁾ on acute ischemic stroke without AF demonstrated that early administration of aspirin (160 mg to 300 mg within 48 hours of stroke onset) offers a modest but significant benefit. The Cochrane Database Systematic Review in 2022,¹³⁾ which included 11 studies with 42226 participants, showed that this aspirin regimen led to a reduction in death or dependency (odds ratio 0.95, 95% confidence interval [CI] 0.91–0.99). For every 1000 people treated with aspirin, 13 people would avoid death or dependency (number needed to treat for an additional benefit outcome 79).

In the 2010s, two large trials, CHANCE⁸⁾ and POINT,⁹⁾ evaluated the efficacy of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in acute noncardiac ischemic stroke. Recent trials on early interventions with antithrombotic drugs including CHANCE and POINT have clearly demonstrated that early stroke recurrence rates are significantly higher than long-term recurrence rates. The CHANCE indicated that 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) significantly reduced stroke within 90 days without increasing hemorrhage risk compared to aspirin alone. The POINT reported that DAPT (clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day for 90 days, plus aspirin at a dose of 50 to 325 mg per day) significantly reduced major ischemic events but slightly increased major hemorrhage risk than aspirin alone at 90 days. The effect of DAPT with aspirin and clopidogrel over aspirin alone was mainly confined to a reduction in the rate of early recurrence, with curves of subsequent event free of stroke after the first several weeks running in parallel in patients with DAPT and those with aspirin alone. Meta-analysis of short-duration trials including CHANCE and POINT favored DAPT over single antiplatelet therapy (SAPT) for reducing recurrent ischemic stroke risk at 90 days (pooled relative risk, 0.68; 95% CI, 0.55 to 0.83; I² = 37.1%) without a significant increase in major bleeding with DAPT vs. single SAPT (pooled relative risk, 1.88; 95% CI, 0.93 to 3.83; I² = 8.9%).¹⁴⁾ In contrast, long-duration trials did not show a significant reduction in recurrent ischemic stroke with DAPT (pooled relative risk, 0.89; 95% CI, 0.79 to 1.02; I² = 1.4%) but noted a higher risk of major bleeding (pooled relative risk, 2.42; 95% CI, 1.37 to 4.30; I² = 75.5%).¹⁴⁾ Prasugrel, an alternative to clopidogrel with rapid, potent platelet aggregation inhibition, lacks sufficient real-world clinical data for acute ischemic stroke treatment.

In anticoagulant therapy for acute ischemic stroke, trials of early administration of low molecular weight heparin or unfractionated heparin failed to show effectiveness and increased hemorrhagic events. Notably, intravenous argatroban, a direct thrombin inhibitor, is used in Japan for noncardioembolic and nonlacunar strokes within 48 hours of symptom onset.

The Japan Stroke Society Guideline 2021 for the Treatment of Stroke (revised version 2023) provides specific recommendations for antithrombotic therapy in the early phase of noncardioembolic stroke, detailed in Table 1.

Table 1. Recommendations in the early phase of noncardioembolic stroke.

Recommendations		Grade of recommendation	Level of evidence
Antiplatelet therapy
1	In patients with acute ischemic stroke in the early phase of onset (within 48 hours), oral administration of aspirin 160 to 300 mg/day is recommended	A	High
2	In patients with mild noncardioembolic stroke in the early phase of onset up to the subacute phase (within 1 month as a rough indication), treatment with DAPT (aspirin and clopidogrel) is recommended	A	High
3	In patients with noncardioembolic stroke within 48 hours of onset, cilostazol 200 mg/day as SAPT or DAPT with low-dose aspirin may be considered	C	Moderate
4	In patients with non-cardioembolic stroke, ozagrel sodium 160 mg/day may be considered	C	Moderate
Anticoagulation
5	In patients with non-cardioembolic and nonlacunar stroke within 48 hours after onset, intravenous administration of argatroban (selective thrombin inhibitor) may be considered	C	Moderate
6	In patients with acute ischemic stroke, the use of unfractionated heparin, low-molecular-weight heparin (unapproved in Japan), or heparinoid (not covered by the Japanese Health Care Insurance System) may be considered	C	Moderate

DAPT: dual antiplatelet therapy; SAPT: single antiplatelet therapy

Early Anticoagulation in Cardioembolic Stroke with AF

Cardioembolic strokes constitute approximately 30% of ischemic strokes, with AF being the most common cause. Antiplatelet drugs might not be beneficial and could even increase the risk of hemorrhagic events in cardioembolic stroke.^15,16) Although anticoagulation therapy with DOACs or warfarin in the acute phase may lower the recurrence of ischemic stroke, it might carry a heightened risk of bleeding, including intracranial hemorrhage. A 1992 study by Yasaka and Yamaguchi found that immediate anticoagulation therapy for cardioembolic stroke prevented the formation or growth of intracardiac thrombi, as detected by two-dimensional echocardiography, compared to a 39% occurrence in patients untreated with anticoagulation.¹⁷⁾ However, several trials that tested early anticoagulation with low molecular weight heparin or unfractionated heparin failed to show benefit and instead suggested an increase in hemorrhagic events with early anticoagulation.^12,18–20). Since DOACs became clinically available in 2011, anticoagulation has become more practical. DOACs are associated with a roughly 50% reduction in intracranial hemorrhage and are effective in preventing stroke or systemic embolism than warfarin.²¹⁾ However, four pivotal trials establishing the efficacy and safety of DOACs in nonvalvular AF excluded patients with acute ischemic stroke.^22–25)

In the SAMURAI-NVAF study of 1192 patients with nonvalvular AF experiencing acute ischemic stroke or TIA, DOAC treatment started at a median of 4 days (interquartile range, 2 to 7 days) of onset.²⁶⁾ Over 2 years, similar rates of stroke or systemic embolism (adjusted hazard ratio [HR], 1.07; 95% CI, 0.66–1.72), ischemic events (adjusted HR, 1.13; 95% CI, 0.72–1.75), and ischemic stroke or TIA (adjusted HR, 1.58; 95% CI, 0.95–2.62) were observed between DOAC and warfarin users, but DOAC users had a significantly lower risk of intracranial hemorrhage (adjusted HR, 0.32; 95% CI, 0.09–0.97) and death (adjusted HR, 0.41; 95% CI, 0.26–0.63).²⁷⁾ Comparing 223 patients with early DOAC initiation (≤3 days) to 276 with later initiation (≥4 days), incidences of stroke or systemic embolism (adjusted HR, 0.86; 95% CI, 0.47–1.57) and major bleeding (adjusted HR, 1.39; 95% CI, 0.42–4.60) were similar.²⁸⁾ This was supported by a propensity score-matched cohort study. A combined cohort study with the SAMURAI-NVAF and RELAXED studies, including 1797 patients, indicated that initiating DOACs within 1 day after a TIA and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively, was linked to a halved risk of stroke or systemic embolism (adjusted HR, 0.50; 95% CI, 0.27–0.89), without an increased risk of major bleeding (adjusted HR, 0.81; 0.28–2.19) or intracranial hemorrhage (adjusted HR, 0.66; 95% CI, 0.09–3.39), when compared to starting after 2, 3, 4, or 5 days, respectively.²⁹⁾ Early DOAC initiation within 1, 2, 3, or 4 days, tailored according to stroke severity, appears to reduce the risk of recurrent stroke or systemic embolism without raising the risk of major bleeding.

Main results from the TIMING³⁰⁾ and ELAN³¹⁾ randomized trials on early DOAC initiation in ischemic stroke patients with AF have been reported. The TIMING trial was terminated prematurely owing to slow recruitment with 888 patients. It showed that early DOAC initiation (≤4 days) was noninferior to delayed initiation (5–10 days), with a risk difference of –1.79% (95% CI, –5.31% to 1.74%; P_{noninferiority} = 0.004). The ELAN trial, with 2013 patients, compared early DOAC initiation within 48 hours after a minor or moderate stroke, or on day 6 or 7 after a major stroke, to late initiation at day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke based on infarct size on brain imaging. The composite endpoint of recurrent ischemic stroke, systemic embolism, major extracranial hemorrhage, symptomatic intracranial hemorrhage, or vascular death within 30 days (the primary outcome) occurred in 29 patients (2.9%) in the early treatment group and 41 patients (4.1%) in the late-treatment group (risk difference, –1.18%; 95% CI, –2.84% to 0.47%). The composite endpoint within 90 days occurred in 36 (3.7%) and 54 (5.6%) patients, respectively (risk difference, –1.92%; 95% CI, –3.82 to –0.02%). Outcomes from two more trials, OPTIMAS and START, along with a meta-analysis, are anticipated.

The Japan Stroke Society Guideline 2021 for the Treatment of Stroke (revised version 2023) mentioned a recommendation for anticoagulation in the early phase of ischemic stroke with nonvalvular AF (Table 2). For patients with mechanical valve replacement, warfarin remains an effective anticoagulant for secondary stroke prevention.

Table 2. Recommendation for anticoagulation in the early phase of ischemic stroke with nonvalvular AF.

Recommendation	Grade of recommendation	Level of evidence
In patients with acute ischemic stroke who have NVAF, DOAC may be considered at an appropriate timing after considering the risk of hemorrhagic infarction	C	Low

AF: atrial fibrillation; DOAC: direct oral anticoagulant; NVAF: nonvalvular atrial fibrillation

Antithrombotic Treatment in Reperfusion Therapy

For patients receiving intravenous alteplase, antithrombotic treatment is generally avoided for initial 24 hours, though in some cases the benefit may outweigh the risks of bleeding.¹⁰⁾ The optimal timing of antithrombotic therapy after mechanical thrombectomy remains undefined due to the conflicting observational data and a lack of randomized controlled trials. Globally, intravenous glycoprotein IIb/IIIa receptor antagonists are not recommended for acute ischemic stroke and are not available in Japan. However, the 2022 Update of the Korean Clinical Practice Guideline for Stroke suggests that they may be considered in highly selected patients requiring rescue therapy during mechanical thrombectomy or emergent carotid angioplasty/stenting, taking into account benefits and risks based on expert committee reports or opinions and/or clinical experiences of respected authorities.³²⁾

The Guidelines for Intravenous Thrombolysis (Recombinant Tissue-type Plasminogen Activator), the Third Edition, March 2019, mentioned a recommendation for antithrombotic therapies within initial 24 hours after receiving intravenous alteplase (Table 3).

Table 3. Recommendation for antithrombotic therapies within initial 24 hours after receiving intravenous thrombolysis.

Recommendations	Grade of recommendation	Level of evidence
During the first 24 hours of treatment, control of blood pressure and restriction of antithrombotic therapies are important. If symptoms worsen, a prompt diagnosis should be made, and neurosurgical procedures, such as hematoma evacuation by craniotomy, should be performed as soon as possible as needed	B	Low

Summary

In noncardioembolic ischemic stroke, especially minor stroke or TIA, initiating DAPT with aspirin and clopidogrel within 24 hours of onset and continuing for 21 days up to 3 months can reduce the risk of ischemic or hemorrhagic stroke and major ischemic events. However, extending DAPT beyond 3 months increases the risk of hemorrhagic complications. For cardioembolic stroke associated with AF, initiating early DOAC therapy based on the infarct size (e.g., within 48 hours after a minor or moderate stroke, or on day 6 or 7 after a major stroke) appears noninferior compared to delayed initiation (e.g., day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Nonetheless, additional data from randomized clinical trials and a meta-analysis are awaited to further inform this approach. When treating with intravenous thrombolysis, antithrombotic treatment is generally avoided within the first 24 hours, although the benefit may outweigh the risks in individual cases. There is currently no clear consensus on when to start antithrombotic therapy initiation in patients who have undergone acute mechanical thrombectomy.

Funding

This review was partly supported by the funding from AMED (23lk0221171h0001) and the Intramural Research Fund (23-B-5) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center.

Disclosure Statement

None.

Acronym

CHANCE trial

The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events trial

POINT trial

The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke trial

SAMURAI-NVAF registry

The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NonValvular Atrial Fibril- lation registry

OPTIMAS trial

The OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke trial

START trial

The Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation trial